The mutual regulation between miR-214 and A2AR signaling plays an important role in inflammatory response.

Inflammation is a pathological course involved in several diseases. Both adenosine A2A receptor (A2AR) and miR-214 play important roles in regulation of inflammation. However, the internal link between them and their synergic modulation in inflammatory response has not been elucidated. In this study, we found that miR-214 and A2AR activation could downregulate the expressions of each other in murine macrophages. Comparing with the well known anti-inflammatory role of A2AR, miR-214 promoted the release of inflammatory cytokines TNF-α and IL-6. Further investigation demonstrated that miR-214 downregulated A2AR expression by directly targeting the 3'-untranslated region of A2AR mRNA. Instead of directly interacting with miR-214, A2AR activation repressed miR-214 expression by stimulating PKA signaling to suppress the nuclear translocation of NF-κB which could enhance the transcript activity of miR-214 gene promoter. Then using an LPS-induced ALI mouse model, in which inflammation is a hallmark, we confirmed their negative relationship and demonstrated that combination of miR-214 antagomir and A2AR agonist CGS21680 exerts more anti-inflammatory effect including alleviating the pathological changes, suppressing the neutrophil infiltration and the expression of inflammatory cytokines than using one of them alone. These findings for the first time uncovered a mutual suppression feedback loop between A2AR signaling and miR-214 in inflammation, which may provide new insight of inflammatory regulation and potential therapeutic significance for some inflammation-associated diseases.