Extracellular CIRP dysregulates macrophage bacterial phagocytosis in sepsis

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 beta PIX, a Rac1 activator. We further demonstrated that STAT3 and beta PIX formed a complex following rmCIRP treatment, preventing beta PIX 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-beta PIX 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.

Automated summary

In this study, we identified a novel mechanism by which eCIRP impairs macrophage bacterial phagocytosis in sepsis. Increased eCIRP levels were associated with decreased bacterial clearance in infected mice. eCIRP inhibited actin remodeling in macrophages through the formation of a STAT3-beta PIX complex, resulting in phagocytic dysfunction. Inhibition of STAT3 rescued the macrophage phagocytic dysfunction induced by eCIRP.