Psoriasis is a chronic skin disease mediated by Th1 and Th17 immune responses and is classified as a systemic inflammatory disorder. Notably, psoriasis is an independent risk factor for myocardial infarction, stroke, and cardiovascular mortality, particularly in severe disease. However, the cellular mechanisms linking psoriasis to cardiovascular disease have not yet been identified. To address this gap, we investigated systemic markers of inflammasome signaling and innate immune activation in patients with psoriasis. Whole blood was collected from 43 patients, including active psoriasis (mild-to-moderate disease) without clinical manifestations of atherosclerosis, inactive psoriasis (minimal disease activity), patients receiving anti-TNF-α therapy, and 19 BMI-matched healthy controls. Multiparametric spectral flow cytometry was performed to profile inflammasome signaling, and mass spectrometry-based proteomics was used to obtain unbiased phenotyping of circulating immune cells. Classical monocytes from patients with active psoriasis exhibited heightened NLRP3 protein expression and caspase-1 activity upon brief physiological stimulation, responses absent in inactive psoriasis and healthy controls. Mechanistically, active psoriasis demonstrated elevated plasma ATP and increased monocyte expression of P2X7R, a potent NLRP3 activator. TNF-α was identified as a key cytokine, selectively upregulating both P2X7R and NLRP3. Baseline proteomics revealed enriched pathways for monocyte extravasation and cell adhesion, suggesting a pro-thrombotic state. Stimulation increased proteins linked to ROS and mitochondrial stress. Monocytes from active psoriasis exhibited increased baseline activation and, upon stimulation, enhanced monocyte-platelet aggregation, both of which were attenuated by inhibition of mitochondrial ROS. Importantly, anti-TNF therapy normalized ATP levels, P2X7R expression, inflammasome responsiveness, monocyte activation, and monocyte-platelet interactions, supporting the restoration of systemic immune homeostasis. In patients with mild-to-moderate psoriasis, we demonstrate persistent systemic stress, resulting in inflammasome hyperreactivity and increased monocyte-platelet aggregation in response to minor perturbations in cellular homeostasis. Notably, TNF-α blockade restores these effects, providing mechanistic insight into how anti-TNF therapy reduces systemic inflammation and cardiovascular risk.
