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 5

Depletion of the post-MI increase in M2-like macrophages in Trib1–/– mice resulted in a critically deteriorated prognosis.

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Depletion of the post-MI increase in M2-like macrophages in Trib1–/– mic...
(A) The post-MI survival of mice was dramatically reduced in the KO group (Trib1–/– mice; n = 12) compared with that of the WT group (WT littermates; n = 26), but this effect was fully reversed by transplanting BMDMs in Matrigel (KO plus BMDMs group, n = 10). The control transplantation (KO plus Matrigel group; injection of Matrigel only, n = 10) did not affect the survival rates of the KO group. *P < 0.05 versus both KO and KO plus Matrigel groups, log-rank test. (B) The cardiac rupture rate over a 28-day post-MI period was increased by 9-fold in the KO group compared with the rupture rate in the WT group. This fatal event was prevented in the KO plus BMDMs group. The control transplantation (KO plus Matrigel group) did not influence the cardiac rupture rate in the KO group. n = the same as in A in each group. P < 0.05 versus both the KO and KO plus Matrigel groups, χ2 test. (C) Echocardiographic analysis revealed exacerbated cardiac dysfunction in the KO group, while this deterioration was ameliorated in the KO plus BMDMs group. n (day 0, day, 7, and day 28) = 12, 10, and 10 in the WT group; 12, 5, and 1 in the KO group; and 10, 6, and 6 in the KO plus BMDMs group. *P < 0.05 versus the corresponding time point for the KO group, repeated-measures ANOVA. (Note that the day-28 data were not included in the calculation, because n = 1 in the KO group; Trib1–/– mice rarely survived for 28 days after MI.) LVDd, LV end-diastolic dimension; LVDs, LV end-systolic dimension; LVEF, LV ejection fraction; MG, Matrigel. See Supplemental Table 1 for more detailed echocardiographic data.