Alternatively activated macrophages determine repair of the infarcted adult murine heart
Manabu Shiraishi, … , Kenta Yashiro, Ken Suzuki
Manabu Shiraishi, … , Kenta Yashiro, Ken Suzuki
Published June 1, 2016; First 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 1

M2-like macrophages were present in the adult murine heart.

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M2-like macrophages were present in the adult murine heart. (A) Flow cyt...
(A) Flow cytometric analysis confirmed that CD206+F4/80+CD11b+ M2-like macrophages were present in normal, no-MI hearts and in day-7 post-MI hearts of adult C57BL/6 mice. More than 90% of F4/80+CD11b+ macrophages in normal hearts were positive for CD206, whereas the percentage of CD206+ cells in F4/80+CD11b+ macrophages was reduced to 78.0% ± 1.4% at day 7 after MI (n = 6 in each group; P < 0.01, 2-tailed, unpaired Student’s t test). Light blue lines indicate the IgG control data. (B) Most (92.7% ± 1.4% and 90.0% ± 2.6% in the no-MI hearts and day-7 post-MI hearts) of the CD11b+CD206+ cells were CCR2– and Ly6C–, while 97.1% ± 1.0% of CD11b+CD206– cells were CCR2+ and LyC6+. Representative results of 6 different studies are presented. (C) CD206+F4/80+CD11b+ M2-like macrophages were collected by FACS from the peritoneal cavity of normal mice [M2 (Peritoneal)], from intact, no-MI hearts [M2 (no MI)], and from day-7 post-MI hearts [M2 (MI)] and subjected to real-time reverse transcription PCR (RT-PCR) analysis. CD11b+CD206– M1-like macrophages were also collected from day-7 post-MI hearts [M1 (MI)] and analyzed. Relative expression to that of cardiac fibroblasts (Fibro) is presented. M2-like macrophages from all 3 sources expressed the M2 macrophage markers Mrc1 (CD206), Retnla (Fizz1), and Chil3 (Ym1). n = 6 different mice in each group. *P < 0.05 versus both Fibro and M1 (MI); †P < 0.05 versus M2 (Peritoneal); #P < 0.05 versus M2 (no MI); ‡P < 0.05 versus Fibro; 1-way ANOVA.