The Danger Signal Extracellular ATP Is Involved in the Immunomediated Damage of α-Sarcoglycan–Deficient Muscular Dystrophy: American Journal of Pathology

E Gazzerro, S Baratto, S Assereto, S Baldassari, C Panicucci, L Raffaghello, P Scudieri, D De Battista, C Fiorillo, S Volpi, L Chaabane, M Malnati, G Messina, S Bruzzone, E Traggiai, F Grassi, C Minetti, C Bruno

Research output: Contribution to journalArticle

Abstract

In muscular dystrophies, muscle membrane fragility results in a tissue-specific increase of danger-associated molecular pattern molecules (DAMPs) and infiltration of inflammatory cells. The DAMP extracellular ATP (eATP) released by dying myofibers steadily activates muscle and immune purinergic receptors exerting dual negative effects: a direct damage linked to altered intracellular calcium homeostasis in muscle cells and an indirect toxicity through the triggering of the immune response and inhibition of regulatory T cells. Accordingly, pharmacologic and genetic inhibition of eATP signaling improves the phenotype in models of chronic inflammatory diseases. In α-sarcoglycanopathy, eATP effects may be further amplified because α-sarcoglycan extracellular domain binds eATP and displays an ecto-ATPase activity, thus controlling eATP concentration at the cell surface and attenuating the magnitude and/or the duration of eATP-induced signals. Herein, we show that in vivo blockade of the eATP/P2X purinergic pathway by a broad-spectrum P2X receptor–antagonist delayed the progression of the dystrophic phenotype in α-sarcoglycan–null mice. eATP blockade dampened the muscular inflammatory response and enhanced the recruitment of forkhead box protein P3–positive immunosuppressive regulatory CD4+ T cells. The improvement of the inflammatory features was associated with increased strength, reduced necrosis, and limited expression of profibrotic factors, suggesting that pharmacologic purinergic antagonism, altering the innate and adaptive immune component in muscle infiltrates, might provide a therapeutic approach to slow disease progression in α-sarcoglycanopathy. © 2019 American Society for Investigative Pathology
Original languageEnglish
Pages (from-to)354-369
Number of pages16
JournalAmerican Journal of Pathology
Volume189
Issue number2
DOIs
Publication statusPublished - 2019

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    Gazzerro, E., Baratto, S., Assereto, S., Baldassari, S., Panicucci, C., Raffaghello, L., Scudieri, P., De Battista, D., Fiorillo, C., Volpi, S., Chaabane, L., Malnati, M., Messina, G., Bruzzone, S., Traggiai, E., Grassi, F., Minetti, C., & Bruno, C. (2019). The Danger Signal Extracellular ATP Is Involved in the Immunomediated Damage of α-Sarcoglycan–Deficient Muscular Dystrophy: American Journal of Pathology. American Journal of Pathology, 189(2), 354-369. https://doi.org/10.1016/j.ajpath.2018.10.008