In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-β and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance.

Defective dystrophic thymus determines degenerative changes in skeletal muscle / A. Farini, C. Sitzia, C. Villa, B. Cassani, L. Tripodi, M. Legato, M. Belicchi, P. Bella, C. Lonati, S. Gatti, M. Cerletti, Y. Torrente. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 12:1(2021 Apr 08), pp. 2099.1-2099.20. [10.1038/s41467-021-22305-x]

Defective dystrophic thymus determines degenerative changes in skeletal muscle

A. Farini
Primo
;
C. Sitzia
Secondo
;
C. Villa;B. Cassani;L. Tripodi;M. Belicchi;C. Lonati;S. Gatti;Y. Torrente
Ultimo
2021-04-08

Abstract

In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-β and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance.
Animals; Autophagy; Ghrelin; Immune Tolerance; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Nude; Muscle, Skeletal; Muscular Atrophy; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; T-Lymphocytes; T-Lymphocytes, Regulatory; Thymus Gland; Transcription Factors
Settore MED/26 - Neurologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/905519
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