How Endothelial Tetraspanins Inhibit Inflammation

Vascular inflammation underlines common pathophysiology of various cardiovascular diseases and determines the progression of infections and autoimmune diseases. Several tetraspanin proteins are highly expressed in endothelial cells (ECs). Some of these tetraspanns inhibit vascular inflammatory responses including i) endothelial leakage, ii) endothelial recruitment of leukocytes, and iii) endothelial release of cytokines. Hence, we call them anti-inflammatory tetraspanins. It is unclear how anti-inflammatory tetraspanins inhibit these vascular inflammatory responses. The goal of this study is to identify the mechanisms by which anti-inflammatory tetraspanins restrain vascular inflammation at the molecular, cellular, and organism levels. We hypothesize that anti-inflammatory tetraspanins restrain the endosome-mediated i) presentation of inflammation- related cell adhesion proteins on the EC surface and ii) release of pro-inflammatory cytokines from ECs, to prevent and inhibit vascular inflammation. In this project, we will first assess the inhibitory roles of anti-inflammatory tetraspanins in inflammation-induced i) leakage and ii) damage of endothelia. Secondly, we will assess how anti- inflammatory tetraspanins prevent endothelial recruitments of leukocytes and platelets in inflammation by revealing anti-inflammatory tetraspanin effects on the i) levels, ii) activities, and iii) trafficking of inflammation-related cell adhesion proteins in ECs in inflammation. Finally, we will determine how anti-inflammatory tetraspanins regulate EC secretion of cytokines to prevent inflammation exacerbation by i) assessing in vivo and in vitro effects of anti-inflammatory tetraspanins on cytokine secretomes, ii) revealing anti-inflammatory tetraspanin roles in Weibel- Palade body formation and maturation, and iii) identifying the molecular machinery crucial for anti- inflammatory tetraspanin-regulated exocytosis. This project will fill important knowledge gaps regarding the molecular and cellular mechanisms that regulate vascular inflammation in cardiovascular and other diseases. This project will also establish tetraspanins as novel therapeutic candidates against vascular inflammation.