A feedback loop in PPARγ-adenosine A2A receptor signaling inhibits inflammation and attenuates lung damages in a mouse model of LPS-induced acute lung injury

Although peroxisome proliferator-activated receptor-gamma (PPAR gamma) and adenosine A(2A) receptor (A(2A)R) are reported to be anti-inflammatory factors in acute lung injury (ALL), their internal link and synergic or antagonistic effect after activation are poorly understood. Here, we found that PPAR gamma and A(2A)R could upregulate the mRNA and protein expressions of each other in lung tissues of LPS-induced mouse ALI model and murine macrophages. Further investigation demonstrated that PPARy upregulated A(2A)R expression by directly binding to a DR10 response element (-218 to-197) within A(2A)R gene promoter region. Instead of directly interacting with PPAR gamma, A(2A)R stimulated PPAR gamma expression via protein kinase A (PKA)-cAMP response element binding protein (CREB) signaling by provoking the binding of CREB to a cAMP responsive element (CRE)-like site in PPARy gene promoter region. In addition, combination of PPAR gamma and A(2A)R agonists was found to exert obviously better effect on suppressing neutrophil infiltration and inflammatory cytokine expressions, attenuating lung edema, pathological changes and improving lung function of blood gas exchange than their single application. These findings reveal a novel functional positive feedback loop between PPAR gamma and A(2A)R signaling to potentialize their effect on inhibiting inflammation and attenuating lung damages in AU. It suggests that targeting this PPAR gamma-A2AR signaling rather than PPAR gamma or A(2A)R alone may be a more attractive and efficient potential therapeutic strategy for ALI. (C) 2013 Elsevier Inc. All rights reserved.