TH2 cells and their cytokines regulate formation and function of lymphatic vessels

Abstract

Lymphatic vessels (LVs) are critical for immune surveillance and involved in the pathogenesis of diverse diseases. LV density is increased during inflammation; however, little is known about how the resolution of LVs is controlled in different inflammatory conditions. Here we show the negative effects of T helper type 2 (T H 2) cells and their cytokines on LV formation. IL-4 and IL-13 downregulate essential transcription factors of lymphatic endothelial cells (LECs) and inhibit tube formation. Co-culture of LECs with T H 2 cells also inhibits tube formation, but this effect is fully reversed by interleukin (IL)-4 and/or IL-13 neutralization. Furthermore, the in vivo blockade of IL-4 and/or IL-13 in an asthma model not only increases the density but also enhances the function of lung LVs. These results demonstrate an antilymphangiogenic function of T H 2 cells and their cytokines, suggesting a potential usefulness of IL-4 and/or IL-13 antagonist as therapeutic agents for allergic asthma through expanding LV mediated-enhanced antigen clearance from the inflammatory sites.

Diphtheria toxin–mediated ablation of lymphatic endothelial cells results in progressive lymphedema

“…Indeed, previous studies have shown that radiation-induced fibrosis markedly decreases interstitial fluid transport and that inhibition of fibrosis effectively preserves lymphatic function independent of LEC survival in this setting (53). Finally, a number of recent studies have shown that T cells are potently antilymphangiogenic and that this effect is mediated, at least in part, by the expression of inflammatory cytokines such as IFN-γ, IL-4, and IL-13 (54)(55)(56). The findings of the current study are consistent with these studies, since we found that depletion of CD4 + cells increased LVD histologically and radiographically.…”

High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation

“…There have been reports of negative regulation of lymphangiogenesis by IFNγ (67) and TH2 cytokines IL-4 and IL-13 (68) and positive regulation by IL-17 (69), LTα, and TNF (38, 70). LT is crucial for both lymphoid organ development and TLOs, and LTα 3 contributes to lymphangiogenesis in development (38).…”

IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease

“…Sphk1 induction was significantly attenuated in Il4ra −/− LECs, consistent with an intrinsic defect of Sphk1 expression in these cells (Figure 5F). LECs have been shown to express IL4RA (23, 24), and stimulation of Il4ra +/+ LECs with dLN media from 7d-sclGvHD mice enhanced IL4RA expression (Supplemental Figure 3A). IL13 induced the expression of Ccl2 , a well-known IL13 target gene (Supplemental Figure 3B) but by itself did not result in upregulated Sphk1 transcription in Il4ra +/+ LECs (Figure 5F).…”

“…Recent studies have shown that LECs express IL4RA and that stimulation with IL13 or IL4 inhibits LEC proliferation (23, 24). While we did not observe a difference in the absolute number of LECs in the dLNs of Il4ra +/+ and Il4ra −/− 7d-sclGvHD mice (Figure 5, D and E), our data suggest that the regulation of Sphk1 expression and S1P production is another function of IL4RA in LECs and the collapsed appearance of the lymphatic vessels in Il4ra −/− hosts (Figure 5G) is consistent with a functionally relevant reduction in S1P levels in the dLNs of these mice (Figure 4C).…”