首页|Extracellular CIRP dysregulates macrophage bacterial phagocytosis in sepsis

Extracellular CIRP dysregulates macrophage bacterial phagocytosis in sepsis

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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.

βPIXeCIRPMacrophagePhagocytosisRac1STAT3

Mian Zhou、Monowar Aziz、Hao-Ting Yen、Gaifeng Ma、Atsushi Murao、Ping Wang

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Center for Immunology and Inflammation,The Feinstein Institutes for Medical Research,Manhasset,NY,USA

Departments of Surgery and Molecular Medicine,Zucker School of Medicine at Hofstra/Northwell,Manhasset,NY,USA

US National Institutes of Health(NIH)US National Institutes of Health(NIH)US National Institutes of Health(NIH)US National Institutes of Health(NIH)US National Institutes of Health(NIH)US NIHUS NIH

R35GM118337R01HL076179R01AA028947U01AI133655U01AI170018R01GM129633U01AI170018

2023

10.1038/s41423-022-00961-3

中国免疫学杂志(英文版)
中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI
影响因子：0.731
ISSN：1672-7681
年,卷(期)：2023.20(1)
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