Positive Allosteric Modulation of A2AR Alters Immune Cell Responses and Ameliorates Psoriasis-Like Dermatitis in Mice

Psoriasis is an immune cell‒mediated inflammatory disease of the skin with a mixed T helper type 1/T helper type17 cytokine environment combined with an innate immune response engaging toll-like receptors. Inflammatory diseases are characterized by dysregulated immune cell responses and elevated levels of adenosine at disease sites. Adenosine, acting through the A2AR, regulates inflammation, immune response, T-cell homeostasis, and tissue repair. We have identified a unique means to enhance A2AR function using a positive allosteric modulator. We show that oral administration of the A2AR-positive allosteric modulator AEA061 reduced ear swelling, skin thickness, erythema, scale formation, and inflammatory cytokine expression in A2Ar+/+ but not in A2Ar-/- mice with imiquimod-induced psoriasis-like dermatitis. Similar clinical and mRNA improvements were observed with topical administration. AEA061 also reduced clinical scores and cytokine expression in a mouse model of IL-23‒induced psoriasis-like dermatitis. In addition, AEA061 attenuated imiquimod-induced expression of IFN-α in plasmacytoid dendritic cells in vivo and IL-23 and IL-36α in conventional dendritic cells. TCR-mediated IL-17 expression in γδT cells in vivo and IL-17 production by CD4+ T cells enriched for γδT cells in vitro were also inhibited. Thus, the enhancement of A2AR responsiveness to the endogenous agonist adenosine through positive allosteric modulation is sufficient to enhance intrinsic homeostatic mechanisms attenuating disease progression.