Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells

• Published in: Immunity (Cambridge, Mass.) Vol. 44; no. 2; pp. 355 - 367
• Main Authors: Kuswanto, Wilson, Burzyn, Dalia, Panduro, Marisella, Wang, Kathy K., Jang, Young Charles, Wagers, Amy J., Benoist, Christophe, Mathis, Diane
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-02-2016; Elsevier Limited
• Subjects: Adipogenesis - immunology; Age; Aging - immunology; Animals; Biomarkers - metabolism; Cell adhesion & migration; Cell Proliferation; Cells, Cultured; Cytokines; Gene expression; Homeostasis; Humans; Interleukin-33 - metabolism; Lymphocytes; Mechanotransduction, Cellular; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal - innervation; Muscle, Skeletal - physiology; Musculoskeletal system; Nerve Fibers - physiology; Neuroimmunomodulation; Population; Regeneration - immunology; Rodents; Stem Cells - immunology; T cell receptors; T-Lymphocytes, Regulatory - immunology; Wound Healing
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.01.009

Normal repair of skeletal muscle requires local expansion of a special population of Foxp3+CD4+ regulatory T (Treg) cells. Such cells failed to accumulate in acutely injured muscle of old mice, known to undergo ineffectual repair. This defect reflected reduced recruitment of Treg cells to injured muscle, as well as less proliferation and retention therein. Interleukin-33 (IL-33) regulated muscle Treg cell homeostasis in young mice, and its administration to old mice ameliorated their deficits in Treg cell accumulation and muscle regeneration. The major IL-33-expressing cells in skeletal muscle displayed a constellation of markers diagnostic of fibro/adipogenic progenitor cells and were often associated with neural structures, including nerve fibers, nerve bundles, and muscle spindles, which are stretch-sensitive mechanoreceptors important for proprioception. IL-33+ cells were more frequent after muscle injury and were reduced in old mice. IL-33 is well situated to relay signals between the nervous and immune systems within the muscle context.
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•Muscle regulatory T (Treg) cells, which aid muscle repair, are reduced in aged mice•IL-33 regulates muscle Treg cell dynamics; its injection into old mice improves repair•Fibro/adipogenic progenitors (FAPs) are the major IL-33-producing cells in muscle•IL-33+ FAPs are often closely apposed to nerve structures in skeletal muscle
Aging is associated with decreased regenerative capacity of skeletal muscle. Mathis and colleagues find that reparative muscle Treg cells do not accumulate in acutely injured muscle of old mice. IL-33 regulates muscle Treg cell homeostasis, and its administration improves muscle Treg cell accumulation and muscle regeneration in old mice.