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

Abstract

SUMMARY 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 (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.

CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms

“…In line with this, Tregs from IL-33-treated mice showed an enhanced suppressive function. Because tissue Tregs express a relatively higher level of IL-33R (also known as ST2) (34,(70)(71)(72), it can be speculated that Tregs at tissue sites are more responsive to IL-33 to expand and mature functionally.…”

Wounds that heal and wounds that don’t − The role of the IL-33/ST2 pathway in tissue repair and tumorigenesis

“…Administration of IL-33 in aged mice was associated with marked improvement in muscle Treg accumulation and muscle regeneration [68]. As defective muscle repair subsequent to injury and atrophy is a major health problem associated with aging populations, it is possible, therefore, that activation of the IL-33/ST2 axis is a potential therapeutic area in this field.…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…In skeletal muscle, they arise from a small pool of resident Tregs and strongly accumulate following muscle damage 115, 116. Under the control of interleukin (IL)‐33, these myophil Tregs execute essential functions in promoting and orchestrating local regeneration upon muscle injury 117, 118. Importantly, they are significantly diminished in aged mice, leading to insufficient muscle repair upon injury 118.…”

“…Under the control of interleukin (IL)‐33, these myophil Tregs execute essential functions in promoting and orchestrating local regeneration upon muscle injury 117, 118. Importantly, they are significantly diminished in aged mice, leading to insufficient muscle repair upon injury 118. A critical role for Tregs during myositis had already been postulated in an experimental autoimmune myositis model during which antibody‐mediated depletion of Tregs leads to significant increase of the histopathological disease score and a more diffuse muscle inflammation pattern 119.…”