Dysregulation of epidermal innate immune signaling as driver of Psoriatic-like arthritis

About This Grant

PROJECT ABSTRACT Psoriasis affects 3% of the US population and a third of patients develop Psoriatic Arthritis (PsA), usually with a delay of 5-7 years. Delayed therapy leads to poorer PsA control, yet diagnosing PsA early remains challenging. Among the most effective therapies for Psoriasis and PsA are those that target IL23, IL17, and TNF; yet, these therapeutics incompletely control arthritis, indicating the existence of other arthritogenic immune pathways. We hypothesize that cutaneous inflammatory processes play a key role in triggering psoriatic joint inflammation, which evolves following cutaneous priming to include additional immune drivers. Addressing these hypotheses may reveal early biomarkers and novel therapeutic targets for PsA. To investigate how skin inflammation drives PsA, we developed a novel mouse model of immune dysregulation initiated within the epidermis. This model, termed A20eKO, uses temporal and keratinocyte- specific loss of the gene A20 (Tnfaip3), polymorphisms of which reduce its expression and are strongly linked to both Psoriasis and PsA in humans. A20 is a key negative regulator of innate immune signaling, and its loss unmasks spontaneous pathogenic tissue immune processes. Remarkably, A20eKO mice not only develop psoriasiform skin disease but also synchronous and fully penetrant PsA-like joint disease. We show that skin and joint pathology in A20eKO mice requires IL23, IL17A, and T cells, demonstrating that epidermal signals alone can drive arthritogenic T cells. This offers a clear model to study how psoriatic skin disease drives PsA. In Aim 1 we focus on the pathogenic T cells triggered by keratinocyte A20 deficiency. We will use single cell transcriptomics and paired TCR sequencing to determine the phenotype and clonal diversity of memory T cells that expand in A20eKO skin prior to clinical onset of dactylitis. Using bioinformatic methods, we aim to identify phenotypically similar cells in human psoriatic plaques, potentially representing skin-educated arthritogenic T cells. In Aim 2 we dissect the pathogenic contributions of two distinct signaling pathways, IL1/TLR and cGAS/Sting, that we discover as potently restricted by A20 in keratinocytes. Using A20eKO mice interbred with loxP-bearing alleles of MyD88 and Sting, we will determine how unrestrained keratinocyte signaling from these two pathways distinctly impacts psoriatic inflammation and PsA-like pathology in A20eKO mice. In Aim 3, we dissect how the immune mechanisms driving PsA-like inflammation evolve after triggering by cutaneous immune dysregulation. We find that delayed anti-IL23 treatment no longer prevents PsA-like inflammation in A20eKO mice. Using Spatial Transcriptomics we will determine the immune mechanisms that drive IL23-independent arthritis following cutaneous priming. Combining the A20eKO model with a novel method to reversibly trigger keratinocyte innate immune signaling, we will dissect how PsA-like inflammation responds once cutaneous immune triggers are reversed.