Alternatively activated macrophages determine repair of the infarcted adult murine heart

Abstract

Alternatively activated (also known as M2) macrophages are involved in the repair of various types of organs. However, the contribution of M2 macrophages to cardiac repair after myocardial infarction (MI) remains to be fully characterized. Here, we identified CD206+F4/80+CD11b+ M2-like macrophages in the murine heart and demonstrated that this cell population predominantly increases in the infarct area and exhibits strengthened reparative abilities after MI. We evaluated mice lacking the kinase TRIB1 (Trib1-/-), which exhibit a selective depletion of M2 macrophages after MI. Compared with control animals, Trib1-/- mice had a catastrophic prognosis, with frequent cardiac rupture, as the result of markedly reduced collagen fibril formation in the infarct area due to impaired fibroblast activation. The decreased tissue repair observed in Trib1-/- mice was entirely rescued by an external supply of M2-like macrophages. Furthermore, IL-1α and osteopontin were suggested to be mediators of M2-like macrophage-induced fibroblast activation. In addition, IL-4 administration achieved a targeted increase in the number of M2-like macrophages and enhanced the post-MI prognosis of WT mice, corresponding with amplified fibroblast activation and formation of more supportive fibrous tissues in the infarcts. Together, these data demonstrate that M2-like macrophages critically determine the repair of infarcted adult murine heart by regulating fibroblast activation and suggest that IL-4 is a potential biological drug for treating MI.

Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing

“…By d7 after MI, proinflammatory factors subside to facilitate collagen deposition and reparative fibroblast activation (16). In MI controls, 70% ± 3% of macrophages at d7 after MI were reparative M2 macrophages ( Figure 1H, second quadrant), consistent with previous findings (14,17). In contrast, only 54% ± 4% of LPS+MI macrophages were reparative M2 macrophages (P < 0.05).…”

“…Ccl2, a homologue of Ccl12, was not significantly different in macrophages isolated from the infarct of d7 post-MI LV controls compared with the LPS+MI group. Since macrophages are known to regulate ECM deposition and scar formation (12,17,19), we hypothesized that chronic inflammation may prolong M1 macrophage polarization to regulate fibroblast function through increased secretion of Ccl12. We provide here the first evidence to our knowledge that chronic inflammation exacerbated macrophage secretion of Ccl12.…”

“…The first phase is dominated by Ly6c high monocytes that give rise to early inflammatory macrophages, which remove necrotic tissue by phagocytosis and secrete proteolytic enzymes including MMP-2 (47). In the second phase, Ly6c low monocytes facilitate wound healing and regeneration to promote myofibroblast accumulation, collagen deposition, and angiogenesis (17,47) whereas, after chronic exposure, macrophage numbers are attenuated at the later phase after MI. In addition, acute LPS exposure increases cardiac fibrosis without the onset of cardiac injury, suggesting that the mechanisms behind LV dysfunction may have distinct signaling attributes that distinguish acute and chronic inflammation mechanisms (50).…”

Ectonucleotidase CD39-driven control of postinfarction myocardial repair and rupture

“…We posit that the absolute increase in numbers of macrophages with a reparative phenotype contributed to the observed protection from cardiac rupture in CD39-null mice. These data complement and validate a recent report demonstrating the necessity of alternatively activated macrophages for repair of infarcted heart tissue and survival (35). In our study, we found that, in mice globally lacking CD39, circulating ATP was elevated and sustained, even days after MI.…”

Colchicine Improves Survival, Left Ventricular Remodeling, and Chronic Cardiac Function After Acute Myocardial Infarction

“…The M2 macrophage has beneficial effects on tissue repair, suppression of inflammation and activation of fibroblast. 20 We assessed the phenotype of infiltrated macrophages in the infarcted area at 7 days after MI by mRNA expression of M1/M2 cytokines in the infarcted tissue ( Figure S2). There was not statistically different but colchicine tended to attenuate M1 cytokines (TNF-α, IL-1β and IL-6) and tended to increase M2 cytokines (IL-10 and TGF-β, Figure S3).…”