The Danger Signal Extracellular ATP Is Involved in the Immunomediated Damage of α-Sarcoglycan-Deficient Muscular Dystrophy.
- Gazzerro E Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy; Charité Universität-Experimental and Clinical Research Center, Berlin, Germany. Electronic address: elisabetta.gazzerro@charite.de.
- Baratto S Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy.
- Assereto S Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy.
- Baldassari S Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy.
- Panicucci C Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy.
- Raffaghello L Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy; Stem Cell Laboratory and Cell Therapy Center, Istituto Giannina Gaslini, Genova, Italy.
- Scudieri P Telethon Institute of Genetics and Medicine, Napoli, Italy.
- De Battista D Unit of Human Virology, Division of Immunology, Transplantation and Infectious Disease, Ospedale San Raffaele, Milano, Italy.
- Fiorillo C Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy.
- Volpi S Pediatria II Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy.
- Chaabane L Unit of Human Virology, Division of Immunology, Transplantation and Infectious Disease, Ospedale San Raffaele, Milano, Italy.
- Malnati M Unit of Human Virology, Division of Immunology, Transplantation and Infectious Disease, Ospedale San Raffaele, Milano, Italy.
- Messina G Department of Biosciences, University of Milan, Milan, Italy.
- Bruzzone S Department of Experimental Medicine, University of Genova, Genova, Italy.
- Traggiai E Novartis Institute for Research in Biomedicine, Basel, Switzerland.
- Grassi F Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy; Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland; Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
- Minetti C Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy.
- Bruno C Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy. Electronic address: claudiobruno@gaslini.org.
- 2018-11-19
Published in:
- The American journal of pathology. - 2019
Adenosine Triphosphate
Animals
Calcium
Chronic Disease
Inflammation
Mice
Mice, Knockout
Muscular Dystrophy, Animal
Myofibrils
Receptors, Purinergic P2X
Sarcoglycans
T-Lymphocytes, Regulatory
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1016/j.ajpath.2018.10.008
- PMID 30448410
- Persistent URL
- https://sonar.ch/global/documents/145951
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