Sex differences in the chronic autoimmune response to myocardial infarction

Abstract

Myocardial infarction (MI) causes a robust inflammatory response, which is necessary for remodeling and scar formation of the infarcted left ventricle (LV). However, this can lead to chronic systemic inflammation and persistent autoimmune responses. In this study, we analyzed sex differences in the inflammatory autoimmune response to chronic MI. MI was induced by permanent left coronary artery ligation in adult male and female C57BL/6J mice for one, four, and eight weeks. Both sexes exhibited similar declines in LV function. Females had higher levels of total immune cells and T cells in the infarct and remote area at D7 post-MI, and B cells at D56. MI increased levels of pro-inflammatory cytokines (Il1b, Il6, Tnf, Ccl2, Ifng, Il18) in the LV infarct that peaked at one week, which was exaggerated in females for Il6, Ifng, and Il10. In the remote LV, females had higher levels of Il6, Tnf, Ccl2, and Il18. MI increased spleen mass in females only, and splenic cytokines were higher in females at several time points, including Il1b, Il12a, Il10, Ifng, Il18, Ccl2, and Il4. IgG and IgM deposition in the LV infarct increased over time in both sexes, but more so in females. In the remote area, both sexes had increased IgG and IgM at eight weeks. Plasma IgM was higher in females at one, four, and eight weeks post-MI compared with males. Plasma IgG and IgM autoantibodies were detected in males and females after MI, but the number of autoantibodies displaying reactivity to autoantigens was much higher in females, particularly at week 8. In summary, MI leads to the development of systemic and myocardial autoimmune activation, which is more pronounced in females.

Keywords: autoimmune disease; heart failure; inflammation; myocardial infarction; sex differences.

Figure 1:. Infarct size, mortality, and post-MI cardiac function.

(A) Representative LV midsections stained with picrosirius red and infarct length expressed as percentage of total LV circumference. (B) Cumulative mortality (D7, D28, D56 groups combined). (C) Plasma troponin measurements at D1 and D7 after MI. (D) Echocardiography parameters. a: P<0.05 vs. day D0, b: P<0.05 vs. D7, c: P<0.05 vs. D28, d: P<0.05 male vs. female. N = 6–10 mice per group.

Figure 2:. Flow cytometry analysis of post-MI LV tissue for (A) infarct area and (B) remote area. a: P<0.05 vs. day D0, d: P<0.05 male vs. female. N = 6–10 mice per group.

Figure 3:. Flow cytometry analysis of spleen tissue after MI. a: P<0.05 vs. day D0, d: P<0.05 male vs. female. N = 6–10 mice per group.

Figure 4:. Gene expression analysis of inflammatory cytokines in the LV infarct (A) and remote (B) after MI. a: P<0.05 vs. day D0, d: P<0.05 male vs. female. N = 6–10 mice per group.

Figure 5:. (A) Spleen mass after MI. (B) Gene expression analysis of inflammatory cytokines in the spleen after MI. a: P<0.05 vs. day D0, d: P<0.05 male vs. female. N = 7–15 mice per group.

Figure 6:. (A) IgG deposition (green) in the LV infarct and remote area. (B) IgM deposition in the LV infarct and remote area. a: P<0.05 vs. day D0, d: P<0.05 male vs. female. N = 7–15 mice per group.

Figure 7:. Changes in plasma cytokines and antibodies.

(A) Plasma levels of CRP, IL-10, and IFN-γ. Plasma levels of (B) total IgG and IgM. (C) Numbers of autoantibodies either increased or decreased after MI. a: P<0.05 vs. day D0, d: P<0.05 male vs. female. N = 7–15 mice per group.