Macrophage C3aR1 Mediates Sepsis-Induced Myocardial Injury by Triggering Neutrophil Necroptosis.

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.