Lymphatic Vessels in Inflammation
Journal of Clinical and Cellular Immunology

Journal of Clinical and Cellular Immunology
Open Access

ISSN: 2155-9899

Review Article - (2014) Volume 0, Issue 0

Lymphatic Vessels in Inflammation

Martina Vranova and Cornelia Halin*
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Switzerland
*Corresponding Author: Cornelia Halin, Ph.D., Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli Str. 10, HCI H413, CH-8093 Zurich, Switzerland, Tel: +41 44 633 29 62, Fax: +41 44 633 13 64 Email:


Lymphatic vessels are important for tissue fluid homeostasis and for the uptake of dietary lipids in the intestine. Moreover, lymphatic vessels are intimately linked with induction of the immune response, as they transport antigen, inflammatory mediators, and leukocytes from peripheral tissues to draining lymph nodes (dLNs). Research of the last 10 years has revealed that lymphatic vessels form a highly plastic network, which rapidly adapts to inflammation in a stimulus- and tissue-specific manner. The inflammatory environment induces changes in gene expression in lymphatic endothelial cells (LECs) and leads to a profound proliferative expansion of the lymphatic network in both the inflamed tissue and the dLNs. Inflammatory changes in the lymphatic network have been shown to impact fluid drainage as well as leukocyte trafficking, suggesting that lymphatic vessels play an active role in the regulation of inflammatory processes. In fact, experimentally enhancing or blocking lymphangiogenesis was shown to modulate the course of inflammatory and immune responses in various disease models. Given these exciting pre-clinical findings, lymphatic vessels and inflammatory lymphangiogenesis are emerging as potential new therapeutic targets for the treatment of chronic inflammatory and autoimmune disorders, and for the prevention of graft rejection. In this review, we will summarize current knowledge about the inflammatory response of the lymphatic network and introduce the main molecular and cellular mediators of inflammatory lymphangiogenesis. Our review will particularly focus on how inflammation-induced changes in lymphatic vessels are thought to impact the course of inflammatory and immune responses and address the therapeutic implications of these findings.

Keywords: Inflammation; Lymphangiogenesis; Lymph node; Lymphatic drainage; Leukocyte migration; Lymphatic endothelial cells; Lymphatic muscle cells


Lymphatic vessels are responsible for draining fluids and macromolecules from tissues and for taking up lipids in the intestine [1-3]. Moreover, lymphatic vessels transport antigen and leucocytes between peripheral tissues, lymph nodes (LNs), and blood and therefore are important for the induction and regulation of immune responses [2,4,5]. Although lymphatic vessels were already described almost 400 years ago [6], molecular and cellular research of the lymphatic vascular system is a fairly young discipline. In fact, this field has only started to advance in the last 18 years, propelled by the identification of lymphatic-specific markers like the vascular endothelial growth factor receptor-3 (VEGFR-3), podoplanin (gp38), the hyaluronan receptor LYVE-1, or the lymphatic-specific transcription factor Prox-1 [2,7]. These markers made it possible to unambiguously identify lymphatic vessels in tissues and to isolate lymphatic endothelial cells (LECs) for in vitro analyses. Ever since we have witnessed a true explosion of research investigating the role of lymphatic vessels in health and disease. It is nowadays well established that lymphatic vessels are highly dynamic structures, which undergo both morphological and functional changes under pathological conditions. The lymphatic network has been shown to play an important role in inflammatory and autoimmune diseases, cancer, lymphedema, graft rejection and wound healing [1,3,8]. One of the most striking changes of lymphatic vessels under inflammatory conditions is the strong proliferative expansion of the lymphatic network. Inflammatory lymphangiogenesis reportedly occurs in human psoriasis [9], rheumatoid arthritis [10], inflammatory bowel disease (IBD) [11,12], lymphedema [13], or transplant rejection [14,15]. Experimentally enhancing lymphangiogenesis was shown to ameliorate the disease course in animal models of skin inflammation [16,17], rheumatoid arthritis [18] and IBD [19]. On the other hand, blocking lymphangiogenesis exacerbated the disease state in rheumatoid arthritis [20], IBD [21] and in type I diabetes [22]. Furthermore, blocking lymphangiogenesis improved graft survival in models of corneal and pancreatic islet transplantation [23-25]. These exciting findings have suggested that lymphatic vessels might play a more important and active role in the initiation and resolution of inflammatory processes than previously assumed. Moreover, they have revealed that inflammatory lymphangiogenesis might be a promising new target for treating a variety of chronic inflammatory and immune-mediated disorders.

In this review we will provide a brief introduction of the lymphatic vascular system and then summarize current knowledge about inflammatory lymphangiogenesis. In particular, we will introduce its main molecular and cellular mediators and discuss the impact of inflammatory lymphangiogenesis on the morphology of the lymphatic network. Next we will address how inflammation-induced changes in the lymphatic network are thought to impact lymphatic function, namely leukocyte trafficking and fluid drainage. Finally, we will discuss the therapeutic implications of these findings.

Anatomy of the Lymphatic Vascular Network

Afferent lymphatic vessels begin in peripheral tissues as a branched network of blind-ended capillaries [2] (Figure 1). These capillaries converge into pre-collecting and collecting vessels, which are connected to LNs. Collecting vessels that leave LNs, so-called efferent lymphatic vessels, may connect with further LNs [26] but eventually merge into the thoracic duct. The latter finally fuses with the subclavian vein, thereby connecting the lymphatic vascular system with the blood circulation [2]. Lymphatic endothelial cells (LECs) in capillaries differ from LECs in collectors in terms of gene expression and morphology. While LECs in capillaries express high levels of the lymphatic marker genes LYVE-1, Prox-1 andVEGFR-3, these genes are down-regulated in collector LECs [27,28]. Moreover, LECs in the capillaries are oak leaf-shaped cells that are connected by discontinuous button-like junctions [29] (Figure 1). These junctions give rise to overlapping flaps, also called primary valves, through which fluid and leukocytes enter lymphatic vessels [29,30]. Collector LECs, on the other hand, are elongated cells that are connected by continuous cell-cell junctions [29]. While lymphatic capillaries only have a thin, discontinuous basement membrane and are devoid of lymphatic muscle cell coverage, lymphatic collectors are surrounded by a continuous basement membrane and lymphatic muscle cells [27,31]. Moreover, collecting vessels contain intraluminal valves to prevent backflow of lymph. The valves divide the collecting vessels into functional units called lymphangions (Figure 1). Lymph is propelled from one lymphangion to the next through phasic contractions of the lymphatic muscle cells, as well as through contractions of the surrounding skeletal muscles and arteries [2,31].


Figure 1: Organization of the lymphatic network. (a) Afferent lymphatic vessels begin as blind-ended capillaries in peripheral tissues. These then merge into collecting vessels, which feed into a dLN. Collecting vessels contain valves and are surrounded by smooth muscle cells (SMCs). The vessel segment between two valves is called lymphangion (LA). Lymph fluid and leukocytes leave the LNs through the efferent collecting vessel. At the level of the thoracic duct the lymphcontent is ejected into the blood vascular circulation. Inserts: (A) LECs in lymphatic capillaries are oak-leaf shaped. Neighboring cells partially overlap and are connected by discontinuous, “button-like” cell-cell junctions (thick black lines). This setup generates open flaps (primary valves) (B) The flaps account for the entry of fluids, macromolecules and leukocytes into lymphatic capillaries. Capillary LECs are connected with the extracellular matrix through filaments, which account for the rapid dilation of lymphatic vessels during tissue edema. (C) LECs in lymphatic collectors have an elongated shape. Neighboring LECs are connected by continuous, “zipper-like” cell-cell junctions. This organization makes the collecting vessels less permeable as compared to initial capillaries and well suited for conducting fluids. (D) LECs in collecting vessels are in intimate association with lymphatic muscle cells (LMCs) lymphatic muscle cell, which mediate lymphatic contractility.

Inflammatory Lymphangiogenesis

Numerous studies have shown that the lymphatic network in peripheral tissues and draining LNs (dLNs) undergoes dramatic expansion and morphologic changes in the context of inflammation. As in other biologic processes, the rate and nature of inflammatory lymphangiogenesis appear to be highly stimulus- and tissue-specific. Depending on the inflammatory stimulus, different molecular and cellular mediators of inflammatory lymphangiogenesis are involved. Consequently, the extent and morphologic characteristics of lymphatic vessel remodeling and its impact on lymphatic function may vary. In the following sections selected aspects of inflammatory lymphangiogenesis will be discussed in greater detail.

Cellular and molecular mediators of inflammatory lymphangiogenesis

Mediators of inflammatory lymphangiogenesis are either produced by leukocytes or by stromal cells. The best-characterized mediators of this process are vascular endothelial growth factor (VEGF)-A and VEGF-C / VEGF-D, which signal through VEGFR-2 and/or VEGFR-3 [32]. Particularly macrophages are considered an important source of VEGF-A and VEGF-C. Macrophages have been shown to drive lymphangiogenesis in the inflamed tissues [33-36] as well as in dLNs [34]. For example, in a mouse model of LPS-induced skin inflammation depletion of macrophages or blockade of VEGF-C/-D or VEGF-A greatly inhibited inflammation-induced lymphangiogenesis [34]. During pulmonary inflammation induce in mice by infection with Mycoplasma pulmonis, dendritic cells (DCs), macrophages and neutrophils were all shown to produce VEGF-C and VEGF-D [33]. More recently, neutrophils have also been implicated in inflammatory lymphangiogenesis occurring in mice upon induction of a contact hypersensitivity (CHS) response or upon immunization with Complete Freund’s Adjuvant (CFA) and protein antigen. Under these conditions neutrophils were found to contribute to lymphangiogenesis by producing VEGF-D and by regulating the bioactivity of VEGF-A in tissues [37]. Besides leukocytes also non-immune cells, such as epithelial cells [33,38], keratinocytes [39], and fibroblastic reticular cells [37] have been identified as major sources of VEGF-A or VEGF-C.

In addition to VEGFR-2 and VEGFR-3 ligands, many other inflammatory mediators, such as LPS [40], IL-17 [41] orIL-8 [42] were shown to induce lymphangiogenesis in vitro and in vivo in animal models. Moreover, lymphotoxin (LTα and LTβ) have been implicated in inflammatory lymphangiogenesis, particularly in the context of tertiary lymphoid organ (TLO) formation [43,44]. Given the pleiotropic effects of most of these mediators, it is difficult to dissect whether their in vivo lymphangiogenic activity is mediated by direct action on LECs or indirectly through factors released by other cell types. Interestingly, some inflammatory cytokines have been shown to inhibit lymphangiogenesis. IFN-γ, which is mainly produced by T helper1 (Th1) and natural killer (NK) cells, was shown to inhibit lymphangiogenesis in vitro and in vivo [45,46]. Furthermore, inhibition of TGF-β was shown to induce lymphangiogenesis in a mouse model of peritonitis [47] and to improve lymphatic drainage in a murine lymphedema model [48]. Moreover, in a mouse model of lymphedema depletion of CD4+T cells promoted lymphangiogenesis and resolution of edema, indicating that T-cell-derived products negatively impact lymphatic network formation and function [49]. Overall, inflammatory lymphangiogenesis appears to be regulated by the expression of both pro-and anti-lymphangiogenic factors, which are expressed from various cellular sources, depending on the nature of the inflammatory stimulus.

Lymphangiogenesis in peripheral tissues

To date three different mechanisms have been described by which the lymphatic network in peripheral tissues expands in the context of inflammation: This may be through dilation and proliferative expansion of existing vessels [50,51] or through sprouting of new vessels [34,36,52]. Moreover, it has been suggested that the lymphatic network may expand by incorporation and trans-differentiation of bone marrow (BM)-derived cells into the existing lymphatic network [14,35,53]. Interestingly, the lymphangiogenic mediators VEGF-A and VEGF-C/-D seem to induce different patterns of vascular remodeling: Adenoviral delivery of mouse VEGF-A164 or human VEGF-A165 or to the murine skin induced a strong dilation and proliferative expansion of existing vessels but little or no sprouting, respectively [50,51]. Conversely, VEGF-C and VEGF-D were shown to preferentially induce sprouting lymphangiogenesis [50]. On the other hand, constitutive or conditional overexpression of VEGF-C in the skin [54,55] or in lungs [56] was shown to induce giant lymphatic vessels. The latter findings indicates that – likely depending on the dose or duration and time-window of exposure - VEGF-C may additionally induce lymphatic dilation in addition to sprouting. Recently, some studies have suggested that inflammatory lymphangiogenesis may also involve the incorporation and trans-differentiation of BM-derived cells into LECs [14,35,53]. Macrophages have been reported to trans-differentiate into LECs in LPS-induced peritonitis [53] and corneal inflammation [35], and trans-differentiation of BM-derived cells into LECs has also been observed in human kidney transplants [14]. However, the occurrence, exact mechanism and general importance of trans-differentiation presently remain controversial.

Interestingly, inflammation-induced or VEGF-C-induced expansion of the lymphatic network in peripheral tissues like the lung [33,56-58] or skin [51,55,59] of mice appears to give rise to long-lived lymphatic vessels, which remain after inflammation has resolved or expression of pro-lymphangiogenic factors has subsided. By contrast, in the cornea lymphatic vessels were observed to partially regress after a first inflammatory episode but to regrow in an accelerated manner during recurrent inflammation [60]. The latter differences might be linked with the fact that the cornea – in contrast to skin or lung – under steady-state conditions is an avascular tissue [8]. Overall, these findings raise the intriguing possibility that the lymphatic vessel network in the peripheral tissues might develop some form of “lymphatic memory” to accelerate tissue drainage and immune induction in the case of recurrent inflammatory episodes.

In addition to the macroscopic expansion of the lymphatic network, lymphatic vessels also change at the cellular level in the context of inflammation: Yao et al. [58] reported that the characteristic button-like junctions in capillaries transform into zipper-like junctions in a mouse model of chronic airway inflammation. Zipper-like junctions are also seen in lymphatic sprouts of capillaries during embryonic development [29,58], indicating that the button-like arrangement represents a mature and differentiated state. Moreover, besides these junctional changes, down-regulation of LYVE-1, VEGFR-3 and Prox-1 has been reported in several studies of inflammation [33,61-63]. Thus, during certain inflammatory conditions, the lymphatic vessels appear to acquire a more collector-like phenotype. The functional implications of these changes are unknown, but they could influence fluid uptake and migration of leucocytes.

LN lymphangiogenesis

An abundant literature demonstrates that inflammatory lymphangiogenesis is not limited to the inflamed peripheral tissues but also occurs in dLNs [34,39,45,59,64-67] (Figure 2A and 2B). Interestingly, the proliferative expansion and structural changes induced in LNs appear to be more profound compared to lymphatic remodeling occurring in the inflamed tissue [34,39,59]. The magnitude of this response may be linked with the fact that LNs themselves are highly dynamic structures that rapidly change in size and cellular content. Although most studies to date have uniformly identified VEGF-A as the main driver of LN lymphangiogenesis, the cellular sources of this mediator may vary, depending on the inflammatory model and the time point analyzed. Particularly B cells have been identified as inducers of inflammatory LN lymphangiogenesis [37,64,68]. In a model of skin inflammation induced by immunization with CFA and protein antigen, VEGF-A-producing B cells were responsible for LN lymphangiogenesis occurring in the early phase of the immune response (i.e. day 1-4) [64]. Interestingly, a follow-up study using the same mouse model revealed that in absence of B cells neutrophils accounted for the induction of LN lymphangiogenesis at later stages of the inflammatory response [37]. Similarly, experiments in a mouse model of immunization with oxazolone showed that the lymphangiogenic response was strikingly delayed but still present in mice lacking B cells [68]. On the other hand, work from our group revealed that during oxazolone-induced CHSLN lymphangiogenesis was induced by VEGF-A that was drained to the LN via the lymphatic network from its site of production, epidermal keratinocytes [39]. More recently also fibroblastic reticular cells in LNs have been shown to contribute to CFA-induced LN lymphangiogenesis by producing VEGF-A [66,67]. Besides pro-lymphangiogenic VEGF-A produced by various LN-resident cell types, also anti-lymphangiogenic IFN-γ derived from T cells was shown to regulate LN lymphangiogenesis [45,46]. In fact, the data suggest that the extent of T cell activation occurring in the context of inflammation may impact the LN lymphangiogenic response [45]: Specifically, inflammation induced by dermal injection of the T cell activating mitogen concanavalin A was accompanied by only weak LN lymphangiogenesis, whereas inflammation induced by dermal LPS injection resulted in profound LN lymphangiogenesis in mice [45].


Figure 2: Lymphatic network in LNs at steady-state and in inflammation. (A) Steady-state condition: The lymphatic network in LNs is organized into the subcapsular sinus (SCS), the medullary sinus (MS) and the cortical sinuses (CS). B cell areas (blue) and T cell zones (green) are shown. (B) Inflammation leads to a massive expansion of the SCS, MS and CS. Pro-lymphangiogenic (+) and anti-lymphangiogenic (-) factors produced by B and T cells respectively, impact the strength of the LN lymphangiogenic response.

Interestingly, Tan et al. found that the pattern of lymphangiogenesis in CFA-induced inflammation displayed remarkable spatial and temporal differences [66]. While the lymphatics of the subcapsular sinus (SCS) already expanded during the early phase of the inflammatory response, the cortical and medullary sinuses only expanded at later time points of inflammation. Functional data indicate that the temporal and spatial differences in LN lymphangiogenesis might serve to sequentially modulate DC and T cell migration to and from LNs, respectively. Notably, DCs arriving in the LN through afferent lymphatic vessels typically enter the node by traversing the SCS [26] (Figure 2A). By contrast, T cells egress from LNs by migrating across the cortical and medullary sinuses [26]. Blockade of VEGFR-2/VEGFR-3-mediated lymphangiogenesis during early time points of inflammation was shown to reduce both lymphangiogenesis in the SCS and DC migration to dLNs in mice [64]. By contrast, at later time points, blockade of VEGFR-2/VEGFR-3 inhibited lymphangiogenesis in the cortical and medullary sinuses and reduced T cell egress from LNs [66]. These findings suggest that LN lymphangiogenesis may serve to fine-tune leukocyte migration and the induction of immune responses in LNs draining sites of inflammation. In line with such a regulatory function, it was found that LN lymphangiogenesis is a transient phenomenon: As the inflammation and the induction of adaptive immunity progresses and eventually resolves, lymphatic vessels in LNs regress back to normal [34,35,45].

Changes in LEC Gene Expression: Impact on Leukocyte Trafficking

From blood vessels it is well known that inflammation-induced changes in gene expression, in particular up-regulation of chemokines and adhesion molecules, regulate the recruitment of leukocytes to sites of inflammation. Similarly, inflammatory stimuli have been shown to profoundly alter the expression of cell adhesion molecules and chemokines in LECs. ICAM-1, VCAM-1, and L1CAM are LEC-expressed adhesion molecules that are upregulated under inflammatory conditions and mediate DC migration into lymphatic vessels [61,69,70]. ICAM-1 and VCAM-1 have also been implicated in DC crawling within lymphatic capillaries [71]. During steady state, however, expression of ICAM-1 and VCAM-1 on LECs is very low and DCs migrate independently of these molecules [72]. In addition to their role in leukocyte trafficking, some inflammation-induced adhesion molecules, such as the integrins α5β1 [73] and α1β1 [74] or ALCAM [75], were shown to support lymphangiogenesis.

Besides adhesion molecules also chemokines are important for leukocyte trafficking through lymphatic vessels. The best-characterized chemokine involved in this process is CCL21 [5,76]. CCL21 is constitutively expressed by lymphatic vessels and mediates the migration of CC-chemokine receptor 7 (CCR7) expressing DCs, T cells, and neutrophils towards and into lymphatic vessels [5,76,77]. A considerable fraction of CCL21 is stored in intracellular vesicles in LECs [61,78], but CCL21 may be rapidly released in vitro upon treatment with TNF-α [78]. CCL21 expression is reportedly upregulated in vivo in the context of inflammation [61,79] and under conditions of increased lymph flow [80]. Although DC migration to dLNs is highly CCR7-dependent in both steady-state and in inflammation [61], other inflammation-induced chemokines in LECs were shown to contribute to this migratory step. Specifically, CXCL12 and CX3CL1 are upregulated in lymphatic vessels during inflammation and support DC migration to dLNs [81,82].

Besides CCL21, CXCL12 and CX3CL1 many other inflammatory chemokines are strikingly upregulated in LECs during ongoing inflammatory responses [61,69,83,84]. Performing a gene expression analysis of LECs isolated from inflamed and resting murine skin we observed that the response of LECs to inflammation is highly stimulus-specific [61]. For example, chemokines like CCL8, CXCL9 or CXCL10 and ICAM-1 were strongly upregulated in inflammation induced by a CHS response to oxazolone but only weakly upregulated during inflammation induced by CFA injection into the skin [61]. A similar stimulus-specific chemokine expression pattern was also observed in in vitro studies when incubating LECs with different TLR ligands [83,84]. It is tempting to speculate that such stimulus specific responses might serve to fine-tune tissue exit and migration of specific leukocyte subsets into lymphatic vessels. However, besides the involvement of CXCL12 and CX3CL1 in DC migration [81,82], only little evidence exists so far for the role of other inflammation-induced chemokines in leukocyte trafficking through lymphatic vessels. During LPS-induced peritonitis LEC-derived chemokines like CCL2, CCL5 or CX3CL1 supposedly induced the association of VEGF-C-producing peritoneal macrophages with lymphatic vessels, thereby accounting for enhanced lymphangiogenesis and macrophage trafficking to dLNs [40]. Moreover, it was recently reported that lymphocyte egress from chronically inflamed murine skin was only partially dependent on CCR7 and completely independent of CXCR4 expression but sensitive to treatment with pertussis toxin [85]. These data indicate that, in addition to the CCL21/CCR7 signaling, other unknown chemotactic stimuli participate in lymphocyte egress from chronically inflamed tissues.

In addition to secreting chemokines, lymphatic vessels also actively contribute to removing chemokines from inflamed tissues. In response to inflammation LECs have been shown to upregulate the chemokine scavenging receptor D6, which binds, internalizes and degrades most CC-chemokine ligands [86]. Analysis of D6-deficient mice has revealed a crucial role for this receptor in the resolution of tissue inflammation [86-88]. In fact, D6 appears to function by constantly removing inflammatory chemokines and allowing for a selective presentation of CCL21 on lymphatic vessels. In absence of D6, a strong accumulation of myelomonocytic cells around lymphatic vessels was observed, what impeded cell trafficking and fluid flow to dLNs [87]. Interestingly, also the expression of other chemokine scavenging receptors on LECs has recently been identified [89,90], but the role of these receptors in the inflammatory response of lymphatic vessels has not been elucidated to date.

Functional Implications of Inflammatory Lymphangiogenesis

It is still unclear whether inflammatory lymphangiogenesis is entirely a protective response that contributes to the resolution of inflammation, or whether it forms part of its pathology. For example, in human IBD the density of lymphatic vessels was shown to correlate with disease severity [11]. At the same time, histologic and imaging studies in human patients have described lymphatic dysfunction and lymphatic obstruction as a characteristic feature of IBD [91-93]. Moreover, VEGFR-3-mediated blockade of lymphangiogenesis was recently shown to exacerbate inflammation in a mouse model of IBD [21], whereas disease amelioration was observed upon VEGF-C-dependent stimulation of lymphatic function [19]. Together, these findings indicate that lymphangiogenesis may have a protective effect in IBD, and that lymphatic vessel dysfunction might even contribute to disease development. On the other hand, highly increased lymphatic vessel densities have been recognized as a hallmark of rejected human kidney transplants [14,15]. Moreover, animal studies have shown that blockade of lymphangiogenesis is a potent strategy for securing allograft survival [14,15,22-25,94]. These findings argue that lymphangiogenesis occurring in transplanted tissues does not reduce but rather contributes to inflammation and the rejection process. Overall, the two examples indicate that the functional significance of lymphangiogenesis might be different, depending on the organ analyzed and the type of inflammation and immune response induced. From an immunologic point of view it seems relevant to distinguish between two different scenarios during which inflammatory lymphangiogenesis typically occurs: This can be (i) in tissues with pre-existing lymphatic immune connectivity, i.e. with a functioning lymphatic network, such as the skin, the intestine or the lung. Alternatively, inflammatory lymphangiogenesis may occur in (ii) tissues with non-existing lymphatic immune connectivity, namely in transplanted organs or in immune-privileged tissues with no pre-existing connectivity with dLNs.

(i) Tissues with pre-existing lymphatic immune connectivity

Inflamed tissues generally become edematous due to increased fluid influx from blood, which exceeds the drainage capacity of the lymphatic vessel network. It is likely that inflammatory lymphangiogenesis serves to adapt the lymphatic network to meet the enhanced demand for removing fluids, inflammatory mediators, and leukocytes from the inflamed tissue. Removal of antigen-presenting cells (APCs) from the inflamed site is thought to contribute to the resolution of inflammation [34,95,96]. Moreover, lymphatic drainage contributes to dampening tissue inflammation. This is best exemplified by lymphedema, a condition in which lymphatic drainage is defective or malfunctioning [1]: Lymphedema not only results in the accumulation of fluids but also of leukocytes and inflammatory mediators in the tissue, leading to tissue inflammation, as was shown in both animal and human studies [13,97]. By now several studies have demonstrated that blockade of inflammatory lymphangiogenesis, e.g. by targeting the VEGF-C/VEGFR-3 axis, aggravated tissue inflammation in various models of immune-mediated, chronic inflammatory disorders. For example, in mouse models of skin inflammation blockade of VEGFR-3 reduced lymphatic drainage and delayed resolution of inflammation [16,34,63]. Similarly, anti-VEGFR-3 treatment worsened edema formation and tissue inflammation in mouse models of IBD[21], rheumatoid arthritis [20], or infection-induced airway inflammation [33]. On the other hand, stimulation of lymphangiogenesis through activation of the VEGFR-3 pathway was shown to accelerate the resolution of chronic and acute skin inflammation [16,17,98], to attenuate joint damage in a mouse model of arthritis [18], or to ameliorate IBD symptoms [19]. Interestingly, in contrast to the documented anti-inflammatory effects of VEGF-C, VEGF-A appears to exacerbate inflammation [16,63,99]. This may be due to different effects of VEGF-A and VEGF-C on the remodeling of the lymphatic network [16,50,51], as well as the well-known pro-inflammatory and permeability-enhancing activity of VEGF-A on blood vessels [1,16,32,63,100].

(ii) Tissues with non-existing lymphatic immune connectivity

In tissues with pre-established lymphatic immune connectivity (e.g. skin, lung, intestine), the lymphatic network in steady-state is thought to play a major role in maintaining immune tolerance, by constantly transporting self-proteins to dLNs [4,101]. Moreover, several studies have shown that LECs in LNs fulfill antigen-presenting functions and thereby directly contribute to tolerance induction [4]. This may explain why in the context of tissues with pre-existing lymphatic immune connectivity lymphangiogenesis seems to generally exert a beneficial, anti-inflammatory effect, due to its drainage-enhancing capabilities. The situation appears to be different in tissues with non-existing lymphatic immune connectivity, such as in transplanted organs, where connectivity with dLNs is only established by inflammatory lymphangiogenesis. Under these conditions, inflammatory lymphangiogenesis accelerates the arrival of alloantigen and alloantigen-presenting leukocytes in dLNs, leading to the induction of adaptive immunity and eventually to graft rejection. Several human and animal studies have investigated the involvement of inflammatory lymphangiogenesis in graft rejection [14,15,22-25,94,102]. Particularly in mouse studies in the cornea it was shown that blockade of inflammatory lymphangiogenesis was an effective strategy for reducing APC migration to dLNs and retarding the graft rejection process [8,23,24]. However, the cornea might be a special tissue, since it lacks blood vessels and lymphatic vessels in the uninflamed state and therefore can be considered an immune-privileged tissue [8]. Similar findings are now also emerging for pancreatic islets, which normally also lack lymphatic vessel but display a strong lymphangiogenic response during transplantation [25,102] or during autoimmune attack [22]. Blockade of lymphangiogenesis was shown to enhance the survival of pancreatic islets allografts transplanted under the kidney capsule in mice [25]. Moreover, blockade of lymphangiogenesis was shown to delay the onset of diabetes in a mouse model of experimentally induced autoimmune diabetes [22]. Similarly, adenoviral treatment with a VEGFR-3-Fc fusion protein was shown to reduce heart allograft rejection [94].

Impact of Inflammation on Lymphatic Drainage Function

Inflammation leads to a rapid influx of fluid into the interstitial space and results in tissue swelling. Since capillary LECs are connected by filaments with the extracellular matrix [103] (Figure 1), tissue swelling leads to the opening of the primary valves, resulting in interstitial fluid influx and dilation of lymphatic vessels [104]. Intuitively, one would assume that inflammation increases the drainage rate of lymphatic vessels. However, both enhanced and reduced drainage rates have been reported in different animal models of acute and chronic inflammation. For example, lymphatic drainage was reduced during acute and persistent CHS-induced skin inflammation [63,105,106]. Moreover, impaired lymphatic drainage and increased leakiness of lymphatic vessels was also observed in UVB-induced skin inflammation [99]. On the other hand, increased lymphatic flow was observed during intestinal inflammation in rats upon treatment with N-formyl-methionyl-leucyl-phenylalanine (fMLP) [107] or in guinea pigs treated with LPS [108]. Moreover, lymphatic drainage was enhanced in a mouse model of atopic dermatitis caused by dermal overexpression of IL-4 [109]. Thus, inflammation appears to alter lymphatic drainage function in a stimulus-dependent manner. In many cases the inflammation-induced changes in lymphatic drainage have been observed to occur very rapidly i.e. in the course of several minutes to hours after applying an inflammatory stimulus [63,99,105-108]. Such rapid responses are less likely explained by profound morphological changes induced by inflammatory lymphangiogenesis. More likely, these changes in lymphatic drainage are caused by immediate effects of the inflammatory stimuli on the vasculature; namely, on the vessel-forming LECs or on lymphatic muscle cells, which control lymphatic pumping (Figure 1).

Effect of inflammation on LEC barrier function

LECs in lymphatic capillaries and collectors express the same junctional proteins, but the organization of cell-cell junctions is different (Figure 1). In both capillaries and collectors VE-cadherin, which is crucial for maintaining endothelial cell barrier function [110], co-localizes with tight junction proteins like ZO-1, claudin-5, JAM-A or ESAM [29]. While these molecules form continuous, zipper-like junctions in collectors, VE-cadherin and tight junction proteins only display a punctuate expression pattern in oak leaf-shaped capillary LECs, thereby giving rise to the characteristic open flaps [29] (Figure 1). To date only few studies have investigated how inflammatory mediators affect lymphatic vessel permeability in vivo [51,99,111,112]. Far more studies have addressed this in in vitro experiments performed with LEC monolayers. LECs cultured in monolayers form continuous cell-cell junctions [111], which resemble the setup observed in collecting lymphatic vessels. This indicates that in vitro experiments rather model the barrier function of collecting vessels than fluid transport across lymphatic capillaries. Many inflammatory and lymphangiogenic mediators modulate LEC barrier function in vitro [99,113-116]. Besides thrombin and histamine [113] alsoVEGF-A [111], VEGF-C [116], inflammatory cytokines like TNF-α, IL-1β, IL-6, IFN-γ, or LPS [114,115] increase permeability of LEC monolayers. A recent study revealed that the permeability-inducing effect of most inflammatory cytokines was largely nitric oxide (NO)-dependent and accompanied by down-regulation of VE-cadherin protein levels in LECs [115]. Moreover, inflammatory cytokines increased the amount of phosphorylated myosin light chain 20 in LECs [115], which is indicative of enhanced cellular actin-myosin contractility and enhanced permeability [110,115]. Interestingly, also transmural flow was shown to increase the in vitro permeability of LEC monolayers, by inducing the down-regulation and internalization of VE-Cadherin and PECAM-1 [80]. On the other hand, adrenomedullin, a peptide with anti-inflammatory and lymphangiogenic activity, was shown to prevent the VEGFA-mediated increase in LEC permeability by stabilizing VE-cadherin and ZO-1 at cell–cell junctions of LECs [111].

Effect of inflammation on lymphatic muscle cells

Lymphatic muscle cells surround the collecting lymphatic vessels, and their phasic contractions result in the propulsion of lymph from one lymphangion to the next (Figure 1). The lymph volume pumped through the lymphatic vessels depends on the frequency and strength of the contraction [31]. Inflammatory cells as well as inflammatory mediators have been shown to affect the contractility of lymphatic muscle cells [31,107,112,117-121]. For example, prostaglandin and prostacyclin were shown to decrease the pumping rate of lymphatic collectors [117]. Similarly, systemic or intradermal injection of IL-6, IL-1β, and TNF-α resulted in decreased lymph pumping frequency and flow velocity, as assessed in in vivo near-infrared-imaging studies in mice [118]. By contrast, substance P [119], a neuropeptide secreted by inflammatory cells, as well as the pro-lymphangiogenic factor VEGF-C [112] and fMLP [107] were shown to increase lymphatic pumping of rat mesenteric vessels. Moreover, NO produced by inflammatory cells was shown to profoundly affect lymphatic pumping: In a mouse model of oxazolone-induced skin inflammation Liao et al. observed that NO production by CD11b+Gr-1+ inflammatory cells, which accumulated on collecting lymphatic vessels, accounted for reduced lymphatic pumping activity [65]. On the other hand, also histamine [120] or NO [121] released from activated mast cells have been identified as modulators of lymphatic contractility.

In conclusion, inflammatory and lymphangiogenic mediators may not only affect lymphatic drainage by inducing morphologic changes in the lymphatic network, but may also acutely impact drainage by modulating LEC barrier function or lymphatic pumping. Intriguingly, the above-mentioned examples reveal that many mediators (e.g. VEGF-C [112], histamine [113,120], NO [65,115,121] or inflammatory cytokines [115,118]) simultaneously act on both LECs and lymphatic muscle cells.

Inflammatory Lymphangiogenesis: Therapeutic Implications

There is growing appreciation that strategies attempting to enhance rather than to block lymphangiogenesis and lymphatic drainage function may represent an effective therapeutic approach for inflammatory disorders like rheumatoid arthritis [20,122], Morbus Crohn [19,21] or psoriasis [16,63], i.e. inflammatory disorders occurring in tissues with pre-established lymphatic immune connectivity. Particularly delivery of VEGF-C into inflamed skin was shown to enhance drainage and to reduce inflammatory symptoms in a murine model of chronic skin inflammation [16,17]. In addition, systemic adenoviral VEGF-C delivery enhanced drainage and reduced joint damage in a mouse model of arthritis [18] and ameliorated disease conditions in a mouse model of IBD [19]. The anti-inflammatory effects of VEGF-C have so far mainly been attributed to direct stimulation of lymphangiogenesis and lymphatic function in LECs. However, also certain leukocytes, such as certain DCs, tissue macrophages or monocytic cells in blood, have been shown to express VEGFR-3 [19,123-125]. In fact, recent experimental findings indicate that VEGF-C may also exert anti-inflammatory activity by directly acting on these cell types [19,125]. In a mouse model of sepsis VEGF-C acting on VEGFR-3-expressing activated macrophages was shown to potently suppress the inflammatory response induced by intraperitoneally administered LPS [125]. Similarly, in mouse models of IBD, VEGF-C was shown to activate anti-inflammatory responses in intestinal macrophages [19]. Thus, it is important to bear in mind that the anti-inflammatory effects of VEGF-C may not be exclusively mediated by its action on lymphatic vessels.

Thus far, neither VEGF-C nor any other pro-lymphangiogenic mediator has entered clinical development. In the context of infection-induced inflammatory disorders, a potential concern of pro-lymphangiogenic treatments might be that enhanced lymphatic drainage and lymphangiogenesis might over-run the filtering and immune surveillance function of dLNs and facilitate systemic spread of pathogens. Clearly, more preclinical experiments are required to demonstrate the therapeutic potential and safety of pro-lymphangiogenic approaches for the treatment of chronic inflammatory and autoimmune diseases. Besides the VEGF-C/VEGFR-3 axis also other recently identified pro-lymphangiogenic signaling pathways may be interesting to investigate as potential therapeutic targets [111,126,127].

In the context of transplant rejection several preclinical studies have revealed a clear benefit of anti-lymphangiogenic treatments for preventing graft rejection, particularly in mouse models of corneal transplantation [8,23,24] or in pancreatic islet transplantation [25]. Furthermore, blockade or VEGFR-3 was able to prolong cardiac allograft survival in mice by reducing immune cell trafficking due to decreased CCL21 production [94]. However, the promising results observed might not be generalizable for all types of transplantation. Several studies have shown that allo-responses to transplanted organs are not exclusively induced in dLNs [128]. In some cases, priming occurs in distant secondary lymphoid organs like the spleen, through APCs that have exited the graft by entry into blood vessels [128]. Thus, blocking lymphangiogenesis will likely only proof to be a useful therapeutic approach in transplant situations, in which DC migration through lymphatic vessels represents the major route for the induction of allo-responses.

Conclusion and Outlook

Over the past 10 years major progress has been made in our understanding of inflammatory lymphangiogenesis and of the general role of lymphatic vessels in the development and resolution of inflammatory responses. Research has revealed that lymphatic vessels form a highly dynamic network, which rapidly responds to tissue inflammation in a stimulus and tissue-specific manner. Moreover, the functional significance of inflammatory lymphangiogenesis appears to be highly context specific, as evidenced by the either pro- or anti-inflammatory effects observed, depending on the tissue analyzed. Several studies performed in animals have identified inflammatory lymphangiogenesis as a potential therapeutic target for modulating inflammatory and immune-mediated responses. Although promising results have been achieved in these preclinical disease models, a lot remains to be investigated to better understand the exact mechanism(s) through which lymphatic vessels and inflammatory lymphangiogenesis participate in the regulation of tissue inflammation and immune induction in LNs.

The emerging picture suggests that the role of the lymphatic network in the regulation of immune responses goes beyond transporting antigen, inflammatory mediators, and leukocytes between peripheral tissues and LNs [4].In fact, several studies are now documenting the direct involvement of LN LECs in dampening the immune response and in tolerance induction [4]. Amongst the inflammatory changes occurring in the lymphatic network, LN lymphangiogenesis probably is least well characterized and functionally understood. In the future, it will be important to further understand how inflammation-induced LN lymphangiogenesis and inflammation-induced gene expression changes in LN LECs impact antigen-presentation and tolerance induction.

Although the lymphatic network typically undergoes a proliferative expansion in both peripheral tissues and dLNs in the context of inflammation, this does not always seem to produce functional lymphatic vessels that enhance tissue drainage. Interestingly, even VEGF-C which is generally considered a potential therapeutic target for stimulating productive lymphangiogenesis and lymphatic function, may give rise to a dysfunctional lymphatic network: Overexpression of VEGF-C in the lungs of neonatal mice -but not in adult mice - induced a disease condition reminiscent of human pulmonary lymphangiectasia [56]. Not so surprisingly, this indicates that the dose, the tissue environment and the time-point at which exposure to VEGF-C occurs may influence the extent of productive as compared to pathologic lymphangiogenesis. Recent studies have also revealed that the anti-inflammatory effects of VEGF-C may not only be mediated by direct effects on lymphatic vessels, but also involve activation of VEGFR-3-expressing leukocytes [19,125]. In light of these findings it will be interesting to further dissect the exact mechanism(s) by which VEGF-C and pro-lymphangiogenic treatment reduce inflammation. It is likely that the relative contribution of leukocytes may vary, depending on the type of inflammation induced and the tissue studied.

With regards to potential therapeutic applications, it will also be important to identify more lymphangiogenic factors, which preferentially stimulate lymphatic vessels yet do not induce angiogenesis in blood vessels. In fact, to date only few lymphatic-specific growth factors have been identified. Moreover, it may be desirable to identify molecules that do not lead to a vast proliferative expansion of the lymphatic network, but rather to an enhancement of lymphatic vessel integrity and drainage function. This could be accomplished by molecules acting on LECs or also on the LEC-surrounding lymphatic muscle cells. Clearly, a lot remains to be investigated to better understand how lymphatic drainage function is regulated in the context of inflammation. In this regard, the advent of new live imaging methodologies, which allow to study inflammatory lymphangiogenesis and drainage in a longitudinal manner [100,118,129], are expected to contribute to a better understanding of the complex relationship between inflammation and lymphatic function.

Grant Support

Swiss National Science Foundation (grant no 310030_138330).


  1. Alitalo K (2011) The lymphatic vasculature in disease. Nat Med 17: 1371-1380.
  2. Schulte-Merker S, Sabine A, Petrova TV (2011) Lymphatic vascular morphogenesis in development, physiology, and disease. J Cell Biol 193: 607-618.
  3. Kerjaschki D (2014) The lymphatic vasculature revisited. J Clin Invest 124: 874-877.
  4. Card CM, Yu SS, Swartz MA (2014) Emerging roles of lymphatic endothelium in regulating adaptive immunity. J Clin Invest 124: 943-952.
  5. Förster R, Braun A, Worbs T (2012) Lymph node homing of T cells and dendritic cells via afferent lymphatics. Trends Immunol 33: 271-280.
  6. Asellius G (1627) De lactibus sive lacteis venis, quarto vasorum mesarai corum genere nova invento. Mediolani, apud Jo Baptistam Bidellium.
  7. Yang Y, Oliver G (2014) Development of the mammalian lymphatic vasculature. J Clin Invest 124: 888-897.
  8. Hos D, Cursiefen C (2014) Lymphatic vessels in the development of tissue and organ rejection. Adv Anat Embryol Cell Biol 214: 119-141.
  9. Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, et al. (1994) Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 180: 1141-1146.
  10. Wauke K, Nagashima M, Ishiwata T, Asano G, Yoshino S (2002) Expression and localization of vascular endothelial growth factor-C in rheumatoid arthritis synovial tissue. J Rheumatol 29: 34-38.
  11. Fogt F, Pascha TL, Zhang PJ, Gausas RE, Rahemtulla A, et al. (2004) Proliferation of D2-40-expressing intestinal lymphatic vessels in the lamina propria in inflammatory bowel disease. Int J Mol Med 13: 211-214.
  12. Pedica F, Ligorio C, Tonelli P, Bartolini S, Baccarini P (2008) Lymphangiogenesis in Crohn's disease: an immunohistochemical study using monoclonal antibody D2-40. Virchows Arch 452: 57-63.
  13. Tabibiazar R, Cheung L, Han J, Swanson J, Beilhack A, et al. (2006) Inflammatory manifestations of experimental lymphatic insufficiency. PLoS Med 3: e254.
  14. Kerjaschki D, Huttary N, Raab I, Regele H, Bojarski-Nagy K, et al. (2006) Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med 12: 230-234.
  15. Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, et al. (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 15: 603-612.
  16. Huggenberger R, Ullmann S, Proulx ST, Pytowski B, Alitalo K, et al. (2010) Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med 207: 2255-2269.
  17. Kajiya K, Sawane M, Huggenberger R, Detmar M (2009) Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis. J Invest Dermatol 129: 1292-1298.
  18. Zhou Q, Guo R, Wood R, Boyce BF, Liang Q, et al. (2011) Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice. Arthritis Rheum 63: 2318-2328.
  19. D'Alessio S, Correale C, Tacconi C, Gandelli A, Pietrogrande G, et al. (2014) VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J Clin Invest .
  20. Guo R, Zhou Q, Proulx ST, Wood R, Ji RC, et al. (2009) Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum 60: 2666-2676.
  21. Jurisic G, Sundberg JP, Detmar M (2013) Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement. Inflamm Bowel Dis 19: 1983-1989.
  22. Yin N, Zhang N, Lal G, Xu J, Yan M, et al. (2011) Lymphangiogenesis is required for pancreatic islet inflammation and diabetes. PLoS One 6: e28023.
  23. Chen L, Hamrah P, Cursiefen C, Zhang Q, Pytowski B, et al. (2004) Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Nat Med 10: 813-815.
  24. Dietrich T, Bock F, Yuen D, Hos D, Bachmann BO, et al. (2010) Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J Immunol 184: 535-539.
  25. Yin N, Zhang N, Xu J, Shi Q, Ding Y, et al. (2011) Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival. Transplantation 92: 25-30.
  26. Girard JP, Moussion C, Förster R (2012) HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 12: 762-773.
  27. Mäkinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, et al. (2005) PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 19: 397-410.
  28. Norrmén C, Ivanov KI, Cheng J, Zangger N, Delorenzi M, et al. (2009) FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol 185: 439-457.
  29. Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E, et al. (2007) Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med 204: 2349-2362.
  30. Pflicke H, Sixt M (2009) Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J Exp Med 206: 2925-2935.
  31. von der Weid PY, Muthuchamy M (2010) Regulatory mechanisms in lymphatic vessel contraction under normal and inflammatory conditions. Pathophysiology 17: 263-276.
  32. Zheng W, Aspelund A, Alitalo K (2014) Lymphangiogenic factors, mechanisms, and applications. J Clin Invest 124: 878-887.
  33. Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, et al. (2005) Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest 115: 247-257.
  34. Kataru RP, Jung K, Jang C, Yang H, Schwendener RA, et al. (2009) Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113: 5650-5659.
  35. Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, et al. (2005) Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 115: 2363-2372.
  36. Kim KE, Koh YJ, Jeon BH, Jang C, Han J, et al. (2009) Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm. Am J Pathol 175: 1733-1745.
  37. Tan KW, Chong SZ, Wong FH, Evrard M, Tan SM, et al. (2013) Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D. Blood 122: 3666-3677.
  38. Wuest TR, Carr DJ (2010) VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J Exp Med 207: 101-115.
  39. Halin C, Tobler NE, Vigl B, Brown LF, Detmar M (2007) VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood 110: 3158-3167.
  40. Kang S, Lee SP, Kim KE, Kim HZ, Mémet S, et al. (2009) Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages. Blood 113: 2605-2613.
  41. Chauhan SK, Jin Y, Goyal S, Lee HS, Fuchsluger TA, et al. (2011) A novel pro-lymphangiogenic function for Th17/IL-17. Blood 118: 4630-4634.
  42. Choi I, Lee YS, Chung HK, Choi D, Ecoiffier T, et al. (2013) Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration. Angiogenesis 16: 29-44.
  43. Furtado GC, Marinkovic T, Martin AP, Garin A, Hoch B, et al. (2007) Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc Natl Acad Sci U S A 104: 5026-5031.
  44. Mounzer RH, Svendsen OS, Baluk P, Bergman CM, Padera TP, et al. (2010) Lymphotoxin-alpha contributes to lymphangiogenesis. Blood 116: 2173-2182.
  45. Kataru RP, Kim H, Jang C, Choi DK, Koh BI, et al. (2011) T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34: 96-107.
  46. Zampell JC, Avraham T, Yoder N, Fort N, Yan A, et al. (2012) Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines. Am J Physiol Cell Physiol 302: C392-404.
  47. Oka M, Iwata C, Suzuki HI, Kiyono K, Morishita Y, et al. (2008) Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood 111: 4571-4579.
  48. Avraham T, Daluvoy S, Zampell J, Yan A, Haviv YS, et al. (2010) Blockade of transforming growth factor-beta1 accelerates lymphatic regeneration during wound repair. Am J Pathol 177: 3202-3214.
  49. Zampell JC, Yan A, Elhadad S, Avraham T, Weitman E, et al. (2012) CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis. PLoS One 7: e49940.
  50. Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, et al. (2007) Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 204: 1431-1440.
  51. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, et al. (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196: 1497-1506.
  52. Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono K, et al. (2010) Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood 115: 418-429.
  53. Hall KL, Volk-Draper LD, Flister MJ, Ran S (2012) New model of macrophage acquisition of the lymphatic endothelial phenotype. PLoS One 7: e31794.
  54. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, et al. (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276: 1423-1425.
  55. Lohela M, Heloterä H, Haiko P, Dumont DJ, Alitalo K (2008) Transgenic induction of vascular endothelial growth factor-C is strongly angiogenic in mouse embryos but leads to persistent lymphatic hyperplasia in adult tissues. Am J Pathol 173: 1891-1901.
  56. Yao LC, Testini C, Tvorogov D, Anisimov A, Vargas SO, et al. (2014) Pulmonary lymphangiectasia resulting from vascular endothelial growth factor-C overexpression during a critical period. Circ Res 114: 806-822.
  57. Yao LC, Baluk P, Feng J, McDonald DM (2010) Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. Am J Pathol 176: 1525-1541.
  58. Yao LC, Baluk P, Srinivasan RS, Oliver G, McDonald DM (2012) Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. Am J Pathol 180: 2561-2575.
  59. Mumprecht V, Roudnicky F, Detmar M (2012) Inflammation-induced lymph node lymphangiogenesis is reversible. Am J Pathol 180: 874-879.
  60. Kelley PM, Connor AL, Tempero RM (2013) Lymphatic vessel memory stimulated by recurrent inflammation. Am J Pathol 182: 2418-2428.
  61. Vigl B, Aebischer D, Nitschké M, Iolyeva M, Röthlin T, et al. (2011) Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. Blood 118: 205-215.
  62. Johnson LA, Prevo R, Clasper S, Jackson DG (2007) Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem 282: 33671-33680.
  63. Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, et al. (2011) An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117: 4667-4678.
  64. Angeli V, Ginhoux F, Llodrà J, Quemeneur L, Frenette PS, et al. (2006) B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24: 203-215.
  65. Liao S, Cheng G, Conner DA, Huang Y, Kucherlapati RS, et al. (2011) Impaired lymphatic contraction associated with immunosuppression. Proc Natl Acad Sci U S A 108: 18784-18789.
  66. Tan KW, Yeo KP, Wong FH, Lim HY, Khoo KL, et al. (2012) Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation. J Immunol 188: 4065-4080.
  67. Benahmed F, Chyou S, Dasoveanu D, Chen J, Kumar V, et al. (2014) Multiple CD11c+ cells collaboratively express IL-1β to modulate stromal vascular endothelial growth factor and lymph node vascular-stromal growth. J Immunol 192: 4153-4163.
  68. Liao S, Ruddle NH (2006) Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J Immunol 177: 3369-3379.
  69. Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, et al. (2006) An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med 203: 2763-2777.
  70. Maddaluno L, Verbrugge SE, Martinoli C, Matteoli G, Chiavelli A, et al. (2009) The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells. J Exp Med 206: 623-635.
  71. Nitschké M, Aebischer D, Abadier M, Haener S, Lucic M, et al. (2012) Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation. Blood 120: 2249-2258.
  72. Lämmermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Söldner R, et al. (2008) Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453: 51-55.
  73. Okazaki T, Ni A, Ayeni OA, Baluk P, Yao LC, et al. (2009) alpha5beta1 Integrin blockade inhibits lymphangiogenesis in airway inflammation. Am J Pathol 174: 2378-2387.
  74. Grimaldo S, Yuen D, Ecoiffier T, Chen L (2011) Very late antigen-1 mediates corneal lymphangiogenesis. Invest Ophthalmol Vis Sci 52: 4808-4812.
  75. Iolyeva M, Karaman S, Willrodt AH, Weingartner S, Vigl B, et al. (2013) Novel role for ALCAM in lymphatic network formation and function. FASEB J: 27: 978-990.
  76. Förster R, Schubel A, Breitfeld D, Kremmer E, Renner-Müller I, et al. (1999) CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99: 23-33.
  77. Beauvillain C, Cunin P, Doni A, Scotet M, Jaillon S, et al. (2011) CCR7 is involved in the migration of neutrophils to lymph nodes. Blood 117: 1196-1204.
  78. Johnson LA, Jackson DG (2010) Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key regulator of integrin-mediated dendritic cell transmigration. Int Immunol 22: 839-849.
  79. MartIn-Fontecha A, Sebastiani S, Höpken UE, Uguccioni M, Lipp M, et al. (2003) Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med 198: 615-621.
  80. Miteva DO, Rutkowski JM, Dixon JB, Kilarski W, Shields JD, et al. (2010) Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ Res 106: 920-931.
  81. Johnson LA, Jackson DG (2013) The chemokine CX3CL1 promotes trafficking of dendritic cells through inflamed lymphatics. J Cell Sci 126: 5259-5270.
  82. Kabashima K, Shiraishi N, Sugita K, Mori T, Onoue A, et al. (2007) CXCL12-CXCR4 engagement is required for migration of cutaneous dendritic cells. Am J Pathol 171: 1249-1257.
  83. Pegu A, Qin S, Fallert Junecko BA, Nisato RE, Pepper MS, et al. (2008) Human lymphatic endothelial cells express multiple functional TLRs. J Immunol 180: 3399-3405.
  84. Garrafa E, Imberti L, Tiberio G, Prandini A, Giulini SM, et al. (2011) Heterogeneous expression of toll-like receptors in lymphatic endothelial cells derived from different tissues. Immunol Cell Biol 89: 475-481.
  85. Geherin SA, Wilson RP, Jennrich S, Debes GF (2014) CXCR4 is dispensable for T cell egress from chronically inflamed skin via the afferent lymph. PLoS One 9: e95626.
  86. McKimmie CS, Singh MD, Hewit K, Lopez-Franco O, Le Brocq M, et al. (2013) An analysis of the function and expression of D6 on lymphatic endothelial cells. Blood 121: 3768-3777.
  87. Lee KM, McKimmie CS, Gilchrist DS, Pallas KJ, Nibbs RJ, et al. (2011) D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion. Blood 118: 6220-6229.
  88. Jamieson T, Cook DN, Nibbs RJ, Rot A, Nixon C, et al. (2005) The chemokine receptor D6 limits the inflammatory response in vivo. Nat Immunol 6: 403-411.
  89. Neusser MA, Kraus AK, Regele H, Cohen CD, Fehr T, et al. (2010) The chemokine receptor CXCR7 is expressed on lymphatic endothelial cells during renal allograft rejection. Kidney Int 77: 801-808.
  90. Ulvmar MH, Werth K, Braun A, Kelay P, Hub E, et al. (2014) The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes. Nat Immunol 15: 623-630.
  91. Heatley RV, Bolton PM, Hughes LE, Owen EW (1980) Mesenteric lymphatic obstruction in Crohn's disease. Digestion 20: 307-313.
  92. Kovi J, Duong HD, Hoang CT (1981) Ultrastructure of intestinal lymphatics in Crohn's disease. Am J Clin Pathol 76: 385-394.
  93. von der Weid PY, Rehal S, Ferraz JG (2011) Role of the lymphatic system in the pathogenesis of Crohn's disease. Curr Opin Gastroenterol 27: 335-341.
  94. Nykänen AI, Sandelin H, Krebs R, Keränen MA, Tuuminen R, et al. (2010) Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts. Circulation 121: 1413-1422.
  95. Bellingan GJ, Caldwell H, Howie SE, Dransfield I, Haslett C (1996) In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes. J Immunol 157: 2577-2585.
  96. Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8: 349-361.
  97. Lin S, Kim J, Lee MJ, Roche L, Yang NL, et al. (2012) Prospective transcriptomic pathway analysis of human lymphatic vascular insufficiency: identification and validation of a circulating biomarker panel. PLoS One 7: e52021.
  98. Huggenberger R, Detmar M (2011) The cutaneous vascular system in chronic skin inflammation. J Investig Dermatol Symp Proc 15: 24-32.
  99. Kajiya K, Hirakawa S, Detmar M (2006) Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol 169: 1496-1503.
  100. Proulx ST, Luciani P, Alitalo A, Mumprecht V, Christiansen AJ, et al. (2013) Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo. Angiogenesis 16: 525-540.
  101. Broggi A, Zanoni I, Granucci F (2013) Migratory conventional dendritic cells in the induction of peripheral T cell tolerance. J Leukoc Biol 94: 903-911.
  102. Källskog O, Kampf C, Andersson A, Carlsson PO, Hansell P, et al. (2006) Lymphatic vessels in pancreatic islets implanted under the renal capsule of rats. Am J Transplant 6: 680-686.
  103. Gerli R, Solito R, Weber E, Aglianó M (2000) Specific adhesion molecules bind anchoring filaments and endothelial cells in human skin initial lymphatics. Lymphology 33: 148-157.
  104. Trzewik J, Mallipattu SK, Artmann GM, Delano FA, Schmid-Schönbein GW (2001) Evidence for a second valve system in lymphatics: endothelial microvalves. FASEB J 15: 1711-1717.
  105. Lachance PA, Hazen A, Sevick-Muraca EM (2013) Lymphatic vascular response to acute inflammation. PLoS One 8: e76078.
  106. Aebischer D, Willrodt AH, Halin C (2014) Oxazolone-induced contact hypersensitivity reduces lymphatic drainage but enhances the induction of adaptive immunity. PLoS One 9: e99297.
  107. Benoit JN, Zawieja DC (1992) Effects of f-Met-Leu-Phe-induced inflammation on intestinal lymph flow and lymphatic pump behavior. Am J Physiol 262: G199-202.
  108. Nemoto K, Sato H, Tanuma K, Okamura T (2011) Mesenteric lymph flow in endotoxemic guinea pigs. Lymphat Res Biol 9: 129-134.
  109. Shi VY, Bao L, Chan LS (2012) Inflammation-driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b+ macrophage recruitment and VEGF-C up-regulation in the IL-4-transgenic mouse model. Microcirculation 19: 567-579.
  110. Giannotta M, Trani M, Dejana E (2013) VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Dev Cell 26: 441-454.
  111. Dunworth WP, Fritz-Six KL, Caron KM (2008) Adrenomedullin stabilizes the lymphatic endothelial barrier in vitro and in vivo. Peptides 29: 2243-2249.
  112. Breslin JW, Gaudreault N, Watson KD, Reynoso R, Yuan SY, et al. (2007) Vascular endothelial growth factor-C stimulates the lymphatic pump by a VEGF receptor-3-dependent mechanism. Am J Physiol Heart Circ Physiol 293: H709-718.
  113. Yuan SY, Wu MH, Ustinova EE, Guo M, Tinsley JH, et al. (2002) Myosin light chain phosphorylation in neutrophil-stimulated coronary microvascular leakage. Circ Res 90: 1214-1221.
  114. Chaitanya GV, Franks SE, Cromer W, Wells SR, Bienkowska M, et al. (2010) Differential cytokine responses in human and mouse lymphatic endothelial cells to cytokines in vitro. Lymphat Res Biol 8: 155-164.
  115. Cromer WE, Zawieja SD, Tharakan B, Childs EW, Newell MK, et al. (2014) The effects of inflammatory cytokines on lymphatic endothelial barrier function. Angiogenesis 17: 395-406.
  116. Breslin JW, Yuan SY, Wu MH (2007) VEGF-C alters barrier function of cultured lymphatic endothelial cells through a VEGFR-3-dependent mechanism. Lymphat Res Biol 5: 105-113.
  117. Rehal S, Blanckaert P, Roizes S, von der Weid PY (2009) Characterization of biosynthesis and modes of action of prostaglandin E2 and prostacyclin in guinea pig mesenteric lymphatic vessels. Br J Pharmacol 158: 1961-1970.
  118. Aldrich MB, Sevick-Muraca EM (2013) Cytokines are systemic effectors of lymphatic function in acute inflammation. Cytokine 64: 362-369.
  119. Davis MJ, Lane MM, Davis AM, Durtschi D, Zawieja DC, et al. (2008) Modulation of lymphatic muscle contractility by the neuropeptide substance P. Am J Physiol Heart Circ Physiol 295: H587-597.
  120. Plaku KJ, von der Weid PY (2006) Mast cell degranulation alters lymphatic contractile activity through action of histamine. Microcirculation 13: 219-227.
  121. Chatterjee V, Gashev AA (2012) Aging-associated shifts in functional status of mast cells located by adult and aged mesenteric lymphatic vessels. Am J Physiol Heart Circ Physiol 303: H693-702.
  122. Zhang Q, Lu Y, Proulx ST, Guo R, Yao Z, et al. (2007) Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res Ther 9: R118.
  123. Jayasena VK, Behe MJ (1991) Oligopurine.oligopyrimidine tracts do not have the same conformation as analogous polypurine.polypyrimidines. Biopolymers 31: 511-518.
  124. Hamrah P, Chen L, Cursiefen C, Zhang Q, Joyce NC, et al. (2004) Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) on monocytic bone marrow-derived cells in the conjunctiva. Exp Eye Res 79: 553-561.
  125. Zhang Y, Lu Y, Ma L, Cao X, Xiao J, et al. (2014) Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-κB signaling and protects against endotoxin shock. Immunity 40: 501-514.
  126. Choi I, Lee S, Kyoung Chung H, Suk Lee Y, Eui Kim K, et al. (2012) 9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema. Circulation 125: 872-882.
  127. Iolyeva M, Aebischer D, Proulx ST, Willrodt AH, Ecoiffier T, et al. (2013) Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage. Blood 122: 2271-2281.
  128. Hara M, Chosa E, Onitsuka T (2008) The spleen's role in transplantation immunology. Transpl Immunol 18: 324-329.
  129. Sevick-Muraca EM, Kwon S, Rasmussen JC (2014) Emerging lymphatic imaging technologies for mouse and man. J Clin Invest 124: 905-914.
Citation: Vranova M, Halin C (2014) Lymphatic Vessels in Inflammation. J Clin Cell Immunol 5:250.

Copyright: © 2014 Vranova M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Top globaltechsummit