690 Adenosine A2A receptor (A2AR) modulation attenuates innate and adaptive immune cell signaling during pathogenesis of psoriasis-like dermatitis in mice

      Psoriasis is an immune cell-mediated inflammatory disease of the skin with a mixed Th1/Th17 cytokine environment combined with an innate immune response engaging Toll-like receptors (TLRs) 7, 8 and 9. Inflammatory diseases are generally characterized by dysregulated immune cell responses and elevated levels of adenosine (ADO) at disease sites. ADO, acting through the A2AR, mediates anti-inflammatory and immunomodulatory activity. We have identified a unique means to enhance A2AR function using a small molecule that acts as a positive allosteric modulator (PAM; AEA061). AEA061 has no discernable biologic activity by itself at the A2AR but enhances ADO-mediated A2AR function, meets the stringent criteria of a PAM and exhibits pharmacological activity in a mouse model of sepsis. Here we investigate the effects of PAM enhancement on immune cell subsets that are central to the initiation and maintenance of psoriasis in a mouse model of psoriasis-like dermatitis induced by the TLR 7 agonist imiquimod (IMQ). Oral administration of the PAM reduced ear thickness, skin erythema, scale formation and inflammatory cytokine expression in the skin and ear tissues. Analyses of dendritic cell (DC) subsets indicated that A2AR functional enhancement by the PAM attenuated IMQ-induced expression of IFN-α in pDCs and IL-23α, IL-36α and IL-36γ in cDCs. TCR-mediated IL-17 expression in γδT cells and IFN-γ expression in CD4+ T cells was also inhibited. Thus, the enhancement of A2AR responsiveness to the endogenous ADO, targeted through positive allosteric modulation, attenuates TLR 7-mediated innate immune signaling in pDCs and cDCs as well as TCR-mediated adaptive immune signaling in γδT and CD4+ T cells and downregulates disease expression.