Angiogenesis DOI 10.1007/s10456-014-9419-4

ORIGINAL PAPER

Inflammatory lymphangiogenesis: cellular mediators and functional implications Kar Wai Tan • Shu Zhen Chong • Ve´ronique Angeli

Received: 29 June 2013 / Accepted: 15 January 2014 Ó Springer Science+Business Media Dordrecht 2014

Abstract In adult mammals, lymphatic vessels have been shown to respond to their environment by undergoing lymphangiogenesis, the formation of new lymphatic vessels from preexisting ones. Accumulating experimental and preclinical studies demonstrate that lymphangiogenesis is associated with many inflammatory diseases and may represent an attractive therapeutic target for inflammatory diseases. Thus, a better understanding of how lymphangiogenesis is regulated and contribution to inflammation is critical and may benefit clinical research targeting chronic inflammatory diseases. This review discusses the biological functions of lymphangiogenesis during inflammation and our current understanding of the key cellular players that can either support or limit lymphangiogenesis. Current data suggest that the context and time frame in which lymphangiogenesis occurs will determine its impact on the course of inflammation. Keywords Inflammation
Lymphangiogenesis
Lymph node
Neutrophils
Macrophages
Fibroblastic reticular cells
Lymphocytes
Cell trafficking

K. W. Tan
S. Z. Chong Singapore Immunology Network, BMSI, A-STAR, Singapore, Singapore V. Angeli (&) Immunology Programme, Department of Microbiology, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore, #03-05, 28 Medical Drive, Singapore 117456, Singapore e-mail: [email protected]

Introduction Lymphatic vessels are present in nearly all vascularized tissues and are conventionally considered as ‘‘inert conduits’’ primarily involved in the transport of interstitial fluid from peripheral tissues. Recent advances in lymphatic vessel biology research have revealed that lymphatic vessels are plastic structures that actively sense and respond to the tissue environment [1]. Notably, evidence suggests that the structure and function of lymphatic vessels in adult mammals may be modulated by inflammation induced by harmful external or internal stimuli including pathogens, damaged cells and irritants [2]. Moreover, lymphangiogenesis, the formation of new lymphatic vessels from preexisting ones, has been shown to occur in experimental and clinical inflammatory diseases including renal [3, 4] and corneal transplant rejection [5–7], inflammatory bowel disease [8–11], rheumatoid arthritis [12–14], chronic airway inflammation [15, 16], atopic dermatitis and psoriasis [17–19]. However, the important question of whether lymphangiogenesis is really a component of the pathology or a productive attempt to resolve the inflammation remains a matter of debate. Because a major function of lymphatic vessels is to drain excess fluid from peripheral tissues in the form of lymph, lymphangiogenesis with the accompanying increase in lymph efflux may be a reciprocal response to injury. In addition, it is apparent from recent literature that the function of lymphatic vessels is not only restricted to fluid balance homeostasis but also extends to regulation of immune cell trafficking, antigen presentation, tolerance and immunity, all which may impact the progression of the inflammatory response. Thus, lymphangiogenesis is expected to have diverse functional consequences on inflammation depending on the context and time frame of its occurrence.

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In this review, we will focus on lymphangiogenesis occurring during acute or chronic inflammation and the current knowledge of major cellular players which contribute to lymphangiogenesis as the molecular signals regulating this process have been reviewed earlier [2, 20]. We will also discuss how lymphangiogenesis may potentially influence the course and outcome of inflammation. Understanding lymphangiogenesis and its biological functions during inflammation is imperative because it accompanies many inflammatory diseases and may represent an important target for therapeutic intervention.

Cellular mediators of inflammatory lymphangiogenesis Immune cells Both non-immune and immune cells have been described to orchestrate lymphangiogenesis in inflamed peripheral sites and the draining lymph nodes (LNs). The most compelling data for a role in lymphangiogenesis exist for macrophages. Seminal studies employing various

Fig. 1 Attenuating neutrophil accumulation inhibits lymphangiogenesis in a murine model of chronic contact hypersensitivity (CHS). a Neutrophil accumulation was attenuated by treatment of mice with NIMP-R14, a neutrophil-specific depleting antibody. Lymphatic vessels in sensitized ears from NIMP-R14-treated mice was decreased compared to control rat IgG-treated mice. b Chimeric mice were

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approaches to deplete macrophages such as liposomal clodronate, anti-macrophage colony-stimulating factor receptor (MCSF-R) antibody, MCSF-R tyrosine kinase inhibitors and M-CSF-/- (op/op) mice have demonstrated that macrophages are indispensable in driving lymphangiogenesis in inflamed peripheral tissues [15, 16, 21–27] and draining LNs [22]. Although dendritic cells (DCs) have been associated with lymphangiogenesis in some models of inflammation [16, 28–30], direct evidence that DCs can drive lymphangiogenesis is lacking. Our group [31] and others [32, 33] have shown that B cells are critical for early lymphangiogenesis in the draining LNs after immunization and skin sensitization. However, we found that the role of B cells in driving LN lymphangiogenesis can be compensated at later phases of the inflammation by, unexpectedly, neutrophils [34]. In a chronic skin inflammation model induced by contact sensitization, neutrophils recruited into the inflamed skin also contributed to lymphangiogenesis (Fig. 1a, b). We have evidence that neutrophils support the expansion of lymphatic vessels by modulating vascular endothelial growth factor (VEGF)-A bioavailability and by secreting VEGF-D

generated by reconstituting irradiated CD45.1 mice with CXCR2-/(CXCR2-/- ? CD45.1) or CD45.2 (CD45.2 ? CD45.1) bone marrow. Neutrophil recruitment into ears following acute CHS was attenuated in CXCR2-/- ? CD45.1 mice, and this reduced lymphangiogenesis compared to CD45.2 ? CD45.1 mice

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[34], the latter observation being consistent with previous observations in murine chronic airway inflammation [16]. T cells have been reported to induce de novo lymphangiogenesis when recruited into murine thyroids overexpressing CCL21 [35]. In contrast, they have been shown to counter-regulate lymphangiogenesis in LNs during inflammation through interferon-c secretion [36]. Different subsets of T cells may be recruited into secondary [36] and tertiary [35] lymphoid organs during inflammation and may account for these contrasting roles of T lymphocytes in lymphangiogenesis. Non-immune cells Epithelial cells have been implicated, though not directly demonstrated, in driving lymphangiogenesis during inflammation [15, 16, 37] and infection [15, 16]. However, in a study employing VEGF-A reporter transgenic mice, Wuest and colleagues first identified herpes simplex virusinfected epithelial cells as the primary source of VEGF-A that induced corneal lymphangiogenesis [38]. It has also been suggested in a model of delayed-type hypersensitivity that activated epidermal keratinocytes were probably the primary source of VEGF-A that led to LN and skin lymphangiogenesis [37]. LN stromal cells like fibroblastic reticular cells (FRCs), which surround the collagen extracellular matrix scaffolding within LNs, have been shown to produce VEGF-A during inflammation to support LN angiogenesis [39]. Our study revealed that FRCs that lie in close proximity to the lymphatic endothelial cells (LECs) (Fig. 2a) can also produce VEGF-A (Fig. 2b, c) or deliver VEGF-A from inflamed extranodal sites to support lymphangiogenesis [40].

Biological functions of lymphatic vessels Balance fluid homeostasis A critical function of lymphatic vessels is to return excess interstitial fluid back to the circulation. Interstitial fluid is first collected by initial (or capillary) lymphatic vessels which are identified by the expression of podoplanin and lymphatic vessel hyaluronan receptor 1 (LYVE-1) and the absence of smooth muscle cells. This fluid is then transported in the form of lymph to larger lymphatic vessels, the collecting vessels. Collecting vessels also express podoplanin but down-regulate LYVE-1 expression and exhibit circumferential smooth muscle cell coverage and luminal valves that propel and maintain unidirectional flow. The biological contribution of lymphatic vessels to the control of tissue fluid balance is well illustrated in patients suffering from lymphedema. These patients typically present

with local edema which results from retention of protein and associated water in the surrounding interstitium. Lymphedema is a consequence of impaired lymph transport which arise either from abnormal lymphatic vessel development (primary lymphedema) or damage to the lymphatic vessels (secondary lymphedema). In addition to inducing chronic and disabling swelling, lymphedema is generally associated with an increased infiltration of leukocytes including neutrophils, macrophages and DCs. It is possible that cytokines and chemokines that are usually cleared from the intersititum by lymphatic vessels now remain in the tissue where they promote leukocyte recruitment and perpetuate an ongoing inflammatory response. Support immune cell trafficking and antigen delivery Lymph fluid is also rich in antigens and immune cells including DCs and T lymphocytes that are drained from surrounding tissues or constitutively present in lymphatic vessels. Antigens, DCs and T lymphocytes are transported by afferent lymphatic vessels to the draining LNs. Within the LN, LECs are mainly found in the subcapsular, cortical and medulla sinuses [40, 41]. DCs are guided to enter lymphatics by haptotactic gradients of chemokine (C–C motif) ligand 21 (CCL21) on the lymphatic endothelium [42]. Under resting conditions, preformed portals in afferent lymphatic vessels allow DCs to intravasate lymphatic vessels without any requirement for integrins [43, 44]. However, it was shown recently that DC migration into lymphatic vessels and the T-cell zone of the LN is dependent on CLEC-2 binding to podoplanin expressed on lymphatic vasculature in peripheral tissue and LNs and on FRCs [45]. Other potential adhesion molecules that may mediate leukocyte transmigration into afferent lymphatic vessels during steady state include the scavenger receptor CLEVER-1 [46]. During steady state, afferent lymphatic vessels also allow naı¨ve [47], effector and memory [48–51] T lymphocytes guided by CCR7 and CCL19/CCL21 directional cues, to migrate from peripheral tissues into draining LNs. During inflammation, expansion of the lymphatic vessel network within the inflamed peripheral site allows lymphcontaining activated DCs, inflammatory cytokines or antigens to arrive in draining LNs to prime an immunological response. Inflammation also induces the lymphatic endothelium to up-regulate expression of CCL21 [52, 53] and integrins such as intercellular adhesion molecule-1 (ICAM1), vascular adhesion molecule-1 (VCAM-1) and E-selectin [54]. CCR7–CCL21 interactions have been shown to be important for facilitating the entry of DCs [52–54] and T lymphocytes [48, 50] into afferent lymphatic vessels during

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Fig. 2 FRCs support LN lymphangiogenesis during inflammation a LN sections from footpad-immunized mice were immunostained for LYVE-1 and ER-TR7. ER-TR7 is a marker for the extracellular matrix fibers ensheathed by FRCs, both of which make up the 3-dimensional conduits within lymph nodes. Confocal microscopic images (i) were processed for volume-rendering analysis (ii), Scale bar represents 50lm. b LNs from footpad-immunized mice were immunostained for VEGF-A and ER-TR7. Orthogonal plane view of

how VEGF-A is aligned on the ER-TR7? reticular fibers lining cortical sinuses. Enlarged image of confocal image stack of boxed region is shown (right panel). VEGF-A can be found on the surface and interior of ER-TR7? reticular fibers. c Intracellular expression of VEGF-A by CD45-CD31- gp38? FRCs was evaluated by flow cytometry in LNs from control and immunized mice postimmunization

inflammation. Migration of DCs into afferent inflamed lymphatic vessels is also dependent on ICAM-1 and VCAM-1 interactions [54]. Interestingly, expression of inflammatory chemokines in LECs may be modulated in a

stimulus-dependent manner in vivo [55], underpinning that LECs possess a complex control mechanism to coordinate immune cell entry during inflammation. In further support of this, D6, a decoy receptor expressed in LECs, scavenges

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inflammatory chemokines and restricts interactions between inflammatory leukocytes and lymphatic surfaces. This prevents lymphatic congestion resulting from excessive accumulation of inflammatory leukocytes [56] and also allows LECs to discriminate between mature and immature DCs [57]. Inflammation has been shown to induce lymphangiogenesis in the activated LN [31, 40]. In our study, skin immunization with complete Freund’s adjuvant induced the expansion of subcapsular sinuses early during inflammation (days 2–4) and of cortical and medullary sinuses later during prolonged inflammation (day 14). Notably, the expansion of subcapsular sinuses promoted a robust DC migration from both proximal inflamed and distal non-inflamed sites into draining LNs [31], whereas expansion of cortical and medulla sinuses supported the egress of lymphocytes from LNs [40]. It is well established that T-cell egress from LNs via cortical and medullary sinuses is dependent on signals generated by lymph-borne sphingosine-1-phosphate (S1P) [58–60] produced by LECs [61]. Therefore, expansion of cortical and medulla sinuses during inflammation may promote lymphocyte egress by providing more physical exits as well as S1P signals. Because lymphatics coordinate immune cell trafficking through the draining LN during inflammation, lymphangiogenesis can influence the immune response by supporting more encounters between antigen-presenting cells and rare antigen-specific T lymphocytes as well as the recirculation of lymphocytes. Maintain immune tolerance CD8? T-cell peripheral tolerance has been shown to be induced by LN stromal cells that directly express otherwise tissue-restricted proteins [62–64]. Recently, LN LECs have been revealed to express and present multiple peripheral tissue antigens which induced PD-1-mediated deletion of antigen-specific CD8? T cells [65, 66]. These data establish that LECs like FRCs [67] are integral for the maintenance of peripheral immune tolerance. In addition to maintaining peripheral tolerance during homeostatic conditions, LN LECs have been demonstrated to use a tightly regulated NOS2-dependent mechanism to suppress CD8? T-cell proliferation during inflammation [68–70]. In the absence of pathogen-derived signals, MAC1: ICAM-1, contact of DCs with inflamed lymphatic endothelium has also been shown to reduce CD86 expression on DCs and suppressed their ability to induce T-cell proliferation [71]. These studies provide evidence that LN LECs are involved in dampening T-cell proliferation during inflammation to avert exacerbated immunological responses.

Lymphangiogenesis: good or bad for inflammation? Lymphangiogenesis has been observed to occur in chronic inflammatory diseases, such as psoriasis [17, 72], atopic dermatitis [73], chronic airway inflammation [15, 16], inflammatory bowel and renal diseases [8–11] and rheumatoid arthritis [12–14]. Furthermore, lymphangiogenesis has been frequently associated with transplant rejection of kidney [3, 4] or cornea [5–7]. Studies in murine corneal transplantation utilizing various strategies to block both angiogenesis and lymphangiogenesis [5, 74, 75] or selectively lymphangiogenesis [7, 76] improved graft survival. This was largely attributed to the inhibition of lymphangiogenesis [76]. Conversely, inhibition of lymphangiogenesis has been described to aggravate mucosal edema in a mouse model of chronic airway inflammation [16], suggesting the possible contribution of lymphangiogenesis to resolving inflammation. Consistent with this concept, recent preclinical studies in models of inflammatory skin diseases [22, 77–79] and rheumatoid arthritis [80–82] convincingly demonstrated that strategies to promote lymphangiogenesis at the inflamed sites may be effective modalities to resolve inflammation. Such contrasting effects of lymphangiogenesis on inflammation may be reconciled if the site and the time frame in which lymphangiogenesis occurs are considered. Corneal allografts are widely considered to be ‘‘immuneprivileged’’ sites, and this unique status is in part maintained by the absence of blood and lymphatic vessels in the noninflamed cornea. This lack of blood and lymphatic vessels restricts immune cells trafficking to the regional LNs and LN access to corneal antigens. Inflammation following surgery induces angiogenesis and lymphangiogenesis in the corneal allograft, and both processes particularly lymphangiogenesis may disrupt the immune privilege status of the cornea. Conversely, the expansion of lymphatic vessel network in other inflamed sites such as skin, lung and joints may support removal of accumulated fluid, immune cells and inflammatory mediators from the tissues and accelerate resolution of inflammation. For a given site, lymphangiogenesis may also have different functional consequences depending on the time frame in which it occurs during inflammation. Early during inflammation, lymphangiogenesis may constitute a positive response to injury by increasing lymph efflux and hence drainage of inflammatory mediators and immune cells from inflamed tissues into LNs. However, the persistence of such lymphatic vessels, by supporting the transport of antigens and leukocytes, can sustain immune activation and this may result in the formation of tertiary lymphoid organs that have been reported in various chronic inflammatory diseases [83, 84]. Overall, these data highlight the need for more studies to clarify the biological role of inflammatory lymphangiogenesis

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in order to justify it as a possible therapeutic target in chronic inflammatory disorders.

Conclusions and Perspectives Lymphangiogenesis is a dynamic process driven by growth factors secreted by non-immune and immune cells present

Fig. 3 Cellular mediators of lymphangiogenesis during inflammation and its resolution. During resting state, initial lymphatics innervate the periphery and these converge to form the collecting and afferent lymphatics. During inflammation, leukocytes including neutrophils and monocyte-derived cells are recruited into the inflamed site. Some monocytes may differentiate into macrophages. Macrophages (tissue resident and monocyte derived), neutrophils and DCs may drive inflammatory lymphangiogenesis in the inflamed periphery via the secretion of VEGFs. In addition, epidermal cells and keratinocytes can also drive inflammatory lymphangiogenesis through the secretion

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in the inflamed site (Fig. 3). Because of the diverse biological functions of lymphatic vessels, lymphangiogenesis has pleiotropic effects on the course and outcome of the inflammation. Indeed, recent experimental and preclinical studies in small animals provide evidence that depending on the inflammatory disorder, manipulating lymphatic drainage by either promoting or blocking the growth of lymphatic vessels can modulate inflammation.

of VEGF-A. Lymphangiogenesis in the draining LNs may be driven by VEGF-A produced locally in the LN by B cells, DCs and/or FRCs. Extranodal VEGFs that are produced at the inflamed tissues and subsequently transported into the draining LNs may also induce the expansion of subcasular, cortical and medullary sinus expansion in a time-dependent manner. As the inflammation resolves, T cells negatively regulate LN lymphangiogenesis through the secretion of IFN-c supporting the regression of lymphatic vessel network in the LN

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It is noteworthy that in contrast to blood vessels that rapidly regress after the resolution of inflammation, new lymphatic vessels once formed can persist [15, 16, 40]. The significance of this lymphatic vessel persistence is unclear; it may reflect measures to prepare the immune system for subsequent episodes of insult or for lymphatic vessels to serve as ‘‘immunological brakes’’ to dampen subsequent immune responses. The specific mechanisms protecting lymphatic vessels from regression are still unknown. As there is currently no clinically approved treatment to specifically manipulate lymphatic vessel for inflammatory disorders, future research on lymphatic vessel biology should focus on the signals and factors that drive or limit lymphangiogenesis. Since angiogenesis typically accompanies lymphangiogenesis and may sustain inflammation by supporting leukocyte recruitment, the use of antiangiogenic together with anti- or pro-lymphangiogenic therapies should be considered. Research on novel targets that specifically manipulate angiogenesis versus lymphangiogenesis should be encouraged. Finally, most of the studies revealing an association between lymphangiogenesis and inflammatory diseases are based on assessment of lymphatic vessel number, size or density on tissue sections and fail to provide data on the functionality of these newly formed lymphatic vessels. Therefore, development of new tools to assess lymphatic function, particularly in humans, is necessary to elucidate the role of lymphatic vessels in chronic inflammatory disorders and to evaluate the efficacy of prospective pro- or anti-lymphangiogenic therapies. Acknowledgments This work was supported by Biomedical Research Council, National Medical Research Council and National Research Foundation. Conflict of interest

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The authors declare no conflict of interest

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