title: Enhancement of Muscle T Regulatory Cells and Improvement of Muscular Dystrophic Process in mdx Mice by Blockade of Extracellular ATP/P2X Axis.
abstract: Infiltration of immune cells and chronic inflammation substantially affect skeletal and cardiac muscle degeneration in Duchenne muscular dystrophy. In the immune system, extracellular adenosine triphosphate (ATP) released by dying cells is sensed as a danger associated molecular pattern through P2 purinergic receptors. Specifically, the P2X7 subtype has a prominent role in regulating immune system physiology and contributes to inflammasome activation also in muscle cells. Here, we show that in vivo blockade of the extracellular ATP/P2X purinergic signaling pathway by periodate-oxidized ATP delayed the progression of the dystrophic phenotype and dampened the local inflammatory response in mdx mice, a spontaneous mouse model of dystrophin deficiency. Reduced infiltration of leukocytes and macrophages and decreased expression of IL-6 were revealed in the muscles of periodate-oxidized ATP-treated mdx mice. Concomitantly, an increase in Foxp3(+) immunosuppressive regulatory T cells was observed and correlated with enhanced myofiber regeneration. Moreover, we detected reduced concentrations of profibrotic cytokines, including transforming growth factor-β and connective tissue growth factor, in muscles of periodate-oxidized ATP-treated mdx mice. The improvement of inflammatory features was associated with increased strength and reduced necrosis, thus suggesting that pharmacologic purinergic antagonism altering the adaptive immune component in the muscle infiltrates might represent a promising therapeutic approach in Duchenne muscular dystrophy.
authors.affiliation: Unit of Pediatric Neurology and Muscle Disease, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gazzerro
authors.affiliation: Unit of Pediatric Neurology and Muscle Disease, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Baldassari
authors.affiliation: Unit of Pediatric Neurology and Muscle Disease, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Assereto
authors.affiliation: Unit of Pediatric Neurology and Muscle Disease, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Fruscione
authors.affiliation: Unit of Epidemiology and Statistics, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Pistorio
authors.affiliation: Unit of Pediatric Neurology and Muscle Disease, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Panicucci
authors.affiliation: Unit of Pediatrics II, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Volpi
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Perruzza
authors.affiliation: Neuromuscular and Molecular Medicine Unit, Stella Maris Foundation, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiorillo
authors.affiliation: Unit of Pediatric Neurology and Muscle Disease, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Minetti
authors.affiliation: Novartis Biologics Center, Novartis Institute for Research in Biomedicine, Basel, Switzerland.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland; Department of Medical Biotechnologies & Translational Medicine, University of Milan, Istituto Nazionale di Genetica Molecolare, Milan, Italy. Electronic address: fabio.grassi@irb.unisi.ch.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
authors.affiliation: Center of Myology and Neurodegenerative Disorders, Department of Neuroscience, Istituto Giannina Gaslini, Genova, Italy. Electronic address: claudiobruno@ospedale-gaslini.ge.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D020388:Muscular Dystrophy, Duchenne / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D010805:Physical Conditioning, Animal; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D058469:Receptors, Purinergic P2X / Q000378:metabolism / Q000502:physiology*; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D058469:Receptors, Purinergic P2X; C004282:periodate-oxidized adenosine 5'-triphosphate; D000255:Adenosine Triphosphate