Year: 2022
Type: article
Abstract: 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.
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
Funders: U.S. Department of Health and Human Services, National Institutes of Health, Feinstein Institutes for Medical Research, National Institute on Alcohol Abuse and Alcoholism, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: G1000596038, G2990038114, Improvement of Organ Function after Severe Hypovolemia, Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction, G5296321455, G567712032, G5834532, Mechanisms of Radiation-Induced Innate Immune Dysfunction and Its Countermeasures, G6040464884, G6206477956, Neutrophils in Sepsis: Role of CIRP, G6437893529, Novel Approaches to Maintaining Organ Function in Sepsis, G7476676021, G7649421911, G7685213603, Promotion of Alzheimers Disease by Alcohol - Role of eCIRP, G9000009051, G9000017191, G9000138087, G9000141619, G9000145983, G9000224020, G919763778
OpenAlex ID: W4310780531