STAT2 Signaling in the Pathogenesis of Psoriasis

Temple Univ Of The Commonwealth, Philadelphia PA

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Abstract

Summary Psoriasis characterized differentiation Interferon ISGF3 mice cytokine in immunometabolic STAT2 gene. Psoriatic STAT2. psoriasis. drastically by dermal infiltration of cells accompanied by hyperproliferation and abnormal of keratinocytes. Along with the IL-23/IL-17/IL-22/IL-36 inflammatory signaling axis, the type I (IFN-I) signaling pathway is another recognized driver of psoriasis. Assembly of the transcriptional complex consisting of STAT1/STAT2/IRF9 mediates the expression of IFN-I target genes. Studies in lacking type I IFN receptor (IFNAR1) or defective in IFNAR1 ubiquitination show IFN-I as a damaging in psoriasis. Aside from being pro-inflammatory, IFN-I can reprogram lipid biosynthesis and alterations lipid metabolism is an important factor in the pathogenesis of psoriasis; which has also been described as an disease. STAT2 is a key signaling mediator of IFN-I signaling and emerging evidence links to psoriasis. skin lesions from patients display an IFN-I transcriptional signature and, notably, activation of For this proposal, we present preliminary data depicting the pro-inflammatory nature of STAT2 in Imiquimod (TLR7/8 agonist)-induced psoriasis-like skin inflammation in attenuated is an incurable multifactorial chronic inflammatory skin disorder of unknown etiology that is immune Genome-wide association studies have identified STAT2 as a psoriasis susceptibility Stat2 deficient mice was . 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-?, 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 in our current understanding of STAT2 in the pathogenesis of psoriasis. We anticipate identifying novel inflammatory markers for monitoring psoriasis, as well.