PROJECT SUMMARY/ABSTRACT Recent literature has identified that psoriasis, a prevalent chronic inflammatory skin disease, is associated with an increased risk of type 2 diabetes (T2D). This is important since the combination of psoriasis and T2D worsen glycemic control to a greater degree, leading to increased secondary complications than either disease alone; however, the molecular mechanisms that predispose patients with psoriasis to develop T2D are unknown. In psoriasis, interferon kappa (IFNκ), a type I IFN, is increased in skin lesions and peripheral blood, leading to systemic inflammation. Our preliminary data identifies that a histone methyltransferase, Mixed lineage leukemia protein 1 (MLL1), may control IFNκ expression in keratinocytes, and this may be mechanistically driven by Tyk2/STAT1 signaling. This overexpression of IFNk by keratinocytes is associated with increased inflammatory macrophages (MΦs) in skin and adipose tissue and hyperglycemia development. To this end, our preliminary data identify that keratinocyte-derived IFNκ can drive MΦs towards an inflammatory phenotype via a JMJD3- mediated mechanism. Further, our group has identified that JMJD3, a histone demethylase, is crucial in regulating inflammatory MΦs in skin and is upregulated in MΦs following IFNκ/JAK1/STAT3 stimulation. This K99/R00 proposal seeks to test the hypothesis that Tyk2/STAT1 signaling upregulates MLL1 in keratinocytes and mechanistically underlies IFNκ overexpression in psoriasis. Further, we propose that this increase in IFNκ by psoriatic keratinocytes drives MΦs towards an inflammatory phenotype in skin and adipose tissue via a JMJD3-mediated mechanism. These inflammatory adipose tissue macrophages (ATMs) then drive adipocyte metabolic dysfunction via regulation of PPARγ and GLUT4. To test these hypotheses, We will pursue the following aims during the K99 phase of this award: AIM 1: Identify the MLL1-mediated mechanism(s) by which keratinocyte IFNκ expression is regulated in psoriasis tissue, AIM 2: Examine the mechanism(s) by which keratinocyte-derived IFNκ regulates MΦ phenotype in psoriasis. During this time, the PI will receive research training in epigenetic techniques, isolating and culturing human keratinocytes, sequence analysis, and isolating macrophages from adipose tissue. During the independent phase(R00), she will determine the mechanism(s) by which ATM-derived TNFα dysregulates adipocyte glucose metabolism in psoriasis and determine if IFNκ inhibition improves glucose metabolism (AIM 3). Training in the proposed techniques during the K99 phase will afford the PI the necessary skills to run a successful independent research program studying the relationship between chronic skin inflammation diseases and metabolic dysfunction.