Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis

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Summary Psoriasis is the most prevalent and intractable immune-mediated chronic inflammatory skin disease. It is clear that dendritic cells (DCs) and keratinocytes in the skin tissues play a central role in the pathogenesis of psoriasis. The objectives of this proposal are to determine the role of epidermal fatty acid binding protein (E- FABP) in promoting psoriasis pathogenesis through simultaneously targeting both DCs and keratinocytes and in linking obesity-associated psoriasis development. E-FABP, first cloned in psoriatic skin tissues (also known as psoriasis associated FABP), has been identified as a critical regulator of both metabolic and inflammatory pathways. Our preliminary studies demonstrate that E-FABP is greatly upregulated in the skin tissue from patients with psoriasis. Intriguingly, deficiency of E-FABP confers protection from imiquimod (IMQ) or IL-23- induced psoriasis-like inflammation in mouse models. While obesity is associated with increased severity of psoriasis and poor responses to therapy, the underlying mechanisms between obesity and psoriasis are unknown. While high fat diet (HFD) increases E-FABP expression in both DCs and keratinocytes and promotes obesity-associated chronic skin inflammation in wild type mice, E-FABP deficiency protects mice against HFD- induced effects. All these data suggest that E-FABP may link obesity and psoriasis via regulating metabolism and function of DCs and keratinocytes. Thus, we hypothesize that E-FABP, as a new link underlying the obesity-psoriasis association, promotes psoriasis pathogenesis through enhancing cellular metabolism and function of both DCs and keratinocytes. Therefore, targeting E-FABP may represent a novel strategy for psoriasis therapy. We design three specific aims (Figure A) to address our hypotheses. Specific Aim 1 will address how E-FABP regulates DC metabolism and function in psoriasis. We hypothesize that E-FABP links FA metabolism and innate immune signaling in DCs and bridges innate and adaptive immune responses for psoriasis pathogenesis. Specific Aim 2 will determine how E-FABP promotes keratinocyte aberrant metabolism and differentiation in psoriasis. We will design experiments to test the hypothesis that E-FABP expression in keratinocytes mediates innate signal-induced metabolic changes that are critical for abnormal keratinocyte differentiation. Specific Aim 3 will examine whether E-FABP links the obesity/psoriasis association using our unique E-FABP global and conditional knock out mouse models and samples from psoriasis patients. In summary, this proposal will demonstrate a novel mechanism by which E-FABP promotes psoriasis pathogenesis and links obesity-associated psoriasis development. Thus, targeting E-FABP may offer a novel strategy for treatment of psoriasis and other inflammatory skin disorders.