Regulatory T cells require IL-6 receptor alpha signaling to control skeletal muscle function and regeneration
BECKER M. 1,2, JOSEPH S. 2,3,4, GARCIA-CARRIZO F. 2,5, ZACHARIAH-TOM R. 2,6,7, OPALEVA D. 1,2, SERR I. 1,2, TSCHÖP M. 2,3,4, SCHULZ T. 2,5,8, HOFMANN S. 2,6,7, DANIEL C. 1,2,9
1 Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Munich, Germany; 2 German Center for Diabetes Research (DZD), Munich, Germany; 3 Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Munich, Germany; 4 Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany; 5 Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; 6 Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Munich, Germany; 7 Department of Medicine IV, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany; 8 University of Potsdam, Institute of Nutritional Science, Nuthetal, Germany; 9 Division of Clinical Pharmacology, Department of Medicine IV, Ludwig-Maximilians-University Munich, Munich, Germany
Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored.
Here, we show that exercise (i.e. voluntary wheel running) fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg, sedentary vs. pre-exercised p= 0.0064; exercised vs. pre-exercised p= 0.0009), EGFR (sedentary vs. exercised p= 0.0192, sedentary vs. pre-exercised p<0.0001, exercised vs. pre-exercised p<0.0001) and ST2 (sedentary vs. pre-exercised p= 0.0031, exercised vs. pre-exercised p= 0.0002).
Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) show significant reductions in muscle Treg phenotypic maturation, satellite cells (IL6Rα floxed vs TKO p= 0.046) and fibro-adipogenic progenitor cells (IL6Rα floxed vs TKO p= 0.0021), which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation and a more pronounced decline in muscle function as assessed by grip strength tests (IL6Rα floxed vs TKO p= 0.0146). Furthermore, a chemical muscle injury model shows that IL6Rα TKO mice have significant impairments in muscle regeneration 14 days post injury as indicated by reduced fiber cross sectional areas (IL6Rα floxed vs TKO p= 0.0017). Importantly, Treg gain-of-function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies impairments in muscle function (control InVivo mAb vs anti-IL6R InVivo mAb p= 0.0014) identified in IL6Rα TKO mice thereby underscoring the clinical implications of these findings.
Overall, the results of this study highlight the relevance of dissecting muscle-specific immune regulation and will be of importance for the design of tailored precision medicines targeting niche-specific Tregs in the future.