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.
View: Text | PDF
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

×

Figure 2

Cardiac M2-like macrophages underwent post-MI area-specific changes.

Options: View larger image (or click on image) Download as PowerPoint
Cardiac M2-like macrophages underwent post-MI area-specific changes. (A)...
(A) IHC confirmed the presence of CD206+ cells in the myocardial interstitium of normal mouse hearts, almost all of which (96.9% ± 2.0%; n = 6 different hearts) were also positive for CD68. Conversely, the majority (92.8% ± 3.0%; n = 6 different hearts) of CD68+ cells were CD206+. Nuclei were stained with DAPI. Scale bar: 50 μm. (B) Immunofluorescence revealed that the number of CD206+ M2-like macrophages was primarily increased in the infarct area (and in the border area to a lesser extent), with a post-MI peak on day 7. No change in the number of M2-like macrophages in the remote area was noted. Scale bars: 50 μm. (C) The post-MI chronological numbers of CD68+, CD206+, and CD11c+ cells in each infarct, border, or remote area were counted in the immunohistochemical samples described above. See Supplemental Figure 2 for representative images of immunostaining for CD68 and CD11c. n = 6 different hearts. *P < 0.05 versus day 0 (no MI, normal heart) in each cell type, repeated-measures ANOVA.