Activin A secretion by muscle-repairing macrophages induces heterotopic ossification in mice
Wenqiang Yin, Kazuo Okamoto, Asuka Terashima, Warunee Pluemsakunthai, Takehito Ono, Taku Ito-Kureha, Shizuo Akira, Yoshinobu Hashizume, Roland Baron, Satoshi Ueha, Kouji Matsushima, Martin M. Matzuk, Yuji Mishina, Hiroshi Takayanagi
Wenqiang Yin, Kazuo Okamoto, Asuka Terashima, Warunee Pluemsakunthai, Takehito Ono, Taku Ito-Kureha, Shizuo Akira, Yoshinobu Hashizume, Roland Baron, Satoshi Ueha, Kouji Matsushima, Martin M. Matzuk, Yuji Mishina, Hiroshi Takayanagi
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Research Article Bone biology Immunology Muscle biology

Activin A secretion by muscle-repairing macrophages induces heterotopic ossification in mice

Abstract

The immune system is not only essential for host defense, but it is also involved in tissue maintenance and disease pathogenesis. Macrophages play a key role in tissue repair, fibrosis, and tumorigenesis, but the mechanisms underlying their multifunctionality have not been fully explored. Here, we identified Mrep (Ly6ChiCX3CR1loPDPN+CD9+) as a crucial subset of macrophages for muscle regeneration after muscle injury. Muscle regeneration required Mrep-derived activin A, which was produced via the TLR4/TIR domain–containing adapter-inducing interferon-β/TANK-binding kinase 1/interferon regulatory factor 3/7 signaling pathway in response to muscle injury. Mrep exerted pathological effects by secreting activin A in a model of genetically induced heterotopic ossification (HO), which was suppressed by TLR4 inhibition. Thus, this study elucidates the context-dependent functions of macrophages and the link between injury and HO, suggesting that Mrep is a potential therapeutic target for regenerating muscles and suppressing HO.

Authors

Wenqiang Yin, Kazuo Okamoto, Asuka Terashima, Warunee Pluemsakunthai, Takehito Ono, Taku Ito-Kureha, Shizuo Akira, Yoshinobu Hashizume, Roland Baron, Satoshi Ueha, Kouji Matsushima, Martin M. Matzuk, Yuji Mishina, Hiroshi Takayanagi

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Figure 8

TLR4/TRIF-mediated signaling is required for proper muscle regeneration.

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TLR4/TRIF-mediated signaling is required for proper muscle regeneration....
(A–C) H&E and immunofluorescence staining of muscle sections from WT (A; n = 4), Tlr4–/– (B; n = 5), and Ticam1–/– mice (C; n = 5) at 4 dpi. Immunofluorescence staining showing eMyHC-labeled (red) regenerating muscle fibers and Hoechst-stained (blue) nuclei. The boxed areas are shown at higher magnification (×4) in the panels to the right. H&E staining and the corresponding immunofluorescence images represent the same field. Scale bars: 100 μm. (D and E) Quantification of regeneration showing the distribution of eMyHC+ CSA (D) and the mean CSA of eMyHC+ fibers (E). The P values were calculated using 1-way ANOVA with Tukey’s multiple-comparison test. A P value < 0.05 was considered significant. Data are shown as the mean ± SEM, and symbols represent individual fibers (D) or individual mice (E).