Does cardiac-specific knockdown of C3aR1 improve cardiac function and reduce myocardial damage in a rat model of sepsis-induced myocardial injury?
C3aR1 mediates macrophage-neutrophil crosstalk in sepsis-induced myocardial injury, and its knockdown improves cardiac function, highlighting it as a potential therapeutic target.
ABSTRACT Sepsis‐induced myocardial injury (SIMI) is a leading cause of mortality in critically ill patients, driven by dysregulated immune‐inflammation responses. Although macrophages and neutrophils are key players in this process, the mechanisms governing their crosstalk in SIMI remain unclear. Here, we demonstrate that the complement C3a receptor 1 (C3aR1) critically mediates this interaction. Using a cecal ligation and puncture (CLP)‐induced SIMI rat model and an in vitro co‐culture system with THP‐1‐derived macrophages, HL‐60 cells and AC16 cardiomyocytes, we show that C3aR1 promotes macrophage M1 polarisation via the TLR4/NF‐κB pathway. The activated M1 macrophages subsequently trigger neutrophil necroptosis, leading to the release of chemokines and establishing a self‐amplifying inflammatory loop from M1 polarisation to neutrophil necroptosis and cardiomyocyte injury, ultimately resulting in cardiac dysfunction. Cardiac‐specific knockdown of C3aR1 in vivo attenuated myocardial damage, reduced inflammatory cell infiltration and improved cardiac function. Our findings identify C3aR1 as a key molecular hub orchestrating macrophage‐neutrophil crosstalk in SIMI and highlight its potential as a therapeutic target for mitigating sepsis‐induced cardiac complications.
Xu et al. (Wed,) studied this question.