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Review
. 2018 Jan 2;215(1):35-49.
doi: 10.1084/jem.20171868. Epub 2017 Dec 14.

Organ-specific lymphatic vasculature: From development to pathophysiology

Tatiana V Petrova  1   2 , Gou Young Koh  3   4
Affiliations
Review

Organ-specific lymphatic vasculature: From development to pathophysiology

Tatiana V Petrova et al. J Exp Med. .

Abstract

Recent discoveries of novel functions and diverse origins of lymphatic vessels have drastically changed our view of lymphatic vasculature. Traditionally regarded as passive conduits for fluid and immune cells, lymphatic vessels now emerge as active, tissue-specific players in major physiological and pathophysiological processes. Lymphatic vessels show remarkable plasticity and heterogeneity, reflecting their functional specialization to control the tissue microenvironment. Moreover, alternative developmental origins of lymphatic endothelial cells in some organs may contribute to the diversity of their functions in adult tissues. This review aims to summarize the most recent findings of organotypic differentiation of lymphatic endothelial cells in terms of their distinct (patho)physiological functions in skin, lymph nodes, small intestine, brain, and eye. We discuss recent advances in our understanding of the heterogeneity of lymphatic vessels with respect to the organ-specific functional and molecular specialization of lymphatic endothelium, such as the hybrid blood-lymphatic identity of Schlemm's canal, functions of intestinal lymphatics in dietary fat uptake, and discovery of meningeal lymphatic vasculature and perivascular brain lymphatic endothelial cells.

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Figures

Figure 1.
Figure 1.
Organization and function of dermal lymphatic vasculature. (A) Skin LVs are organized in superficial and deep lymphatic plexuses. Superficial LVs are mostly capillaries, whereas deep lymphatic plexus contain collecting LVs draining to the regional LNs. ECM, extracellular matrix. (B) CCR7+ CD4+ T cells, Langerhans cells (specialized skin DCs residing in epidermis), and DCs are the main immune populations trafficking via dermal LVs in response to CCL21 gradient produced by capillary LECs. Dermal macrophages sense tissue osmotic pressure and maintain tissue fluid homeostasis and systemic blood pressure by activating transcription factor NFAT5 and producing VEGF-C, which induces expansion of dermal LVs and enhances tissue clearance. LVs also play a major role in reverse cholesterol transport through recirculation of high-density lipoprotein (HDL)–bound cholesterol from the interstitial space. dLEC, dermal LEC. (C) During bacterial infection, neutrophils, extravasated from BVs, also migrate through LVs to LNs to enhance adaptive immune response. Inflamed LECs produce adhesion receptors, such as VCAM-1 and ICAM-1, and chemokines (e.g., CXCL12) that enhance the attraction, adhesion, and intralymphatic crawling of immune cells. Lymphatic capillary hyaluronan receptor LYVE1 mediates interaction of LECs with hyaluronan-coated DCs and with the hyaluronan-containing capsule of some skin bacterial pathogens, such as GAS.
Figure 2.
Figure 2.
Meningeal lymphatic vasculature and brain mural LECs. Localization and distribution of LVs in dura matter of mouse brain. Cerebrospinal fluid (CSF) and interstitial fluid of brain parenchyma drain into meningeal LVs and reach the deep cervical LNs. Trafficking of brain immune cells, including T cells, DCs, and macrophages, and clearance of neurotoxic misfolded proteins and peptides, such as amyloid β, are among the potential important functions of meningeal LVs. A unique, LV-derived population of muLECs surrounding brain BVs was recently found in zebrafish. muLECs express Prox1, LYVE1, and mannose receptor 1 (MR1), and are highly endocytotic. Unlike all other EC, muLECs do not form cell–cell junctions or lumenized structures. Whether muLECs are equivalent to perivascular Mato cells (LYVE1+, Prox1−, MR1+, and lipid droplet+), found in mammalian brain, remains to be established. Perivascular Mato cells are also detected in surrounding meningeal LVs.
Figure 3.
Figure 3.
Schlemm's canal. (A) SC is an endothelium-lined channel that encircles the cornea and provides an exit route for aqueous humor. (B) Aqueous humor is produced from the ciliary body and drained into aqueous and episcleral veins through the trabecular meshwork and SC. (C) Aqueous humor is drained transcellularly and transported from the basal to luminal side through SC ECs, causing formation of giant vacuoles. SC ECs have an intermediate blood-lymphatic EC phenotype and express Prox1, VEGFR3, Tie2, and integrin α9, but not LYVE1 or podoplanin. Angpt1+ stromal cells adjacent to the SC LECs may produce proteins of trabecular meshwork. When SC function is impaired, aqueous humor drainage is impeded and intraocular pressure is increased, ultimately leading to glaucoma. Angpt–Tie2 signaling maintains SC integrity, and loss of such signaling induces primary congenital and open-angle glaucoma. AHO, aqueous humor outflow; E & A vein, episcleral & aqueous vein; VEC, venous endothelial cell.
Figure 4.
Figure 4.
LN lymphatic vasculature. (A) Afferent LVs deliver lymph carrying antigens and immune cells to the LN SCS. From the SCS, lymph flows to the cortical and medullary sinuses and exits via efferent LVs. SCS “ceiling” LECs (cLECs) express the decoy CCL19/CCL21 receptor CCRL1, which creates a gradient of CCL21 enhancing transmigration of DCs into T zones. CD169+ SCS macrophages inserted in the “floor” LEC (fLEC) layer take up antigens and pathogens. The majority of lymph drains via LN LVs, whereas a proportion of small solutes is absorbed from lymph via specialized conduits, a network of collagen fibrils, surrounded by follicular reticular cells. Molecular diaphragms formed by plasmalemma vesicle-associated protein restrict access of larger substances into conduits. Similar to fLECs, medullary sinus LECs are in close contact with macrophages, which clear pathogens and antigens. S1P produced by medullary and cortical sinuses LECs induces egress of lymphocytes into efferent LVs and promotes T cell survival. (B) Specialized functions of LN LECs. LN LECs contribute to maintenance of tolerance against self-antigens through the expression of peripheral tissue antigens and deletion of self-reactive CD8+ T cells. LN LECs can tolerize CD4+ cells either by transferring peptide–MHC-II complexes to DCs or acquiring them from DCs. LN LECs also produce immunosuppressive nitric oxide (NO) and indoleamine-2,3-dioxygenase (IDO1), which restrains proliferation of activated T cells. During acute viral infection, proliferating LN LECs uptake and store viral antigens. During the LN contraction stage, such antigens are transferred by dying LECs to DCs, which cross-present them to T cells to promote CD8+ T cell memory responses. Ag, antigen; FRC, follicular reticular cell; PLVAP, plasmalemma vesicle–associated protein.
Figure 5.
Figure 5.
LVs of the small intestine. (A) Intestinal lacteals are positioned in the middle of intestinal villi. Smooth muscle cells in the villi are closely associated with lacteals, and their contractions promote lymph uptake and transport. Another lymphatic vascular plexus is located in the intestinal muscular layer. Lymph from both plexuses is drained to mesenteric collecting vessels, mesenteric LNs, and the thoracic duct and returned to the blood circulation. (B) Intestinal lacteals transport chylomicrons, cholesterol, gut hormones, and immune cells. Lymphatic trafficking of CD103+ DCs carrying food antigens and apoptotic intestinal epithelial cells to mesenteric LN drives the development of T reg cells and tolerance. The role of LVs trafficking in intestinal ILC3 function is not understood. (C) Role of villus SMCs in the maintenance of intestinal LVs. VEGF-C, produced by villus SMCs, and VEGF-C–dependent DLL4 signaling in LECs fuel continuous lacteal regeneration. Periodic contraction of villus SMCs, controlled by the autonomic nervous system, promotes lymph transport. Ag, antigen; IEC, intestinal epithelial cell; TD, thoracic duct.
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