Adenosine A2a receptor stimulation blocks development of nonalcoholic steatohepatitis in mice by multilevel inhibition of signals that cause immunolipotoxicity
2017
Lipotoxicityand 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
lipotoxicityand 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
tensinhomologue 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.
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