Interleukin-17A negatively regulates lymphangiogenesis in T helper 17 cell-mediated inflammation

Abstract

During inflammation lymphatic vessels (LVs) are enlarged and their density is increased to facilitate the migration of activated immune cells and antigens. However, after antigen clearance, the expanded LVs shrink to maintain homeostasis. Here we show that interleukin (IL)-17A, secreted from T helper type 17 (T17) cells, is a negative regulator of lymphangiogenesis during the resolution phase of T17-mediated immune responses. Moreover, IL-17A suppresses the expression of major lymphatic markers in lymphatic endothelial cells and decreases in vitro LV formation. To investigate the role of IL-17A in vivo, we utilized a cholera toxin-mediated inflammation model and identified inflammation and resolution phases based on the numbers of recruited immune cells. IL-17A, markedly produced by T17 cells even after the peak of inflammation, was found to participate in the negative regulation of LV formation. Moreover, blockade of IL-17A resulted in not only increased density of LVs in tissues but also their enhanced function. Taken together, these findings improve the current understanding of the relationship between LVs and inflammatory cytokines in pathologic conditions.

Role of TH17 Responses in Increasing Herpetic Keratitis in the Eyes of Mice Infected with HSV-1

“…CD4 + T cell, CD8 + T cell, ILCs, CD4 − CD8 − T cells, γ δT cells, iNK T cells, NK cells, neutrophils, and mast cells) secrete IL17A, [21][22][23][24][25][26][27][28][29][30][31] which contributes to many autoimmune disorders in humans. 8,[12][13][14][15][16][17][18][19] Thus, IL17A secretion by many of the immune cells listed above suggests that the pathology associated with these cell types could be due to IL17A producing cells. IL17A binds to IL17RA and IL17RC receptors to form a heterodimer.…”

“…Similar to the results of our study, the IL17 pathway has been shown to play a pathogenic role in many human autoimmune diseases, including psoriasis, RA, MS, and inflammatory bowel disease. 8,[12][13][14][15][16][17][18][19] Recently, fever induced T H 17 cells were also shown to induce expression of transcription factors involved in induction of EAE. 86 IL17 is also known to have a negative effect on the proliferation of hepatitis B virus-related hepatocellular carcinoma.…”

“…11 It has been implicated in the pathogenesis of many common autoimmune disorders, including multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. 8,[12][13][14][15][16][17][18][19] Two anti-IL17A monoclonal antibodies were approved for treatment of psoriasis, spondyloarthropathies, psoriatic arthritis, and ankylosing spondylitis, 20 although both these antibody therapies had significant side effects.…”

“…Published studies suggest T H 17 cells protect against certain diseases and infection, and are associated with autoimmunity and pathogenesis. 8,[12][13][14][15][16][17][18][19][38][39][40][41] Previous studies implicating T H 17 cells in diseases, such as psoriasis, inflammatory bowel disease, RA, EAE, and MS, led us to examine the possibility that IL17A, IL17RA, and IL17RC regulate HSV-1 infectivity in vivo.…”

Corneal Lymphangiogenesis: Current Pathophysiological Understandings and Its Functional Role in Ocular Surface Disease

“…Although the mechanism by which IL-17 induces VEGF-D/C remains unclear, pathways involving direct upregulation of VEGF-D by IL-17 receptor-expressing cells such as corneal epithelial and stromal cells and indirect upregulation of VEGF-C through IL-1β-mediated pathways are suspected [ 55 , 60 ]. However, IL-17 has recently been reported as a negative regulator of lymphangiogenesis during the resolution phase of Th17-mediated immune responses in a model of cholera toxin-mediated lung inflammation [ 61 ], suggesting that the effect of IL-17 on lymphangiogenesis may differ depending on the organ or situation.…”