AUTHOR=Gentile Daniela , Lazzerini Pietro E. , Gamberucci Alessandra , Natale Mariarita , Selvi Enrico , Vanni Francesca , Alì Alessandra , Taddeucci Paolo , Del-Ry Silvia , Cabiati Manuela , Della-Latta Veronica , Abraham David J. , Morales Maria A. , Fulceri Rosella , Laghi-Pasini Franco , Capecchi Pier L. 

TITLE=Searching Novel Therapeutic Targets for Scleroderma: P2X7-Receptor Is Up-regulated and Promotes a Fibrogenic Phenotype in Systemic Sclerosis Fibroblasts

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00638

DOI=10.3389/fphar.2017.00638

ISSN=1663-9812

ABSTRACT=<p><bold>Objectives:</bold> Systemic sclerosis (SSc) is a connective tissue disorder presenting fibrosis of the skin and internal organs, for which no effective treatments are currently available. Increasing evidence indicates that the P2X7 receptor (P2X7R), a nucleotide-gated ionotropic channel primarily involved in the inflammatory response, may also have a key role in the development of tissue fibrosis in different body districts. This study was aimed at investigating P2X7R expression and function in promoting a fibrogenic phenotype in dermal fibroblasts from SSc patients, also analyzing putative underlying mechanistic pathways.</p><p><bold>Methods:</bold> Fibroblasts were isolated by skin biopsy from 9 SSc patients and 8 healthy controls. P2X7R expression, and function (cytosolic free Ca<sup>2+</sup> fluxes, α-smooth muscle actin [α-SMA] expression, cell migration, and collagen release) were studied. Moreover, the role of cytokine (interleukin-1β, interleukin-6) and connective tissue growth factor (CTGF) production, and extracellular signal-regulated kinases (ERK) activation in mediating P2X7R-dependent pro-fibrotic effects in SSc fibroblasts was evaluated.</p><p><bold>Results:</bold> P2X7R expression and Ca<sup>2+</sup> permeability induced by the selective P2X7R agonist 2′-3′-O-(4-benzoylbenzoyl)ATP (BzATP) were markedly higher in SSc than control fibroblasts. Moreover, increased αSMA expression, cell migration, CTGF, and collagen release were observed in lipopolysaccharides-primed SSc fibroblasts after BzATP stimulation. While P2X7-induced cytokine changes did not affect collagen production, it was completely abrogated by inhibition of the ERK pathway.</p><p><bold>Conclusion:</bold> In SSc fibroblasts, P2X7R is overexpressed and its stimulation induces Ca<sup>2+</sup>-signaling activation and a fibrogenic phenotype characterized by increased migration and collagen production. These data point to the P2X7R as a potential, novel therapeutic target for controlling exaggerated collagen deposition and tissue fibrosis in patients with SSc.</p>