Timd4+ cardiac resident macrophages promote neutrophil chemotaxis and exacerbate sepsis-associated myocardial injury.

This study investigated the role of T-cell immunoglobulin and mucin domain-containing protein 4 (Timd4) in sepsis-associated myocardial injury. A murine sepsis model was established by cecal ligation and puncture. Timd4 was modulated in vivo by adeno-associated virus serotype 9-mediated overexpression or prophylactic administration of a Timd4-neutralizing antibody. Cardiac function, macrophage phagocytosis, chemokine expression, and neutrophil infiltration were evaluated. Sepsis reduced Timd4 expression and the proportion of Timd4-positive cardiac-resident macrophages (CRMs) in the heart. Timd4 overexpression enhanced the phagocytic capacity of macrophages, but also increased cardiac Cxcl1 and Cxcl2 expression, promoted cardiac neutrophil accumulation, and aggravated myocardial injury. In contrast, Timd4 neutralization attenuated these harmful effects. Notably, under neutrophil-depleted conditions, the detrimental effect of Timd4 overexpression was abolished, supporting neutrophils as downstream effector cells in Timd4-related myocardial injury. Mechanistically, Timd4 overexpression was associated with reduced Dusp1 mRNA expression and sustained p38 and JNK phosphorylation in the septic heart. In LPS-stimulated macrophages, JNK inhibition abolished the additional increase in Cxcl2 caused by Timd4 overexpression, whereas p38 inhibition did not eliminate this response. These findings indicate that Timd4 supports macrophage phagocytic function, but under septic conditions its net effect is to amplify chemokine expression, promote neutrophil accumulation, and worsen myocardial injury. The reduction of Timd4 during sepsis may therefore represent a compensatory but insufficient feedback response that limits Timd4-associated inflammatory amplification. These results suggest that the JNK-Cxcl2 axis may represent a potential target for immune intervention in sepsis-associated myocardial injury.