Extracellular CIRP dysregulates macrophage bacterial phagocytosis in sepsis  

作　　者：Mian Zhou Monowar Aziz Hao-Ting Yen Gaifeng Ma Atsushi Murao Ping Wang 

机构地区：[1]Center for Immunology and Inflammation,The Feinstein Institutes for Medical Research,Manhasset,NY,USA [2]Departments of Surgery and Molecular Medicine,Zucker School of Medicine at Hofstra/Northwell,Manhasset,NY,USA

出　　处：《Cellular & Molecular Immunology》2023年第1期80-93,共14页中国免疫学杂志（英文版）

基　　金：supported by the US National Institutes of Health(NIH)grants R35GM118337,R01HL076179,R01AA028947,U01AI133655 and U01AI170018;MA is supported by the US NIH grants R01GM129633 and U01AI170018.

摘　　要：In sepsis, macrophage bacterial phagocytosis is impaired, but the mechanism is not well elucidated. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that causes inflammation. However, whether eCIRP regulates macrophage bacterial phagocytosis is unknown. Here, we reported that the bacterial loads in the blood and peritoneal fluid were decreased in CIRP^(−/−) mice and anti-eCIRP Ab-treated mice after sepsis. Increased eCIRP levels were correlated with decreased bacterial clearance in septic mice. CIRP−/− mice showed a marked increase in survival after sepsis. Recombinant murine CIRP (rmCIRP) significantly decreased the phagocytosis of bacteria by macrophages in vivo and in vitro. rmCIRP decreased the protein expression of actin-binding proteins, ARP2, and p-cofilin in macrophages. rmCIRP significantly downregulated the protein expression of βPIX, a Rac1 activator. We further demonstrated that STAT3 and βPIX formed a complex following rmCIRP treatment, preventing βPIX from activating Rac1. We also found that eCIRP-induced STAT3 phosphorylation was required for eCIRP’s action in actin remodeling. Inhibition of STAT3 phosphorylation prevented the formation of the STAT3-βPIX complex, restoring ARP2 and p-cofilin expression and membrane protrusion in rmCIRP-treated macrophages. The STAT3 inhibitor stattic rescued the macrophage phagocytic dysfunction induced by rmCIRP. Thus, we identified a novel mechanism of macrophage phagocytic dysfunction caused by eCIRP, which provides a new therapeutic target to ameliorate sepsis.

关 键 词：βPIX eCIRP MACROPHAGE PHAGOCYTOSIS RAC1 STAT3 

分 类 号：R515.3[医药卫生—内科学]