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 (TH2) 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 TH2 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 anti-lymphangiogenic function of TH2 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.
Highlights
Lymphatic vessels (LVs) are critical for immune surveillance and involved in the pathogenesis of diverse diseases
We found that recombinant IL-4 or rIL-13 treatment reduced the expression of Prox-1 and LYVE-1 mRNA by mouse LECs effects of TH2 cells (mLECs) in a dose-dependent manner (Fig. 1b,c)
We investigated the roles of TH2 cells and their cytokines, IL-4 and IL-13, in lymphangiogenesis using an in vitro lymphatic endothelial cells (LECs) culture system and an allergic asthma model
Summary
Lymphatic vessels (LVs) are critical for immune surveillance and involved in the pathogenesis of diverse diseases. IL-4 and IL-13 downregulate essential transcription factors of lymphatic endothelial cells (LECs) and inhibit tube formation. Identification of an LEC-specific transcription factor, prospero homeobox protein-1 (Prox-1), as well as lymphatic markers like LV endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin, has facilitated investigation of LV’s role in various diseases. TH2 cells predominantly secrete interleukin (IL)-4 and IL-13, potent pro-inflammatory cytokines that play critical roles in allergic diseases such as asthma[23,24]. We investigate the effects of TH2 cells and their cytokines on LECs in vitro and on remodelling of LVs in mouse models of allergic asthma in vivo. Our results show that IL-4 and IL-13 have strong anti-lymphangiogenic effects affecting the density, and the function of LVs. the anti-lymphangiogenic effects of IL-4 and IL-13 are predominant even in a pro-lymphangiogenic factor-rich environment, the density of airway LVs is not increased in murine allergic asthma models. The finding that blockade of TH2 cytokines can improve lymphatic function is important and clinically relevant as it suggests that enhanced lymphatics mediated-rapid clearance of antigens from inflammatory sites could be a means of preventing or treating allergic diseases
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