Myocardial infarction promotes local and systemic autoimmune signatures in male and female mice

Myocardial infarction (MI) induces a strong inflammatory response that is essential for left ventricle (LV) remodeling and scar formation. However, the chronic inflammatory and autoimmune response to MI is not well understood. In this study, we hypothesized that MI would lead to local and systemic autoimmune responses in mice. Permanent left coronary artery ligation was performed in adult male and female C57BL/6J mice, which were studied at 1, 4, and 8 weeks (WK) post-MI. Females showed higher survival rates at all time points. Both sexes exhibited significant LV dilation, wall thinning, contractile dysfunction (assessed by echocardiography), and progressive LV hypertrophy. Spleen mass was elevated in females at all time points, peaking at 1WK. Flow cytometry analysis indicated that both sexes displayed immune cell infiltration after MI. However, females exhibited higher total immune cells at 1 and 4WKs, while males had higher levels of neutrophils. Females also had elevated CD3+ T cells at 1WK, and B220+ B cells at 8WK. In the remote area, both sexes had increased immune cells at 1WK, albeit higher in females. Females also exhibited increased levels of B cells in the remote area at 8WK. Both males and females had elevated expression of inflammatory cytokines (Il1b, Il6, Tnf, Ccl2, Ifng, Il18) in the infarcted LV, peaking at 1WK, but this response was more pronounced in females for Il6 and Ifng. In the remote area, females showed higher levels of Il6 at all time points, Tnf at 1 and 8 weeks, Ccl2 at 1 and 4WK, and Il18 at 8WK. In addition, splenic cytokine levels, including Il1b, Il12a, Il10, Ifng, Il18, Ccl2, and Il4, were increased in females at multiple time points. IgG antibody deposition was observed in the LV infarct at 1 week in females, subsequently increasing at 4 and 8WK; this effect was less pronounced in males at 4 and 8WK. LV infarct IgM deposition was higher in females at 1 week but exhibited similar peaks for both sexes by 4WK. In both sexes, IgG and IgM deposition occurred at 8WK in the remote LV area. Plasma IgG levels were higher in females at all time points, but they did not change post-MI in either sex. Plasma IgM was higher in females at 1, 4, and 8WK post-MI compared to males and increased relative to the no-MI controls at 8WK. IgG and IgM autoantibodies to several autoantigens were detected in both sexes after MI, with a greater number of autoantigens targeted in females. We detected anti-nuclear autoantibodies in females at WK 1 and 4 (ssDNA, dsDNA, histone H1, histone H2A), a classic hallmark of autoimmune disease, and anti-cardiac antibodies at 8WK (ACE2, mitochondrion, myosin). We also detected increased anti-IL-6 IgM autoantibodies in females at 8WK, which may be due to increased IL-6 levels in the female heart after MI. In conclusion, MI triggers systemic and myocardial autoimmune activation, which is more pronounced in females. NIH R01 HL166737, AHA CDA856365 (Mouton) NIH R00 HL146888, NIH U54 HL169191 (Taylor) NIH P20 GM104357, P30 GM149404, U54 GM115428 (Hall) NIH T32HL105324 (Spitz) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.