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 8

IL-4 treatment improved post-MI prognosis and cardiac function.

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IL-4 treatment improved post-MI prognosis and cardiac function. (A) Post...
(A) Post-MI survival rates of the mice were improved in the IL-4–treated group (n = 31) compared with those of the PBS-treated group (n = 29). *P < 0.05 versus the PBS-treated group, log-rank test. (B) The cardiac rupture rate over a 28-day post-MI period was reduced in the IL-4–treated group (n = 31) compared with that of the PBS-treated group (n = 29). *P < 0.05 versus the PBS-treated group, χ2 test. (C) Echocardiographic analysis revealed that the IL-4–treated group showed improved cardiac function and attenuated ventricular dilatation compared with the PBS-treated group. n = 12 for each point in each group. *P < 0.05 versus the PBS-treated group at the corresponding time point, repeated-measures ANOVA. See Supplemental Table 2 for additional pre- and post-MI echocardiographic data. (D) Cardiac catheterization assessments detected improved hemodynamics and enhanced cardiac performance at day 28 after MI in the IL-4–treated group (n = 10) compared with the PBS-treated group (n = 10). *P < 0.05 versus the PBS-treated group, 2-tailed, unpaired Student’s t test. See Supplemental Table 3 for more detailed data. dP/dt, LV contractility; LVEDP, LV end-diastolic pressure; Max, maximum.