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 13

IL-1α and osteopontin played a vital role in cardiac M2-like macrophage–induced fibroblast activation.

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IL-1α and osteopontin played a vital role in cardiac M2-like macrophage–...
(A) Schematic of the coculture experimental protocol. Primary cardiac fibroblasts were cocultured with or without CD206+F4/80+CD11b+ M2-like macrophages from intact, no-MI or MI (day 7 after MI) hearts in the Boyden chamber culture system for 48 hours. Neutralizing Abs against osteopontin and/or IL-1α were added to the relevant groups at the beginning of the coculture with M2-like macrophages. (B) Activation of cardiac fibroblasts (ratio of vimentin+αSMA+ myofibroblasts to vimentin+ fibroblasts) was increased in the cocultures with M2 (MI) macrophages but not with M2 (no MI) macrophages. Representative images are presented in C. This increased activation was eliminated by neutralizing Abs against osteopontin and IL-1α. n = 8–10 in each group. *P < 0.05, 1-way ANOVA. (C) Representative images of immunocytochemical staining for vimentin and αSMA. Nuclei were counterstained with DAPI. Scale bars: 200 μm.