Alternatively activated macrophages determine repair of the infarcted adult murine heart
Manabu Shiraishi, … , Kenta Yashiro, Ken Suzuki
Manabu Shiraishi, … , Kenta Yashiro, Ken Suzuki
Published May 3, 2016
Citation Information: J Clin Invest. 2016;126(6):2151-2166. https://doi.org/10.1172/JCI85782.
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Research Article Cardiology

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.

Authors

Manabu Shiraishi, Yasunori Shintani, Yusuke Shintani, Hidekazu Ishida, Rie Saba, Atsushi Yamaguchi, Hideo Adachi, Kenta Yashiro, Ken Suzuki

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Figure 3

Cardiac M2-like macrophages strengthened their post-MI reparative ability.

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Cardiac M2-like macrophages strengthened their post-MI reparative abilit...
(A) CD206+F4/80+CD11b+ M2-like macrophages were collected by FACS from intact hearts [M2 (no MI)], day-7 post-MI hearts [M2 (MI)], and from the peritoneal cavity of intact mice [(M2 (Peritoneal)] and subjected to microarray analysis. Macrophages from different origins showed distinct molecular signatures. M2 (MI) had a different expression profile from that of M2 (no MI), although both were clustered distinctly from the M2 (Peritoneal) profile. (B) Heatmap revealed that among the genes encoding secreted proteins, 13 genes were upregulated and 3 were downregulated in M2 (MI) compared with M2 (no MI) macrophages. The upregulated genes included antiinflammatory and repair-associated genes. (C) Quantitative RT-PCR (qRT-PCR) analysis confirmed the post-MI upregulation of these repair-associated genes in CD206+F4/80+CD11b+ cardiac M2-like macrophages [M2 (MI)]. CD11b+CD206– M1-like macrophages from day-7 post-MI hearts [M1 (MI)] expressed these genes at lower levels. Expression levels relative to those of M2 (Peritoneal) are presented. n = 6 in each group. *P < 0.05 versus both M2 (Peritoneal) and M1 (MI); †P < 0.05 versus M2 (no MI); #P < 0.05 versus M2 (Peritoneal); 1-way ANOVA.