707 Responsiveness of the Adenosine A2A receptor (A2AR) regulates immune and keratinocyte responses in psoriasis

Abstract

Psoriasis is a chronic inflammatory disease of the skin and joints associated with both innate and adaptive immunity. An imbalance between the activators and the modulators of immunity and their interactions with keratinocytes leads to the chronic inflammatory hallmarks of the disease. The A2AR is a key modulator of both immunity and inflammation. We have described a means to enhance A2AR function through a small molecule that acts as a positive allosteric modulator (PAM; AEA061). The PAM has no intrinsic biologic activity at the A2AR but enhances adenosine-mediated A2AR function. In a mouse model of TLR 7 agonist imiquimod (IMQ)-induced psoriasis-like dermatitis, the oral administration of the PAM reduced ear thickness, skin erythema, scale formation and inflammatory cytokine expression in the skin, ear tissue and in plasma. Transcriptome analysis of the skin indicated differential expression of 111 genes upon PAM treatment. Ex-vivo and in culture, the PAM decreased IMQ-induced expression of IFN-α in pDCs and IL-23, IL-36α and IL-36β in cDCs. Moreover, the PAM inhibited TCR-mediated IL-17 expression in γδT cells and IFN-γ expression in CD4+ T cells. In human epidermal keratinocytes, the PAM attenuated IFN-α-mediated IL-22R expression, reducing their proliferative response to IL-22. We have extended our investigation into the effects of the PAM on human immune cell subsets that are central to the initiation and maintenance of psoriasis in man. We observed attenuation of mRNA expression of IFN-α, IFN-β, and IL-23 in human pDCs and IL-17F in human γδT cells. The PAM also inhibited the production of cytokines by Th cells that are implicated in psoriasis, including IL-2, IFN-γ, TNF-α, sCD40, GM-CSF, CXCL10, MIP-1α, MIP-1β, RANTES and eotaxin. Thus, the enhancement of A2AR responsiveness to endogenous adenosine, targeted through positive allosteric modulation, alters innate and adaptive immune responses towards a homeostatic state and reduces disease expression.