How Tetraspanins Regulate Sepsis

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Vascular inflammatory responses determine the onset, progression, and consequence of sepsis. Tetraspanin CD82 proteins are expressed in endothelial cells (ECs) and leukocytes. Our recent study revealed that CD82 facilitates vascular inflammatory responses during sepsis. We demonstrated that, to facilitate inflammation, endothelial CD82 promotes lipopolysaccharide (LPS)- induced vascular leakage, leukocyte recruitment, and endothelial release of cytokines, leading to marked increase in mortality of animal with sepsis. How CD82 promotes the inflammatory events in blood vessels during sepsis is unclear. The goal of this study is to identify the mechanisms by which CD82 facilitates vascular inflammatory responses in sepsis at the molecular, cellular, and organism levels. We hypothesize that, CD82 facilitates the vesicular trafficking of inflammation-related molecules such as VE- cadherin, E-selectin, and cytokines, to promote inflammatory responses in sepsis and therefore exacerbate sepsis. In this project, we will first determine how CD82 inhibits vascular stability in sepsis by assessing the regulatory roles of CD82 in i) inflammation-induced disruption of EC-EC contacts/junctions and ii) recovery of endothelial barriers from the disrupted EC-EC contacts/junctions. Secondly, we will determine the mechanism by which CD82 promotes vascular recruitment of leukocytes during sepsis by assessing CD82 effects on the i) levels, ii) activities, and iii) turnover of inflammation- related cell adhesion proteins in ECs and leukocytes during sepsis. Finally, we will determine how CD82 inhibits cytokine secretion in sepsis by i) assessing in vivo and in vitro effects of CD82 on cytokine secretomes, ii) revealing CD82 roles in exosome formation and exocytosis, and iii) identifying the Rab GTPase(s) crucial for CD82-regulated exocytosis. This project will fill important knowledge gaps for the regulatory mechanisms of vascular inflammatory events in response to septic injury, leading to systemic vascular dysfunction, at the molecular, cellular, and organism levels. This project will also establish CD82 as a novel therapeutic target for ameliorating systemic vascular dysfunction during sepsis and improving the survival of sepsis patients.