Abstract 4359428: Psoriasis Patients Have Elevated Levels of Lymphocyte-Platelet Aggregates Associated With a Distinct Platelet Inflammatory Transcriptome

Abstract

Background: Psoriasis is a T-cell mediated inflammatory disease that is associated with elevated cardiovascular (CV) risk. Platelets are key players in psoriasis CV risk development through their role in immunomodulation and atherogenesis. Psoriasis patients have been found to have elevated levels of circulating lymphocyte-platelet aggregates (LyPA), although the significance of these aggregates in relation to CV risk is poorly understood. We investigated LyPA in psoriasis using platelet RNA sequencing. Methods: Blood samples were collected from 42 psoriasis subjects and 29 healthy controls without history of clinical CV disease. Lymphocytes and LyPA were identified using flow cytometry. Psoriasis patients were stratified by median LyPA into high and low LyPA. Platelet RNA was isolated and sequenced from 24 psoriasis subjects and 17 controls. Differential expression analysis was performed with DESeq2, adjusted for age, sex, and biologic medications. Downstream analysis was performed using gene set enrichment analysis and Ingenuity Pathway Analysis. Results: Psoriasis patients (mean age 46, 60% male, 81% white) compared to healthy controls (mean age 42, 55% male, 69% white) had higher LyPA levels (p = 0.001) but had no difference in platelet count (Fig. 1A). Among psoriasis patients, CV risk score, psoriasis severity and duration did not differ by high or low LyPA (Table 1). In platelet RNA analysis of psoriasis patients with high LyPA (n=9) compared to controls (n=17), 235 genes were differentially expressed (p < 0.01) with 107 differentially expressed pathways (p adj < 0.05). Top dysregulated pathways were inflammatory pathways including interferon (IFN) signaling, tumor necrosis factor (TNF) signaling, and IL-6 signaling (Fig. 1B). Dysregulated upstream cytokine regulators included IFN-gamma, TNF, and IL-1β. In psoriasis patients with low LyPA (n=15) compared to controls, 295 genes were differentially expressed but with only 4 differentially expressed pathways, including dysregulation of IFN-gamma response (Fig. 1C). Upstream cytokine regulator analysis only yielded dysregulation of IFN-gamma. Conclusion: Increased LyPA in psoriasis is associated with a platelet transcriptomic profile characterized by dysregulation of key inflammatory pathways known to be linked to CV risk (IFN, TNF, IL-6). These inflammatory pathway alterations are largely not observed in platelets of psoriasis patients with LyPA levels similar to those of healthy controls.