Ocansey et al. J Transl Med (2021) 19:254 https://doi.org/10.1186/s12967-021-02922-2 Journal of Translational Medicine

REVIEW Open Access Cellular and molecular mediators of lymphangiogenesis in infammatory bowel disease Dickson Kof Wiredu Ocansey1,2†, Bing Pei3†, Xinwei Xu1, Lu Zhang1, Chinasa Valerie Olovo1,4 and Fei Mao1*

Abstract Background: Recent studies reporting the intricate crosstalk between cellular and molecular mediators and the lymphatic endothelium in the development of infammatory bowel diseases (IBD) suggest altered infammatory cell drainage and lymphatic vasculature, implicating the lymphatic system as a player in the occurrence, development, and recurrence of intestinal diseases. This article aims to review recent data on the modulatory functions of cellular and molecular components of the IBD microenvironment on the lymphatic system, particularly lymphangiogenesis. It serves as a promising therapeutic target for IBD management and treatment. The interaction with gut microbiota is also explored. Main text: Evidence shows that cells of the innate and adaptive immune system and certain non-immune cells participate in the complex processes of infammatory-induced lymphangiogenesis through the secretion of a wide spectrum of molecular factors, which vary greatly among the various cells. Lymphangiogenesis enhances lymphatic fuid drainage, hence reduced infltration of immunomodulatory cells and associated-infammatory cytokines. Interestingly, some of the cellular mediators, including mast cells, neutrophils, basophils, monocytes, and lymphatic endothelial cells (LECs), are a source of lymphangiogenic molecules, and a target as they express specifc receptors for lymphangiogenic factors. Conclusion: The efective target of lymphangiogenesis is expected to provide novel therapeutic interventions for intestinal infammatory conditions, including IBD, through both immune and non-immune cells and based on cellular and molecular mechanisms of lymphangiogenesis that facilitate infammation resolution. Keywords: Infammatory bowel disease, Lymphangiogenesis, Lymphatic system, Immune cells, Molecular pathways, Gut microbiota

Background afects predisposed individuals. CD is an intestinal trans- IBD, including Crohn’s disease (CD) and ulcerative coli- mural infammatory disease in which reactive changes are tis (UC), is characterized by a dysregulated immune observed in mesenteric lymph nodes. Evidence suggests response to normal gut microbial antigens and genetically that reactive lymphadenopathy is a recognized cardinal sign of CD [1]. It was suggested in early 1946 that a CD is

*Correspondence: [email protected] more common in the intestinal tract where lymphatic fol- †DicksonKofWiredu Ocansey and Bing Pei have contributed equally to licles are concentrated. Te evidence of lymphatic altera- this work tion being an important factor in the pathogenesis of IBD 1 Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, is stronger in CD than UC. A growing body of evidence Zhenjiang 212013, Jiangsu, People’s Republic of China suggests that IBD is often accompanied by intestinal lym- Full list of author information is available at the end of the article phatic aberrations, infammatory lymphatic proliferation,

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat​ iveco​ ​ mmons.org/​ licen​ ses/​ by/4.​ 0/​ . The Creative Commons Public Domain Dedication waiver (http://creat​ iveco​ mmons.​ org/​ publi​ cdoma​ in/​ ​ zero/1.0/​ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ocansey et al. J Transl Med (2021) 19:254 Page 2 of 16

and lymphangiogenesis [2, 3]. However, whether lym- the lymphatic system via upregulating or downregulat- phangiogenesis represents a component of the pathology ing lymphangiogenesis. Adequate exploration of these or a salutary attempt to resolve the infammation is still cellular and molecule mediators is necessary to provide an open question. Several scholars have indicated that treatment targets for IBD. Tis paper examines available lymphangiogenesis facilitates clearance of infammatory literature on the contribution of cellular mediators and cells, cytokines, and antigens from the infamed site and molecular pathways associated with lymphangiogenesis promotes resolution of infammation [4, 5]. Terefore, it in IBD and the interaction with gut microbiota, as these is enticing to agree to these fndings that lymphangiogen- mediators serve as novel therapeutic targets in IBD man- esis plays a key role in the modulation of infammation in agement and treatment. IBD. Lymph vessel density increases in the intestinal mucosa Cellular mediators of lymphangiogenesis in IBD of patients with IBD. Studies reporting abnormalities Te lymphatic system helps maintain tissue homeosta- such as lymphangitis, immune cell trafcking, and lym- sis, including tissue fuid balance, interstitial protein phangiogenesis in IBD patients suggest impaired lym- transport, and the development of cellular immunity. It phatic drainage and lymphatic pumping, implicating the contains a large number of cells such as macrophages, lymphatic system as a noticeable player in IBD pathogen- lymphocytes, and antigen-presenting cells that together esis [6, 7]. It is noteworthy that local tissue infammation trigger a primary immune response, in addition to spe- leads to a transient and profound remodeling of draining cialized LECs in the cortex that contribute to the pri- lymph nodes (DLNs), with volume dilation, lymphoid mary immune response via recruiting intravascular hyperplasia, and a marked increase in lymphatic vessel lymphocytes. In IBD-associated lymphatic changes, there density in IBD [8, 9]. Te increase in lymphatics may be is mixed infammatory cell response with signifcant an adaptation against tissue edema and accumulation of increases in T-helper (T), T-regulatory (Treg), neutro- immune cells. A study that revealed the clinical moni- phils, macrophages, and dendritic cells (DCs), among toring signifcance of lymphatic vessel density in IBD other immune cell populations. Tese cellular compo- suggested that decreased lymphatic vessel density is asso- nents directly or indirectly participate in regulating lym- ciated with postoperative endoscopic recurrence in CD phangiogenesis in the infammatory environment [17]. [10]. Compared with blood vessels that regress rapidly after the resolution of infammation, the new lymphatic Lymphatic endothelial cells vessels can persist once formed [11]. Baluk and col- In the mammalian embryo, lymphatic endothelial pro- leagues report that despite the decreased leukocyte fow genitors bud from the cardinal vein and intersomitic ves- and the diminished stimulation of lymphangiogenesis sels [18] with their identity and number maintained by following the amelioration of infammation, lymphatic the Prospero homeobox 1 (Prox1)-vascular endothelial vessels formed during infection persist, ready for the next growth factor receptor 3 (VEGFR3) feedback loop [19]. infection [12]. Te signifcance of this lymphatic vessel LEC progenitors produce Prox1, an important transcrip- persistence is unclear; it may refect measures to prepare tional factor for diferentiation of LECs, in the cardinal the immune system for subsequent events of insult or for vein of embryonic day (E) 10–11.5 mice. LEC progeni- lymphatic vessels to serve as immunological brakes to tors accumulate to form pre-lymphatic clusters which suppress subsequent immune responses [13]. Te specifc sudsequently exit the cardinal vein wall to constitute mechanisms protecting lymphatic vessels from regres- superfcial lymphatic vessels and lymph sacs [18, 20]. sion remain to be elucidated. Again, persistent lymphatic Te VEGF-C induces the sprouting from the lymph sac vessels’ main mediators and functions post recovery from through its receptor VEGFR, triggering receptor modu- intestinal infammation or antibiotic treatment are yet to lators such as β1 integrin and Ephrin B2 Neuropilin 2, be defned. to produce the lymphatic vascular network. A primary While an increase in the other forms of lymphatic lymphatic network undergoes remodeling to become a alterations, including lymphadenopathy, lymphangiec- mature lymphatic network composing of initial lymphatic tasia, lymphangitis, and lymphatic vascular occlusion, vessels, collecting vessels, and pre-collectors [21–23]. denotes poor prognosis, an increase in lymphangiogen- LEC-specifc ADP ribosylation factor 6 (Arf6) [21] and esis indicates a good prognosis. Studies have therefore Pannexin-1 [24] also play pivotal roles in the formation focused on investigating the factors that modulate lym- of lymphatic vessel networks and the regulation of lym- phagiogenesis as a means to understanding the patho- phangiogenesis. It is reported that knockdown of Arf6 genesis of IBD and exploring therapeutic targets [14–16]. in human LECs prevents in vitro directed cell migration Within the IBD microenvironment, several cells and and capillary tube formation triggered by VEGF-C via molecules directly or indirectly infuence and modulate the inhibition of VEGF-C-induced internalization of β1 Ocansey et al. J Transl Med (2021) 19:254 Page 3 of 16

integrin [21]. Moreover, the loss of LEC-specifc CPT1A in CD11b+ macrophages from the draining lymph (carnitine palmitoyltransferase 1A), a rate-controlling nodes [DLNs]) enhance the formation of new lym- enzyme in fatty acid β-oxidation, inhibits lymphatic phatic vessels, which act to reinforce the recruitment development. LECs employ fatty acid β-oxidation to of macrophages. Prolymphangiogenic growth factors facilitate their proliferation and epigenetic modulation secreted by infltrating macrophages in infamed tissue of lymphatic markers expression during LEC diferentia- and DLNs appear to be critical in lymph fow, antigen tion. In this process, the transcription factor Prox1 trig- clearance, and mobilization of infammatory cells from gers increased CPT1A expression, which upregulates the infamed tissue to the DLNs through enhancement of production of acetyl coenzyme A, dependent on fatty lymphangiogenesis and lymphatic vessel expansion [35, acid β-oxidation. Te expressed acetyl coenzyme A is 36]. Te recruitment of monocyte/macrophages and utilized by the histone acetyltransferase p300 to acetylate neutrophils via interleukin (IL)-1β in an infammatory histones at lymphangiogenic genes, thus promoting lym- model induced lymphangiogenesis and up-regulated phangiogenesis [25, 26]. VEGF-C, VEGF-A, and VEGF-D. Conversely, the deple- Except for the central nervous system, bone marrow, tion of macrophages inhibited lymphangiogenesis and and avascular tissues such as the cornea and epidermis, its associated factors [37]. Moreover, Zampell and col- lymphatic capillaries are found in the skin and most leagues demonstrated that CD4+ cells (macrophages, internal organs [8]. In the resting state, LECs are nor- monocytes, T cells, and DCs) regulate lymphangi- mally quiescent [27]. In the course of infammatory or ogenesis during infammatory lymphangiogenesis and malignant lesions, LECs can undergo proliferation or wound repair in response to lymphatic fuid stasis [17]. lymphangiogenesis under the stimulation of infamma- Te notion that lymphangiogenesis occurs mainly tory or physicochemical factors. Adhesive interactions through paracrine action by a large number of infltrat- such as leukocyte rolling, adherence, and transendothe- ing macrophages has been demonstrated, during which lial migration regulated by various integrins, chemokines, the role of toll-like receptor 4 (TLR4) in LECs sup- and adhesion molecules between leukocyte and LECs are ported the crucial role of macrophages in lymphangi- recognized to represent an early and rate-limiting step in ogenesis via the lipopolysaccharide (LPS)-induced the leukocyte infltration. It is often accompanied by neo- peritoneal infammation model [38, 39]. It is reported plastic tissue lesions associated with acute and chronic that the inhibition of lymphangiogenesis is related to infammatory diseases of the intestinal tract, ultimately reduced lymphatic drainage and decreased infamma- resulting in a net up-regulation or down-regulation of tory cell mobilization from the infamed tissue to the the infammatory response [28, 29]. However, extensive DLNs in 2 diferent animal models of experimental IBD lymphangiogenesis, a sequence of processes including [5]. Moreover, macrophage mobilization plays an indis- sprouting, migration, proliferation, and tubule forma- pensable role in antigen clearance from the infamed tion by preexisting LECs, induced by leukocyte includ- colon to the DLNs described in the same study [5]. Te ing macrophages, DCs, and neutrophils which generate critical role of macrophages/monocytes in intestinal diverse VEGF in response to the stimulus may play an infammation-associated lymphangiogenesis is further important role in draining infammatory macromol- confrmed by Becker and colleagues. Tey proposed a ecules, immune cells, and debris from infamed tissues dual role of the macrophage in promoting acute infam- [30, 31]. mation and contributing to infammation-associated lymphangiogenesis [40]. It is possible to speculate that Macrophages macrophage-mediated lymphangiogenesis in IBD may During infammation, macrophages are actively represent an attempt to compensate for the impaired involved in inducing lymphangiogenesis [5, 13, 32, 33]. lymphatic drainage to maintain a clearance of inter- Meanwhile, LECs express chemotactic molecules that stitial fuid and infammatory infltrate, thus restoring promote macrophage infltration. Te macrophages, gut homeostasis. Te observation that IL-10 suppresses in turn, secrete paracrine prolymphangiogenic growth VEGF from bone marrow-derived M1 macrophages but factors such as VEGF-C, VEGF-D, and VEGF-A in not VEGF production from M2 macrophages, and that response to infammatory stimuli. One hypothesis has activation signals determine the infuence of IL-10 on been proposed that lymphangiogenic macrophages VEGF production, further supports the idea that mac- can become incorporated into the lymphatic vessels rophages can adapt to their environment and respond and transdiferentiate into LECs, but it still requires with a coordinated set of signals to promote or resolve more validation [34]. Increased levels of prolym- infammation [41]. However, the role of macrophage phangiogenic growth factors (particularly enriched polarization in lymphangiogenesis during the develop- ment of IBD remains to be explored. Ocansey et al. J Transl Med (2021) 19:254 Page 4 of 16

Neutrophils Dendritic cells Neutrophils are mostly considered pro-infammatory Based on phenotype, function, and development crite- cells since their involvement in infamed sites in IBD, ria, DCs are categorized into two main groups: plasma- rheumatoid arthritis, and psoriasis correlates with the cytoid DCs (pDCs) and conventional or classical DCs degree of tissue damage [42]. Available studies show (cDCs). Te cDC produces VEGF-C via stimulation by that neutrophils contribute to regulating lymphangi- IFN-γ from activated natural killer (NK) cells, when co- ogenesis in the infamed environment. Neutrophils cultured with them. In turn, VEGF-C downregulates primarily regulate lymphangiogenesis by modulating the expresion of interferon (IFN)-γ by NK cells. VEGF- VEGF-A bioactivity and bioavailability, and to a lesser C also encourages immune tolerance by enhancing the extent, expressing VEGF-D [43]. In the infammat- cross-presentation of self-proteins by MHC (major pry-associated lymphangiogenic process, it is easy to histocompatibility complex) class I in LECs. Tus, NK assume that neutrophils cooperate with macrophages, cell-dependent VEGF-C secretion might be part of a considering the integral role played by macrophages in modulatory network involving DCs, NK cells, and LECs infammation. Moreover, the same study documented to maintain the needed balance between peripheral that in the absence of B cells, intranodal lymphangi- immune tolerance and infammation [48, 49]. It is easier ogenesis triggered in prolonged infammation due to to speculate that cDCs contribute to lymphangiogenesis immunization, is associated with neutrophil accumula- in secondary lymph nodes both indirectly and directly by tion, and that heparanase and matrix metalloprotein- secreting VEGF-C. In IBD, up-regulation of chemokines ase 9 (MMP-9) obtained from neutrophils cooperate to expressed by infamed LECs and elevated interstitial fuid upregulate VEGF-A bioactivity and bioavailability and pressure may increase leukocyte fux from the intesti- in turn, infammatory lymphangiogenesis [43]. How- nal mucosa into lymphatic vessels. Te importance of ever, this study was based on a model of skin infamma- this fow-induced mechanism is afrmed by studies that tion, which is yet to be confrmed in gut infammation. reported that chemokine (C–C motif) ligand 21 (CCL21) At the early stage of pregnancy and corpus luteum is barely produceed in the mouse tail lymphedema model, development in mammals, the major angiogenic fac- in which lymphatic fow was surgically blocked [50, 51]. tors, VEGF and fbroblast growth factor 2 (FGF2) con- In their study, Pficke and Sixt indicated that immigra- tribute to the development of the corpus luteum. Tey tion heavily relies on a C–C chemokine receptor type 7 may also act as a chemoattractant for polymorphonu- (CCR7)-dependent mechanism, as CCR7-defcient DCs clear neutrophils. Evidence indicates that these neutro- neither approached nor entered lymphatic vessels [52]. phils are highest in the new corpus luteum where they Tese observations suggest that CCL21 interaction with interact with IL-8 to actively induce lymphangiogenesis immune cells expressing its receptor, CCR7, provides the and angiogenesis [44]. chemotactic gradient necessary to recruit leukocytes into Impaired intestinal lymphatic drainage function in a lymph nodes, especially for DCs. mice model of experimental colitis, associated with ele- Regardless of DCs being linked with lymphangiogene- vated colonic neutrophil, macrophage, and T cell infl- sis in some experimental models of IBD, more direct evi- tration triggers lymphangiogenesis in addition to other dence that they promote lymphangiogenesis is minimal. functional (greater submucosal edema, higher immune A study found that lymphadenopathy and lymphangi- cell burden) and structural (dilated tortuous lymphatic ogenesis were still evident after intestinal infammation vessels) alterations in the intestinal lymphatic vascula- recovery, and correlated with higher numbers of DCs in ture [45]. It is reported that although Ang-2−/− mice lymphatic and mucosal tissues [2]. Te functional and show the benefcial efect of reduced neutrophil infl- morphological changes in the lymphatics could compro- tration and infammatory angiogenesis in IBD, there mise DCs’ migration and function, potentially enhancing is also blocked lymphatic maturation and expansion, susceptibility to further intestinal disease and the recur- resulting in dysregulated lymphatic function, which is rence of intestinal infammation. Te induction of DCs detrimental in IBD. Te inhibited lymphangiogenesis and macrophages with IgG immune complexes produce could be attributed to reduced migration of leukocytes VEGF-A, which triggers VEGF-A-dependent intranodal especially neutrophils, into the infamed gut since neu- lymphangiogenesis and increased DC level [53]. Moreo- trophils infltrate the infamed gut in IBD provide sev- ver, DCs stimulate increased fbroblastic VEGF during eral growth factors, cytokines, proteolytic enzymes, the initial phase of vascular-stromal proliferation, impli- and oxidants which are signifcant contributors to tis- cating that lymph node-resident DCs orchestrate the ini- sue injury and infammatory-associated lymphangi- tiation of lymphatic and blood vascular growth [54]. ogenesis [46, 47]. ALCAM (activated leukocyte cell adhesion molecule) is implicated in several pathophysiological processes, Ocansey et al. J Transl Med (2021) 19:254 Page 5 of 16

including leukocyte trafcking, lymphangiogenesis, and the blockade of infammatory cells clearance [58]. T cell activation. Te inhibition of ALCAM downregu- Other studies afrm that C-type lectin-like receptor-2 lates antigen-presenting DCs activities and the transmi- (CLEC-2) in platelets bind to podoplanin in LECs when gration of DCs across lymphatic endothelial monolayers, lymphatic vessels separate from cardinal veins at the alongside reduced lymphangiogenesis in vivo and in vitro developmental stage, resulting in platelet activation and [55]. It is reported that lymphangiogenesis facilitates the release of platelet granule contents which potently initial lymph formation, hence boosting the DCs’ mobi- suppresses the migration, proliferation, and tube forma- lisation of chemokine CCL21 [56]. Tese fndings imply tion of LECs to facilitate blood/lymphatic vessel separa- that lymphatic proliferation promotes initial lymph for- tion [59–61]. Conversely, the co-culture of platelets with mation, thereby increasing the transport rate and reduc- podoplanin-positive monocytes (PPMs) augments the ing infammatory mediators. Nevertheless, hyperplastic secretion of lymphangiogenic cytokines including IL-1β lymphatic vessels cannot induce increased immune cell via podoplanin/CLEC-2 axis, which capably enhances the migration despite an enhanced production of immune migration, viability, and proliferation of LECs in vitro and cell chemoattractants. Te failure to collect accumulat- signifcantly increases lymphatic neovascularization and ing fltered fuid, including immune cells and some types facilitates wound healing in nude mice [62]. Tis calls for of antigens, aggravates lymphocytic lymphangitis in IBD. more investigations to clarify the mechanisms underlying DC trafcking in tissues decreases in mice with defective the opposite efects of platelet in the induction of lym- dorsal meningeal lymphatic vessels but and increases in phangiogenesis. Figure 1 illustrates the participation of mice with enhanced dorsal meningeal lymphangiogenesis the cells discussed above in the expression of lymphangi- [57]. ogenic factors and other chemokines to enhance lym- phatic fow. Platelets In investigating the efect of platelets in lymphangiogen- B cells esis in colonic mucosal specimens from IBD patients, the B cells contribute to the intestinal infammatory milieu authors found that regardless of the upregulated levels of in IBD. ­CD27−IgD− B cells are reduced in blood, while lymphangiogenic factors during colonic infammation, ­CD27−IgD− B cells are increased in gut-associated lym- platelets inhibited the proliferation of LECs and increased phoid tissue in IBD [63]. Lymph node B lymphocytes in migration to LVs, causing a suppressed lymphangi- orchestrate lymphangiogenesis, which enhances elevated ogenesis which leads to the aggravation of colitis through DCs migration from the periphery into lymph nodes [64].

Fig. 1 Cellular mediation of lymphangiogenesis. Both immune cells and non-immune cells play a role in the complex process of infammatory-associated lymphangiogenesis in vitro and in vitro. LECs express chemotactic molecules that promote macrophage infltration. In turn, macrophages secrete paracrine prolymphangiogenic growth factors such as VEGF-C, VEGF-D, and VEGF-A in response to infammatory stimuli. Neutrophils conduce to lymphangiogenesis primarily by modulating VEGF-A bioavailability and bioactivity, and to a lesser extent, secreting VEGF-D. However, the suppressive mechanism of lymphangiogenesis by platelets might further contribute to persistent infammation. cDCs produce VEGF-C when stimulated by IFN-γ released from NK cells during co-cultured with activated NK cells. In turn, VEGF-C reduces the secretion of IFN-γ from NK cells Ocansey et al. J Transl Med (2021) 19:254 Page 6 of 16

Te B cell-dependent expansion of the lymphatic network tail model lymphedema and an infammatory lymphangi- reveals a unique relationship between B cells, lymphatic ogenesis model [17]. vessels, and migratory DCs in infammatory conditions. As a prominent growth factor for both lymphangiogen- Monocytes esis and angiogenesis, VEGF-A is produced in infamed tissues and draining lymph nodes. B cells are a source of Tere are three main distinct subpopulations of this growth factor. Tis is confrmed in a study in which human monocyte defned as the classical monocytes transgenic mice that express human VEGF-A specifcally (CD14+ CD16+), intermediate (CD14+ CD16+), and in B cells not only induced lymphangiogenesis in lymph non-classical monocytes (CD14− CD16+) [73]. Several nodes but also triggered the expansion of lymph nodes infammatory stimuli can activate VEGF production and the development of high endothelial venules [65]. from human monocytes [74, 75]. In an infammatory Similarly, IgG immune complexes induced-VEGF-A pro- environment, monocytes can be easily induced to pre- duction by B cells triggered VEGF-A-dependent intran- sent lymphatic phenotypes by expressing specifc lym- odal lymphangiogenesis and increased DC number [53]. phatic endothelial markers such as LYVE-1 (lymphatic Several other studies have demonstrated the signifcance vessel endothelial hyaluronan receptor-1), Prox-1, and of VEGF-A in the induction of the growth of lymphatic Podoplanin [76]. However, in acute colitis, monocyte- endothelial cells and lymphangiogenesis in infammation depleted mice are protected from intestinal injury and [66–70]. B cells interact with fbroblastic reticular cells to exhibit decreased infammation-associated lymphangi- drive mesenteric lymph node lymphangiogenesis partly ogenesis, which is reversed after the administration of through VEGF-A and VEGF-C produced by the B cells wild-type monocytes to CCR2 mice. Although CCR2 [71]. Te growth of the lymphatic vasculature occurs in defciency does not attenuate infammation in chronic two distinct phases of vascular-stromal growth; an initia- colitis, it rather reduces infammation-associated lym- tion phase characterized by increased vascular-stromal phangiogenesis [40]. It could be speculated that intestinal proliferation, and a subsequent expansion phase. While infammation and infammation-associated lymphangi- ogenesis occur independently since infammation-asso- the initiation phase is CD11c(+) cell-dependent and T/B cell-independent, the expansion phase is rather B and T ciated lymphangiogenesis is decreased in the absence of cells dependent [54]. monocytes/macrophages. Monocytes expressing TIE2 receptors are both lymphangiogenic [77] and angio- genic [78, 79], and podoplanin-positive monocytes are T cells also involved in the enhancement of lymphangiogenesis Elevated colonic levels of infltrating cells in IBD, includ- [62]. Monocyte-derived Wnt5a is directly involved in the ing T cells, are associated with structural and functional pathological response of infammatory lymphangiogen- changes in the intestinal lymphatic vasculature [45]. Te esis. Moreover, Wnt5a acts via the monocyte-derived cells to modulate VEGF-C production and macrophage depletion of CD4+ cells in the infammatory site attenu- ates lymphangiogenesis and the expression of VEGF-C phenotype [80]. Trombospondin-1 acts as an endog- and VEGF-D. Mechanistically, the RAMP1 (receptor enous inhibitor of lymphangiogenesis by ligating CD36 activity modifying protein 1) signaling in immune cells, on monocytic cells and also suppressing macrophage- including T cells plays an important role in infam- expressed lymphangiogenic factors VEGF-C and -D [81]. mation-associated lymphangiogenesis by increasing VEGF-C and VEGF-D expression [32]. It is reported that Mast cells CD4(+) T cells interact with macrophages to enhance Several other efector cells of infammation, includ- lymphangiogenesis and that both lymphangiogenesis and ing mast cells, basophils, and eosinophils are important edema are signifcantly decreased in CD4(+) T-cell-def- sources of a wide spectrum of lymphangiogenic and cient mice or lymphocyte-defcient Rag2(?/?) mice and angiogenic molecules. For instance, human primary macrophage-depleted mice. Te underlying mechanism mast cells express lymphangiogenic factors VEGF-C and indicates that T helper type 1 (T1) and T17 cells induce VEGF-D, and angiogenic factors VEGF-A and VEGF-B, macrophages to secrete VEGF-C, promoting lymphangi- in addition to the receptors VEGFR-1 and VEGFR-2 [82], ogenesis [72]. Lymphedema in the mouse-tail causes a which regulate the development of lymphangiogenesis mixed infammatory cell response with signifcant upreg- in IBD. Moreover, Sammarco and colleagues report that ulation in T cells, Treg, neutrophils, DCs, and mac- gastric mast cells release lymphangiogenic and angio- rophages. Contrary to the observation presented above genic factors such as VEGF-C, VEGF-A, VEGF-F, C-X-C [32, 72], the depletion of CD4+ cells but not CD8+ or motif chemokine ligand 8 (CXCL8), and matrix metallo- CD25+ cells greatly enhances lymphangiogenesis in both peptidase 9 (MMP9) [83]. Ocansey et al. J Transl Med (2021) 19:254 Page 7 of 16

(See fgure on next page.) Fig. 2 Infammatory-associated cells and their secretome that initiate lymphatic expansion. Most of the infammatory cells do not only secrete lymphangiogenic factors but also exhibit lymphangiogenic phenotypes by expressing specifc lymphatic endothelial markers such as LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1), Prox-1, and Podoplanin. These factors trigger pre-existing lymphatic vessels in the infammatory environment to give rise to new vessels via lymphatic endothelial cell sprouting

Basophils stimulate lymphangiogenesis in vivo [30]. Te interac- Basophils obtained from peripheral blood of healthy tions between fbroblastic reticular cells and B cells pro- individuals constitutively express mRNA for VEGF-A mote mesenteric lymph node lymphangiogenesis. By and VEGF-B [84]. Similarly, immunologically activated regulating fbroblast reticular cells, the production of human basophils selectively express VEGF-A, VEGF-B, B-cell-activating factor can be promoted, and then the and Angiopoietin1, which further activates Tie2 on mast production of lymphangiogenic factors VEGF-A and cells [82]. In IBD patients Eotaxin, a potent and selective VEGF-C is enhanced by B cells in collaboration with IL-4 chemoattractant for basophils and eosinophils is signif- [71]. Figure 2 summarizes the induction of lymphangi- cantly upregulated in the serum of both active CD and ogenesis as discussed above. UC patients, suggesting that this cytokine may play an important role in the pathogenesis of IBD [85]. Although Molecular mediators of lymphangiogenesis in IBD basophils are key contributors of infammation [86, 87], Several growth factors, cytokines, and chemokines par- participate in tumor growth and metastasis [88, 89], and ticipate in the regulation of lymphangiogenesis. Tese have been demonstrated in draining lymph nodes of can- constitute coordinated molecular mechanisms and axes cer patients [90], the production of lymphangiogenic fac- that directly or indirectly drive lymphatic expansion. tors by these cells needs to be further evaluated. Te molecular mediators of lymphangiogenesis are pri- marily expressed by interacting with the infammatory Eosinophils environment’s cellular components. Te mechanisms An eosinophil is a potent infammatory cell thought to of lymphatic formation have been extensively studied play an important role in the pathogenesis of IBD [91]. in the neonatal stage but less in adults [100]. LYVE-1 is Clinical studies in IBD patients have provided increasing the frst indicator of lymphatic endothelial commitment evidence that eosinophils contribute to chronic intes- and LECs that express LYVE-1 can diferentiate into tinal infammation with a clear indication of changes lymphatic vessels via signaling pathways involving tran- in cytokine, chemokine, and receptor mediator profl- scription factors such as Prox-1 and VEGF-C/VEGF-R3. ing [92, 93]. Inactive sites of IBD patient biopsies, copi- In the adult colonic infamed site, several factors such as ous numbers of eosinophils, neutrophils, and mast cells tumor necrosis factor (TNF)-α, IL-1β, and IL-6 stimu- have been quantifed [94, 95]. Increased lymphangiogen- late infammatory cells such as macrophages to induce esis in fbroinfammatory areas of Riedel thyroiditis also lymphangiogenesis by secreting VEGF-C/D [101–103] contained eosinophils in addition to lymphocytes, and as illustrated in Figs. 1 and 2. Activated platelets also IgG4+ plasma cells [96]. Eosinophils also regulate the interact with podoplanin to cause blood vessel/lymphatic resolution of infammation and draining lymph node vessel divergence, leading to the extension of lymphatic hypertrophy [97], participate in lymph node trafcking vessels. CLEC-2, a platelet-activating receptor, and podo- and antigen presentation [98], and contribute to infam- planin (an endogenous ligand for CLEC-2) expressed on mation in lymph nodes [99]. Regardless, no study has LECs interact in this process. Te interaction activates currently implicated eosinophils in the production of platelets and induces platelet aggregation, which blocks lymphangiogenic factors, hence more studies are needed lymphatic-venous connections and facilitates the sepa- to further address this observation. ration of lymphatic and blood vascular systems via the inhibition of proliferation, migration, and tube formation Others cells of LECs [60]. Te suppressive mechanism of lymphangi- VEGF-C and -D are strong inducers of lymphangiogene- ogenesis by platelets might be responsible for prolonged sis and have essential (VEGF-C) and modulatory (VEGF- infammation in IBD [58]; therefore, modulating the D) roles during developmental lymphangiogenesis. A interaction between platelets and lymphatics could be a myeloid population comprising largely of M2-polar- new therapeutic target for managing IBD. Furthermore, ized mononuclear cells and characterized by tyrosine the efects of the interaction between platelets and other kinase Syk’s expression robustly expresses VEGF-C/-D, immune cells in lymphangiogenesis are also worthy of among other lymphangiogenic chemokines, and potently investigation. Ocansey et al. J Transl Med (2021) 19:254 Page 8 of 16 Ocansey et al. J Transl Med (2021) 19:254 Page 9 of 16

VEGF‑C/VEGFR3 signaling pathway mediators of the infammatory response are dimeric Lymphangiogenesis is mainly mediated by the lym- transcription factors that belong to the NF-κB family phatic VEGF-C and VEGF-D binding to VEGFR-3 [104]. consisting of RelA (p65), NF-κB1 (p50), RelB, c-Rel, and Researchers have investigated the efect of a stimulated NF-κB2 (p52). In unstimulated cells, NF-κB is seques- lymphatic function on the adaptive immune response via tered in an inactive form in the cytoplasm bound to spe- VEGF-C/VEGFR3 signaling on various factors, includ- cifc inhibitory proteins of the inhibitor (I)-B family. After ing intestinal infammation, lymphatic drainage, bacterial stimulation through TLRs, proinfammatory cytokines or antigen clearance, and macrophage activation during gut antigen receptors, I-κB is phosphorylated, ubiquitinated, infammation. It is demonstrated that VEGFR-3 blockade and fnally proteolytically degraded, leading to de-repres- signifcantly afects lymphangiogenesis, reducing both sion of NF-κB, which rapidly translocate to the nucleus area density and lymphatic vessel dimension while sig- and activates the transcription of several target genes nifcantly increasing infammatory edema formation and [112]. It has also been thoroughly established that intesti- inhibiting disease resolution [5]. Tis is consistent with nal infammation occurring in IBD is accompanied by an other fairly recent studies in which blockade of VEGFR-3 NF-κB driven overexpression of pro-infammatory adhe- aggravated IBD and lymphatic vessel enlargement [105], sion molecules and mediators, leading to disturbances in degradation of VEGFR-3 inhibited lymphagiogenesis mucosal immunity [113, 114]. [106], and VEGF-C/VEGFR3-dependent autophagy and Besides the classic targets (chemokines and cytokines), polarization triggered lymphangiogenesis [107]. Te sys- it has also been described that infammation-induced temic delivery of VEGF-C provides signifcant protec- NF-κB directly upregulates two major transcripts tion against acute and chronic colitis. Additionally, the involved in lymphangiogenesis, VEGFR-3, and its key VEGFR-3 signaling promotes human intestinal LECs transcription factor Prox1 (Prospero-related home- proliferation, migration, and organization in vitro [5]. obox-1), resulting in a sustained infammatory-induced Tese fndings demonstrate that stimulation of func- lymphatic formation [115]. A study identifed VEGFR-3 tional lymphangiogenesis via VEGFR-3 accelerates dis- and Prox1 as downstream targets of the NF-κB path- ease resolution and inhibits chronic infammation in the way in infammation-induced lymphangiogenesis. Te experimental model of IBD. induction of the NF-κB pathway by infammatory stimuli Several immune cells, including macrophages, DCs, activates Prox1, and both NF-κB and Prox1 activate the and mast cells, express VEGF-C [108]. For instance, the VEGFR-3 promoter, leading to increased receptor expres- polarizing and resolving efects of macrophages are medi- sion in LECs. Tis, in turn, enhances the responsiveness ated by the VEGF-C/VEGFR3 pathway through signal of pre-existing lymphatic endothelium to VEGFR-3 bind- transducer and activator of transcription (STAT)6 activa- ing factors, VEGF-C and VEGF-D, ultimately resulting tion [5]. Tis is intriguing because some reports suggest in robust lymphangiogenesis [116]. Te NF-κB pathway that there may be a dysregulation of STAT6 signaling in presents an auspicious mechanistic connection between the ungoverned immune response associated with colitis, a variety of infammatory stimuli and infammation- wherein the activation of this transcription factor pro- induced lymphatic hyperplasia as well as lymphangio- motes mucosal repair and resolution of IBD [109]. How- genesis through a Prox-1 regulated increase of VEGFR-3 ever, there are conficting fndings that demonstrate that expression, amplifying cellular responses to local growth the stimulation of lymphangiogenesis by VEGF-C during factors like VEGF-C/D [115, 116]. Te enhancement of acute colitis promotes infammatory lymphangiogenesis lymphangiogenesis and lymphatic vessel remodeling also in the colon and aggravates intestinal infammation [42]. occurs via NF-κB/VCAM-1 (vascular cell adhesion mol- Tis implies that infammatory lymphangiogenesis may ecule 1) signaling pathway in human LECs [117], and the have pleiotropic efects at diferent stages of IBD and that NF-κB/HIF-1α (hypoxia-inducible factor-1α) axis [118]. VEGF-C exhibits a dual efect in infammation, making it Te upregulation of VEGFR-3 expression by infam- an important therapeutic target for IBD. matory cytokines through NF-κB and Prox-1 may result in increased receptor availability, but a lower net avail- NF‑κB signaling pathway ability of local VEGF-C/D might potentially contribute Te key factors that regulate infammation-induced tran- to "aberrant" IBD associated intestinal lymphatic charac- scription are members of the nuclear factor-kappa B teristics [115, 116, 119, 120]. Tis might lead to a shift in (NF-κB) family. Multiple intracellular signaling cascades IBD toward defcient VEGFR-3 signaling. Tese fndings rely on NF-κB to orchestrate the transcriptional control may indicate that an IBD-associated depression in lym- of various pro- and anti-infammatory mediators shap- phatic activation (possibly through NF-κB pathway sup- ing infammatory responses and homeostatic processes pression) could lead to insufcient lymphatic density, loss like growth control apoptosis [110, 111]. Te primary of lymphatic specifcation, and inappropriate patterning Ocansey et al. J Transl Med (2021) 19:254 Page 10 of 16

or remodeling, any of which would be anticipated to a balance is required in the therapeutic induction of lym- intensify the disease activity of IBD [8, 121]. Regard- phangiogenesis to arrive at a maximum beneft. less, it is still uncertain whether and when a lymphatic vessel expansion in IBD is accompanied by impaired or Other signaling pathways improved lymphatic function. As discussed above, the Tere are many other signaling pathways involved in the role of NF-κB in IBD-related intestinal infammation is by development of lymphangiogenesis in IBD and its asso- now clearly established. However, there are still gaps in ciated CRC. In recent years, sphingosine-1-phosphate knowledge regarding infammatory induced lymphangi- (S1P) has been recognized for its role in infamma- ogenesis through Prox-1 and VEGFR-3 and their activa- tion and cancer as a multipotent lipid mediator [126]. tion growth factors (VEGF-C, VEGF-D), thus remaining Te level of S1P concentration in the blood and lymph a new and promising area. Tese fndings further suggest is important for regulating lymphatic transport in the that identifying mechanisms that support and induce pathology of infammation. Key chemokines like IL-6 and expression of lymphatics in the infamed intestine may TNF-α in IBD are also associated with S1P signal activa- reveal novel therapeutic approaches for treating IBD. tion. S1P binds to SIP receptor 1 (S1PR1) and amplifes chronic infammation through the S1P-STAT3-S1PR1 TLR4 signaling pathway amplifcation ring, thus exacerbating the disease. Besides, Lymphatic endothelial progenitors originate from plastic the S1P gene is highly expressed in many cancer cells, myeloid cells induced through TLR4 [122], which is also such as colon cancer cells, where a high concentration of important in lipopolysaccharide (LPS)-induced infam- S1P are released to act on lymphatic endothelial cells and mation. Studies show that LECs produce high amounts immune cells in the tumor microenvironment, induce of TLR4 in the intracellular region. Te TLR4 of LECs is lymphatic generation and metastasis and promote the the main mediator of NF-κB activation in LPS-induced invasion and lymphatic metastasis of colorectal cancer VEGF-C-dependent lymphangiogenesis [36, 123]. LPS- [126, 127]. TLR4 signaling in LECs cuases the production of vari- Lacteals are lymphatic capillaries of the small intestine ous chemokines for chemotaxis of macrophage, which and play crucial roles in the gut immune response and in turn infltrate the lymphatic vessel to contribute to the dietary fat absorption. According to Bernier-Latmani induction of lymphangiogenesis by expressing lymphang- and colleagues, lacteals reside in a permanent regen- iogenic growth factors. Because NF-κB is persistently erative and proliferative state unique from embryonic active in LECs to maintain their phenotypic specifcation, lymphangiogenesis or quiescent lymphatic vessels pre- TLRs may provide key links between pattern recognition, sent in other tissues. Notch signaling and its ligand, lymphatic structure, maturation, and function. TLRs delta-like 4 (DLL4), expressed in lacteals via the activa- likely regulate responses towards lymphatically fltered tion of VEGFR2 and VEGFR3 ensure the continuous antigens or assist LEC responses to internalized antigens. regeneration process [128]. Te role of certain exosomal Te importance of the balancing role of TLR4 in intes- components such as microRNAs (miRNA) in lymphangi- tinal injury and repair is also reported by Yun-Jie and ogenesis has been explored. Stem cells treated with colleagues, who found that moderate activation of TLR4 VEGF-C express a high concentration of miR-132 which signaling both promotes infammation and repairs the is directly transferred from the stem cells to the LECs by intestinal epithelium in DSS-induced colitis and radia- the mediation of exosomes, inducing LECs proliferation, tion damage [124]. TLR4-mediated signaling is impor- migration, and tube formation. Te VEGF-C-dependent tant for the recruitment of immune cells to the site of lymphangiogenesis occurs via miR-132 directly target- infammation, promoting reparative mechanisms, but ing Smad-7 and modulating transforming growth fac- can be described as a double-edged sword, as aberrant tor (TGF)-β/Smad signaling [129]. As potent regulators stimulation can induce chronic infammation and mes- of infammatory-associated lymphangiogenesis, various enteric lymphatic alterations in a TLR4-PAMP (patho- sources of stem cells and their secretory products are gen-associated molecular patterns)/DAMP (-associated being explored as a possible treatment option for IBD molecular patterns) discriminative manner [125]. Te [130, 131]. Te various pathways linked with lymphangi- observation that reduced lymphangiogenesis improves ogenesis are summarized in Table 1. DSS-induced phenotype implies that the restoration of lymphatic function to a “normal” phenotype, signifcantly Lymphangiogenesis and gut microbiota aids the repair of DSS-induced disease activity, which is Te gut microbiota composition is infuenced by difer- achieved through TLR4 blockade with C34 [125]. Tis ent factors, including host genotype, diet, immunological apparent contradiction of the general observation that status, and environment. Delayed or inefective elimi- increased lymphangiogenesis improves IBD implies that nation of bacteria that penetrate the intestinal mucosal Ocansey et al. J Transl Med (2021) 19:254 Page 11 of 16 [ 134 , 135 ] [ 133 ] [ 128 ] [ 126 , 127 ] [ 123 ] [ 125 , 132 ] [ 116 , 117 ] [ 43 ] [ 5 ] [ 60 ] References lymphatic valve formation and maintenance and exhibits a modulatory and maintenance formation lymphatic valve - acting by molecule in the migra as a "guiding" function in the proliferation tion of LECs facilitates the extension of LEC growth leading edge, and promotes the and promotes leading edge, the extensionfacilitates of LEC growth and of the sprouting axis is also the foundation This polarization of LECs. of a new networkformation of lymphatic vessels mediated by Notch signaling and the expression of the Notch ligand delta- of the Notch and the expression signaling Notch by mediated VEGFR2 VEGFR3 and activationlike of 4 (DLL4) in lacteals which requires in infammation is afected, thereby promoting the accumulation of pro- promoting thereby in infammation is afected, the disease aggravate TNF-α to and infammatory factors such as IL-6 ogenesis through the TLR4- NF-κB/JNK signaling the ogenesis through NF-KB receptor availability, resulting in reduced local VEGF-C/D net availability to local in reduced resulting availability, receptor and blocked lymphoid activation defciency, in IBD, VEGFR3 signal cause exacerbating the disease of MMP-9, heparinase, and to a lesser extent VEGF-D a lesser extent and to heparinase, of MMP-9, intestinal LECs, ultimately leading to functional which leading to lymphangiogenesis ultimately LECs, intestinal IBD can alleviate inhibit LECs-mediated lymphangiogenesis inhibit LECs-mediated EMILIN1 interacts with integrin α9 in the lymphatic vasculature to promote promote to α9 in the lymphatic vasculature EMILIN1 interacts with integrin The activation of the VEGF-C/D-NRP-2 axis stimulates lymphatic sprouting, VEGF-C/D-NRP-2 lymphatic sprouting, axis stimulates activationThe of the The continuous regeneration and proliferation of lymphatic capillaries are of lymphatic capillaries are and proliferation continuous regeneration The Through the S1P-STAT3-S1PR1 amplifcation ring, the lymphatic transport amplifcation ring, the S1P-STAT3-S1PR1 Through LPS increases VEGF-C expression to promote cell motility- and lymphangi promote VEGF-C to expression LPS increases Highly expressed in LECs; it is the main regulating medium for LPS to activate LPS to medium for Highly in LECs; it is the main regulating expressed NF-κB and Prox1 synergistic control of VEGFR3 expression lead to increased increased lead to VEGFR3 expression of control synergistic NF-κB and Prox1 Neutrophils increase VEGF-A bioavailability and bioactivity via the secretion increase Neutrophils vitro proliferation, migration, and tissue formation of human and tissue formation migration, proliferation, in vitro Promotes Activates platelets by interacting with the LECs surface by to platelets Activates ligand Podoplanin, Mechanism and a blockage in the dissipation of infammation regression phatic transport and lymphangiogenesis of cancer cells, thereby promoting promoting phatic transport thereby of cancer cells, and lymphangiogenesis metastasis and CAC infammation progression tube-like and lymph lymphangiogenesis and accelerates in vitro formation node metastasis in nude mice via LPS induction and improve the enteritis phenotype DSS induced by and improve response in the IBD process response The downregulation of EMILIN-1 leads to an inhibited lymphangiogenesis lymphangiogenesis an inhibited of EMILIN-1 leads to downregulation The Promote tumor cell migration, invasion, and lymph node metastasis invasion, tumor cell migration, Promote The genetic inactivationThe lacteal of Dll4 in lymphatic endothelial cells led to The concentration grade of S1P in lymph and carcinoma tissues afects lym - tissues afects of S1P in lymph and carcinoma concentration grade The Promotes human dermal lymphatic endothelial cells’ (HDLECs’) capacity of (HDLECs’) human dermal lymphatic endothelial cells’ Promotes Blocking TLR4 can reduce the formation of infammatory the formation TLR4 can reduce lymphatic vessels Blocking Result in infammatory-induced lymphatic formation Promote lymphangiogenesis and decrease local infammation and decrease lymphangiogenesis Promote Prevents chronic infammation and promotes disease regression infammation and promotes chronic Prevents Inhibits LEC-mediated lymphangiogenesis to cause a sustained infammatoryInhibits to lymphangiogenesis LEC-mediated Functions in the IBD Functions Molecular pathways regulating lymphangiogenesis in infammatory lymphangiogenesis disease regulating bowel Molecular pathways EMILIN-1/α9β1 NRP-2 Notch/DLL4 signaling Notch/DLL4 S1P TLR4- NF-κB/JNK pathways TLR4 NF- Κ B VEGF-A and VEGF-D VEGF-C/VEGFR3 CELC2 1 Table Molecule(s) Ocansey et al. J Transl Med (2021) 19:254 Page 12 of 16

Fig. 3 The interaction between the mesenteric lymphatics and the intestinal fora. Invading intestinal mucosal bacteria interact with various immune cells in mesenteric lymph nodes, such as T cells, B cells, DC cells, macrophages, NK cells, and neutrophils. When bacteria stimulate the mesenteric lymph nodes, more IFN-C is secreted. At the same time, bifdobacteria can lead to decreased IL-6, TNF-α, and IL-12 secretion of DC cells. Also, the presence of microorganisms can activate the CD40 pathway and make CD103 cells migrate from lamina propria to MLN, playing an + important role in immune regulation, hence lymphangiogenesis

barrier can result in a prolonged innate immune by L. acidophilus, which is also observed in splenic DC, responses and encourage the presentation of bacterial but not in MLN DC. Meanwhile, MLN cells respond to antigens to promote the induction of adaptive immune bacterial stimulation with higher IFN-c production than responses. Hence, while IBD could lead to an aberrant spleen cells, possibly due to the presence of more respon- immune response against intestinal bacteria, inefective sive natural killer (NK) cells [139]. CD40-signalling as a or slow clearance of local bacteria could also be a key microbe-independent signal, can trigger the migration of contributing event associated with the disease patho- CD103+ DCs from the gut lumen for transport to drain- genesis [136]. Past studies characterizing the colonic ing lymph nodes and generate receptor-related orphan microbiome typically relied on stool samples, which do γt+ (RORγt+) Helios-induced Treg (iTreg) cells [140]. not accurately recapitulate the composition of bacteria at Te participation of some gut bacteria in lymphatic mod- the mucosal surface [137]. Te mesenteric lymph nodes ulation is illustrated in Fig. 3. (MLNs)’ microbiome correlates closely with that found at nearby all mucosal sites. Commensal bacteria, therefore, Discussion and conclusions play specifc roles in the gut immune system and lym- A key function of lymphatics is to transport immune cells phagiogenesis, distinguishable from the efect they would to the lymph nodes and drain interstitial fuid; thus, the have if recognized by the systemic immune system. Gut blockade of lymphangiogenesis through any signaling microbiota regulates lacteal or small intestine lymphatic means promotes the exacerbation of IBD and vice versa. capillaries structure, and integrity as germ-depleted mice Obstructed and dysfunctional lymphatics are known his- sufer signifcant lacteal regression during adulthood and topathological features of IBD. Although a dysfunction delayed lacteal maturation during the postnatal period in the lymphatics might not be the direct consequence [138]. of the disease, the resultant infammation presumably Gut microbiota regulates the expression of both infam- afects the lymphatic vascular function, aggravating an matory and anti-infammatory mediators that directly or already compromised condition. Te infammatory mod- indirectly contribute to the modulation of lymphangio- ulators produced in UC and CD impair lymphatic fuid genesis. For instance, the production of IL-6, TNF-α, and fow and change lymphatic vessel function, worsening IL-12 is downregulated by bifdobacteria induced in DC tissue edema and accumulating bacteria and dead cells, Ocansey et al. J Transl Med (2021) 19:254 Page 13 of 16

which together exacerbate the existing infammatory Acknowledgements Not applicable. condition. Reports indicate that intestinal wall lymph edema of patients with IBD originates from obstruc- Authors’ contributions tive lymphocytic lymphangitis. Te inability of the lym- DKWO wrote the manuscript; BP performed the conception; XX performed the design; LZ data analysis and interpretation; CVO collection and/or assem- phatic vasculature to collect accumulating fltered fuid, bly of data; FM study design, data analysis and interpretation, manuscript including the immune cells and some types of antigens, writing, and fnal approval of manuscript. All authors read and approved the aggravates lymphocytic lymphangitis in IBD; therefore, fnal manuscript. enhancing lymphatic function is of key importance in the Funding management of IBD. This study is supported by the National Natural Science Foundation of China Several cytokines, chemokines, and infltrating (Grant No. 81670502), Scientifc research project: Suqian Technology and Social Development Project (S201901), and Nature Project of Anhui Medical and local cells induce lymphangiogenesis, which cor- College (YZ2020ZR006). relates with a good prognosis of IBD. For example, VEGF-induced lymphangiogenesis and increased tis- Availability of data and materials Not applicable. sue drainage inhibit acute and chronic infammatory conditions such as IBD, wherein an activated lymphatic Declarations endothelium might mediate peripheral tolerance by establishing an immune-inhibitory microenvironment Ethics approval and consent to participate characterized by upregulated levels of Treg cells, imma- Not applicable. ture CD11c+ CD11b+ DCs, and CD8+ cells exhibit- Consent for publication ing reduced efector function [140]. Tis implies that Not applicable. activated LECs induce lymphangiogenesis and potently Competing interests suppress DCs maturation by reducing the expression The authors declare that they have no competing interests. of MHCII, CD40, and IL-6 while increasing IL-10 and CCL2 expression favoring an anti-infammatory micro- Author details 1 Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu environment. Te exploration of the cellular and molecu- Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenji- lar mediators in this process is of great signifcance since ang 212013, Jiangsu, People’s Republic of China. 2 Directorate of University 3 it will help to clarify the exact molecular mechanisms of Health Services, University of Cape Coast, Cape Coast, Ghana. Department of Clinical Laboratory, The Afliated Suqian First People’s Hospital of Nan- lymphatic changes in IBD, especially lymphangiogenesis jing Medical University, Suqian 223800, Jiangsu, People’s Republic of China. to serve as a possible efective therapeutic target in IBD. 4 Department of Microbiology, University of Nigeria, Nsukka 410001, Nigeria. Specifc studies on the mesenteric lymphatic system in Received: 30 April 2021 Accepted: 2 June 2021 IBD have provided several efective and valid targets for therapeutic intervention and it is expected to provide novel therapeutic approaches to intestinal infammation through both immune and non-immune cells, and based References on cellular and molecular mechanisms of lymphangi- 1. Behr MA. The path to Crohnʼs disease: is mucosal pathology a second- ogenesis that facilitate infammation resolution. ary event? Infamm Bowel Dis. 2010;16:896–902. 2. Rehal S, Stephens M, Roizes S, Liao S, von der Weid P-Y. 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