PECAM-1 protects against DIC by dampening inflammatory responses via inhibiting macrophage pyroptosis and restoring vascular barrier integrity

Abstract

Disseminated intravascular coagulation (DIC) is a frequent complication of sepsis that affects patient outcomes due to accompanying thrombo-inflammation and microvascular permeability changes. Platelet endothelial cell adhesion molecule-1 (PECAM-1), a cellular adhesion and signaling receptor that is expressed on both hematopoietic and endothelial cells, plays an important anti-inflammatory role in acute and chronic inflammatory disease models. Little is known, however, about role and mechanism of PECAM-1 in septic DIC. Here, we investigated whether PECAM-1 might play a protective role in hindering the development of septic DIC. Plasma levels of soluble PECAM-1 were markedly elevated in septic patients that developed DIC, with a correspondingly poorer outcome. PECAM-1 knockout exhibited more severe DIC and poorer outcome in the LPS induced- and cecal ligation and puncture-induced DIC model, which could be alleviated by tissue factor inhibitor. This phenomenon seemed to be equally linked to PECAM-1 expression by both endothelial and blood cells. Furthermore, PECAM-1 was found to exert its protective effect on developing septic DIC by the following 2 distinct mechanisms: the inhibition of macrophage pyroptosis and the acceleration of the restoration of the endothelial cell barrier. Taken together, these results implicate PECAM-1 as a potentially attractive target for the development of novel therapeutics to manage and treat septic DIC.