Type 2 Innate Signals Stimulate Fibro/Adipogenic Progenitors to Facilitate Muscle Regeneration

• Published in: Cell Vol. 153; no. 2; pp. 376 - 388
• Main Authors: Heredia, Jose E., Mukundan, Lata, Chen, Francis M., Mueller, Alisa A., Deo, Rahul C., Locksley, Richard M., Rando, Thomas A., Chawla, Ajay
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.04.2013
• Subjects: adipocytes; Animals; Cobra Cardiotoxin Proteins; eosinophils; Eosinophils - physiology; immunity; Immunity, Innate; innate immunity; Interleukin-13 - genetics; Interleukin-13 - metabolism; interleukin-4; Interleukin-4 - genetics; Interleukin-4 - metabolism; Mice; Muscle Development; Muscle, Skeletal - cytology; Muscle, Skeletal - injuries; Muscle, Skeletal - physiology; muscles; Myeloid Cells - metabolism; Receptors, Cell Surface - metabolism; Regeneration; Signal Transduction; skeletal muscle; STAT6 Transcription Factor - metabolism; stem cells; vertebrates
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.02.053

In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here, we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues. [Display omitted] [Display omitted] ► Type 2 cytokine signaling via IL-4Rα is required for muscle regeneration ► Eosinophils secrete IL-4 and are required for regeneration of injured muscle ► Myeloid or satellite cell IL-4Rα signaling is dispensable for muscle regeneration ► IL-4Rα signaling regulates the functions of fibro/adipogenic progenitors in muscle Muscle injury promotes recruitment of eosinophils, immune cells that provide a niche for proliferating stem cells in regenerating muscle. Secretion of IL-4 by eosinophils promotes proliferation of fibro/adipogenic progenitors (FAPs) while inhibiting their differentiation into adipocytes, facilitating the engulfment of necrotic debris by FAPs.