A Role for Macrophage Adenosine 2A Receptor in Diet-Induced Nonalcoholic Fatty Liver Disease

Recent evidence suggests that adenosine 2A receptor (A_2AR) exerts a protective role in NAFLD. However, the role of the A_2AR in macrophages in NAFLD pathophysiology remains unknown. In the present study, hepatic inflammation and fat deposition were examined in myeloid cell-specific A_2AR-deficient mice and control mice fed a HFD for 12 weeks. In addition, bone marrow cells were isolated from global and/or myeloid cell-specific A_2AR-deficient mice and differentiated into macrophages (BMDM) for inflammatory analysis and for macrophage-hepatocyte co-cultures. Upon HFD feeding, the activity of JNK p46 and NFκB p65 and the mRNA levels of proinflammatory cytokines such as TNFα, IL-1β, and IL-6 in livers of myeloid cell-specific A_2AR-defcient mice were significantly higher than their respective levels in livers of control mice. These increases were accompanied with increased severity of diet-induced hepatic steatosis, indicated by the results from liver histology and by elevated levels of liver triglycerides. When BMDM were analyzed for inflammatory activation, the phosphorylation states of JNK p46 and NFκB p65 and the production of proinflammatory cytokines in A_2AR-deficient BMDM were significantly higher than their respective levels in control BMDM. Moreover, in macrophage-hepatocyte co-culture systems, hepatocytes co-cultured with A_2AR-deficient BMDM revealed significant increases in TNFα, IL-1β, and IL-6 mRNAs in relative to hepatocytes co-cultured with control BMDM. Additionally, hepatocytes co-cultured with A_2AR-deficient BMDM accumulated much more fat upon palmitate stimulation than hepatocytes co-cultured with control BMDM. Taken together, these results suggest that the inflammatory status of macrophages can be altered by A_2AR in a manner to critically determine the development of NAFLD. Moreover, targeting A_2AR to suppress inflammation may be a viable preventive and/or therapeutic approach for inflammation-associated diseases including NAFLD.