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 4

Post-MI increase in M2-like macrophages was abolished in Trib1–/– mice.

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Post-MI increase in M2-like macrophages was abolished in Trib1–/– mice. ...
(A) IHC indicated that the presence of CD206+ M2-like macrophages in intact, no-MI hearts in the KO group (Trib1–/– mice) was similar to that seen in the WT littermates group. n = 6 hearts in each group. Scale bars: 50 μm. (B) The increased number of CD206+ M2-like macrophages on day 7 after MI in the infarct and border areas of the WT group hearts (n = 6) was completely eliminated in the KO group hearts (n = 5). Scale bars: 50 μm. (C) The numbers of CD206+ cells were serially counted in each area. It was evident that the post-MI increase in CD206+ M2-like macrophage numbers in the damaged myocardium was abolished in Trib1–/– mice. n = 5–6 for each point in each group. *P < 0.05 versus intact, no-MI hearts in each group; †P < 0.05 versus the WT group at the corresponding time and area; repeated-measures ANOVA. (D) On day 7 after BMDM transplantation (WT mice derived and labeled with CM-DiI) into KO (Trib1–/–) mice with MI, the frequency of CD206+ M2-like macrophages in the infarct area was recovered to a degree similar to that in the WT group (see Figure 4, B and C). Most of the CD206+ M2 macrophages originated from the donor cells (Host, CD206+CM-DiI– cells; Donor, CD206+CM-DiI+ cells). Scale bar: 50 μm. n = 6 hearts.