Rationale Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6Chigh and reparative Ly-6Clow monocytes/macrophages (Mo/MΦ). According to one model, Mo/MΦ heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from one circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, Nr4a1, is essential to Ly-6Clow monocyte production but dispensable to Ly-6Clow macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity. Objective This study tested the role of Nr4a1 in MI in the context of the two Mo/MΦ accumulation scenarios. Methods and Results We show that Ly-6Chigh monocytes infiltrate the infarcted myocardium and, unlike Ly-6Clow monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6Chigh monocytes accrue in response to a brief Ccl2 burst. In the second, reparative phase, accumulated Ly-6Chigh monocytes give rise to reparative Ly-6Clow F4/80high macrophages that proliferate locally. In the absence of Nr4a1, Ly-6Chigh monocytes express heightened levels of Ccr2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function. Conclusions Ly-6Chigh monocytes orchestrate both inflammatory and reparative phases during MI and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.
The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death1,2; however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis—a major underlying cause of mortality worldwide—to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.
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