title: Adenosine A2a receptor stimulation blocks development of nonalcoholic steatohepatitis in mice by multilevel inhibition of signals that cause immunolipotoxicity.
abstract: Lipotoxicity and immunoinflammation are associated with the evolution of steatosis toward nonalcoholic steatohepatitis (NASH). This study reports the ability of adenosine A2a receptor (A2aR) activation to inhibit NASH development by modulating the responses of CD4+T-helper (Th) cells to avoid an immuno-mediated potentiation of lipotoxicity. The effect of the A2aR agonist CGS21680 on immunoinflammatory signals, CD4+Th cell infiltration and immunolipotoxicity was analyzed in steatotic C57BL/6 mice fed with a methionine-choline-deficient (MCD) diet and in mouse hepatocytes exposed to palmitic acid (PA). CGS21680 inhibited NASH development in steatotic mice and decreased cytokines and chemokines involved in Th cell recruitment or polarization (namely CXCL10, CCL2, tumor necrosis factor alfa [TNFα], tumor growth factor [TGFβ], and IL-12). CGS21680 also reduced the expansion of Th17, Th22, and Th1 cells and increased the immunosuppressive activity of T regulatory cells. In PA-treated mice hepatocytes, CGS21680 inhibited the production of CXCL10, TNFα, TGFβ, IL-12, and CCL2; CGS21680 also prevented JNK-dependent lipotoxicity and its intensification by IL-17 or IL-17 plus IL-22 through Akt/PI3-kinase stimulation and inhibition of the negative regulator of PI3-kinase, (phosphatase and tensin homologue deleted from chromosome 10 (PTEN), which is upregulated by IL-17. In MCD livers, CGS21680 reduced JNK activation and PTEN expression and increased Akt phosphorylation. In conclusion, A2aR stimulation inhibited NASH development by reducing Th17 cell expansion and inhibiting the exacerbation of the IL-17-induced JNK-dependent lipotoxicity. These data promote the implementation of further studies to evaluate the potential clinical application of A2aR agonists that, by being able to function as both cytoprotective and immunomodulatory agents, could efficiently antagonize the multi-faced pathogenesis of NASH.
authors.affiliation: Department of Health Science, University of Piemonte Orientale, Novara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Alchera
authors.affiliation: Center for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy; Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rolla
authors.affiliation: Department of Health Science, University of Piemonte Orientale, Novara, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Imarisio
authors.affiliation: Center for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy; Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bardina
authors.affiliation: Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Valente
authors.affiliation: Center for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy; Immunogenetics and Transplantation Biology Unit, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.affiliation: Department of Health Science, University of Piemonte Orientale, Novara, Italy. Electronic address: rita.carini@med.uniupo.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Carini
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008055:Lipids / Q000633:toxicity*; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D010627:Phenethylamines / Q000494:pharmacology / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D008055:Lipids; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000241:Adenosine