Neuronal, stromal, and T-regulatory cell crosstalk in murine skeletal muscle

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 10; pp. 5402 - 5408
• Main Authors: Wang, Kathy, Yaghi, Omar K., Spallanzani, Raul German, Chen, Xin, Zemmour, David, Lai, Nicole, Chiu, Isaac M., Benoist, Christophe, Mathis, Diane
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10-03-2020
• Subjects: Accumulation; Animals; Biological Sciences; Calcitonin; Calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - pharmacology; CD4 antigen; Cell Communication; Crosstalk; Foxp3 protein; Interleukin-33 - metabolism; Interleukins; Lymphocytes T; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - physiology; Mesenchyme; Mice; Mice, Inbred C57BL; Muscle, Skeletal - drug effects; Muscle, Skeletal - injuries; Muscle, Skeletal - physiology; Muscles; Musculoskeletal system; Nerves; Neuropeptide receptors; Neuropeptides; Nociceptors - physiology; Receptors; Receptors, Calcitonin Gene-Related Peptide - metabolism; Regeneration; Repair; Sensor arrays; Sensory neurons; Skeletal muscle; Stromal cells; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; regulatory T cells; muscle repair; stromal cells; CGRP; IL-33
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1922559117

A distinct population of Foxp3⁺CD4⁺ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association among muscle nerves, IL-33⁺ mSCs, and Tregs has been reported, and invites a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33⁺ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors, and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene–related peptide (CGRP); and demonstrate that up- or down-tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell crosstalk in tissue repair, suggesting future therapeutic approaches.