CD40-TRAF2/3/5 signaling promotes post-MI cardiac repair by facilitating macrophage efferocytosis, highlighting a potential mechanistic target for improving tissue remodeling.
BACKGROUND: After myocardial infarction (MI), macrophage-mediated clearance of dead cells, a process known as efferocytosis, represents a pivotal role in tissue remodeling. Efficient efferocytosis contributes to rescuing neighboring viable cardiomyocytes, drives the phenotypic transition of reparative macrophages, and facilitates the resolution of inflammation. In this study, we explored the roles of CD40 and the signals transduced by its 2 downstream adaptor-protein binding sites (TRAF2/3/5 and TRAF6) in the cardiac macrophage efferocytosis after MI. METHODS: mice were used to explore the roles of CD40 downstream signaling intermediates in MI and macrophage efferocytosis. RESULTS: mice confirmed that the CD40-TRAF2/3/5 signaling served as a crucial determinant in mediating CD40-related efferocytosis. STAT6 was identified as a key downstream factor in this process. Adenovirus-mediated gene transfer to overexpress a CD40 variant retaining TRAF2/3/5 binding site but lacking the TRAF6 in cardiac macrophages led to improvements in cardiac function and macrophage efferocytosis after MI. CONCLUSIONS: Our study established a pivotal positive role of macrophage CD40 in post-MI repair by facilitating macrophage efferocytosis. Specifically, TRAF2/3/5 rather than TRAF6 serves as the crucial signaling pathway that mediates CD40-associated efferocytosis.
Zhang et al. (Thu,) studied this question.