Positive Allosteric Modulation of A_2AR 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 A_2AR, regulates inflammation, immune response, T-cell homeostasis, and tissue repair. We have identified a unique means to enhance A_2AR function using a positive allosteric modulator. We show that oral administration of the A_2AR-positive allosteric modulator AEA061 reduced ear swelling, skin thickness, erythema, scale formation, and inflammatory cytokine expression in A_2Ar^+/+ but not in A_2Ar^-/- 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 A_2AR responsiveness to the endogenous agonist adenosine through positive allosteric modulation is sufficient to enhance intrinsic homeostatic mechanisms attenuating disease progression.