Summary Psoriasis is an incurable multifactorial chronic inflammatory skin disorder of unknown etiology that is characterized by dermal infiltration of immune cells accompanied by hyperproliferation and abnormal differentiation of keratinocytes. Along with the IL-23/IL-17/IL-22/IL-36 inflammatory signaling axis, the type I Interferon (IFN-I) signaling pathway is another recognized driver of psoriasis. Assembly of the transcriptional ISGF3 complex consisting of STAT1/STAT2/IRF9 mediates the expression of IFN-I target genes. Studies in mice lacking type I IFN receptor (IFNAR1) or defective in IFNAR1 ubiquitination show IFN-I as a damaging cytokine in psoriasis. Aside from being pro-inflammatory, IFN-I can reprogram lipid biosynthesis and alterations in lipid metabolism is an important factor in the pathogenesis of psoriasis; which has also been described as an immunometabolic disease. STAT2 is a key signaling mediator of IFN-I signaling and emerging evidence links STAT2 to psoriasis. Genome-wide association studies have identified STAT2 as a psoriasis susceptibility gene. Psoriatic skin lesions from patients display an IFN-I transcriptional signature and, notably, activation of STAT2. For this proposal, we present preliminary data depicting the pro-inflammatory nature of STAT2 in psoriasis. Imiquimod (TLR7/8 agonist)-induced psoriasis-like skin inflammation in Stat2 deficient mice was drastically attenuated. Conventional dendritic cells (cDCs) are active players in psoriatic inflammation. We show that deletion of Stat2 only in cDCs impaired TLR7/8 mediated maturation in vivo. Furthermore, we found Stat2 to be critical for the psoriasis-associated cytokine IL-36 to enhance IFN-I signaling. In an unrelated study on colon cancer, we show that Stat2 mediates the expression of pro-inflammatory cytokines IL1-β, IL-6, IL-17 and IL-22 and alters lipid metabolism. These latter findings lend support to the potential involvement of STAT2 in promoting inflammation and lipid dysregulation in the skin. Based on these observations, we will test the hypothesis that aberrant STAT2 signaling contributes to the pathogenesis of psoriasis by disrupting immune/epithelial homeostasis and altering lipid metabolite composition, thereby promoting an inflammatory amplification cycle that leads to severe skin inflammation. For this proposal, we have developed two specific aims in which we will employ conventional Stat2KO mice and our recently generated conditional Stat2KO mouse. Aim 1 will determine whether Stat2 signaling in cDCs drives the generation and reactivation of a Th17/IlL22 axis to obstruct normal keratinocyte maturation. Aim 2 will determine whether Stat2 signaling in keratinocytes obstructs epidermal regeneration; preserves cell stemness and promotes changes in lipid composition of the skin and incites an inflammatory positive feedback loop causing aberrant immune cell activation. Significance: Successful completion of this project will bridge a significant gap ...