An Immunological Fingerprint Differentiates Muscular Lymphatics from Arteries and Veins

Abstract

The principal function of the lymphatic system is to transport lymph from the interstitium to the nodes and then from the nodes to the blood. In doing so lymphatics play important roles in fluid homeostasis, macromolecular/antigen transport and immune cell trafficking. To better understand the genes that contribute to their unique physiology, we compared the transcriptional profile of muscular lymphatics (prenodal mesenteric microlymphatics and large, postnodal thoracic duct) to axillary and mesenteric arteries and veins isolated from rats. Clustering of the differentially expressed genes demonstrated that the lymph versus blood vessel differences were more profound than between blood vessels, particularly the microvessels. Gene ontology functional category analysis indicated that microlymphatics were enriched in antigen processing/presentation, IgE receptor signaling, catabolic processes, translation and ribosome; while they were diminished in oxygen transport, regulation of cell proliferation, glycolysis and inhibition of adenylate cyclase activity by G-proteins. We evaluated the differentially expressed microarray genes/products by qPCR and/or immunofluorescence. Immunofluorescence documented that multiple MHC class II antigen presentation proteins were highly expressed by an antigen-presenting cell (APC) type found resident within the lymphatic wall. These APCs also expressed CD86, a co-stimulatory protein necessary for T-cell activation. We evaluated the distribution and phenotype of APCs within the pre and postnodal lymphatic network. This study documents a novel population of APCs resident within the walls of muscular, prenodal lymphatics that indicates novel roles in antigen sampling and immune responses. In conclusion, these prenodal lymphatics exhibit a unique profile that distinguishes them from blood vessels and highlights the role of the lymphatic system as an immunovascular system linking the parenchymal interstitium, lymph nodes and the blood.

Colonic Insult Impairs Lymph Flow, Increases Cellular Content of the Lymph, Alters Local Lymphatic Microenvironment, and Leads to Sustained Inflammation in the Rat Ileum

“…Currently, we are trying to determine what the triggers early recruitment of immune cells to the tissue surrounding the lymphatic vessels since we believe this is a critical early factor that could modulate lymph flow. However, based on the literature we speculate that it is likely some form of innate immune cells that reside near the vessel releasing chemoattractive substances (22). Additionally we would also like to address if this paradigm is common to other chronic inflammatory states, that is whether or not the reduction of lymph flows from different tissues is a common triggering factor in human inflammatory diseases and if preserving lymphatic flow may attenuate inflammation in those diseases.…”

“…This suggests that the primary function of the lymphatic system is to serve and support the adaptive immune system. Indeed anatomically the body’s network of lymphatic vessels is centered on the lymph nodes, with the afferent lymphatic network delivering immune elements from the interstitium to the node and the efferent lymphatic network transporting immune elements from the node to the blood for eventual distribution throughout the body (15, 22–26). CSF1R and PU.1 knockout mice show that interruptions of monocyte development and differentiation leads to the formation of a dysplastic lymphatic network, supporting this principle since the monocyte lineage is responsible for regulating innate and adaptive immunity (27, 28).…”

“…Furthermore it has been show that certain macrophage cells express a common lymphatic endothelial marker LYVE-1, and associate with and integrate into lymphatic vessels, which further strengthens the argument that the lymphatic system primarily serves the immune system (24, 29, 30). Our group has reported that a unique population of innate immune cells resides on muscular lymphatic vessels and that the mesenteric collecting lymphatics have a significant investment of these cells that are very dynamic (22, 30). What roles these cells are playing for the lymphatic system during different immune responses are not known.…”

Emerging roles of lymphatic endothelium in regulating adaptive immunity

“…(19)(20)(21). LECs both attract and facilitate transmigration of immune cells through a number of signaling axes, many of which have been identified in LEC gene expression studies (22)(23)(24)(25)(26). In addition to identifying multiple cytokines and receptors expressed by LECs under steady-state conditions (22), these studies also identified genes that are upregulated during localized inflammatory processes such as in models of contact hypersensitivity (23), tumor drainage (25), and inflammation (26).…”

Mechanical forces and lymphatic transport

“…The collecting lymphatics are distinguished by having both endothelial and smooth muscle layers, and an adventitia that can contain fibroblasts, connective tissue, MHC-II+ antigen presenting cells, nerves that innervate the vessel, and vasa vasorum (Bridenbaugh et al, 2013; Schmid-Schonbein, 1990; Zawieja et al, 2008). While the lymphatic smooth muscle cell organization varies between species, in general the amount of smooth muscle increases when moving centrally along the lymphatic tree.…”