TNF-α-Driven Systemic Inflammasome Hyperactivity Links Psoriatic Inflammation to monocyte inflammatory response and platelet activation

Background

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 risk have not yet been identified. To address this gap, we investigated systemic markers of inflammasome signaling and innate immune activation in patients with psoriasis.

Methods

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.

Results

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.

Conclusions

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.

What is already known about this topic?

• Psoriasis is a systemic, immune-mediated skin disease that is associated with an increased risk of cardiovascular disease (CVD), particularly in severe disease.

• The NLRP3 inflammasome, an innate immune sensor, has been implicated in the pathogenesis of CVD.

• Anti-TNF therapy, which is effective in treating psoriasis, is proposed to reduce CVD risk, but the underlying mechanisms remain unclear.

What does this study add?

• Patients with mild-to-moderate psoriasis without clinical manifestations of atherosclerosis demonstrate elevated plasma ATP levels, increased monocyte P2X7 receptor expression, and enriched pathways for monocyte activation and extravasation, suggesting persistent systemic stress.

• Monocytes from these patients display ROS-dependent hyperactivation of the NLRP3 inflammasome and increased formation of monocyte-platelet aggregates in response to minor perturbations in cellular homeostasis.

• TNF-α was identified as a key cytokine, selectively upregulating both P2X7R and NLRP3.

• Anti-TNF therapy normalized these aberrant immune responses, suggesting a mechanism for its proposed cardioprotective effects.

Novelty and significance

This study provides evidence that patients with mild to moderate psoriasis, without clinical manifestations of atherosclerosis, exhibit concurrent elevations in plasma ATP levels, monocyte P2X7 receptor expression, inflammasome responsiveness, and monocyte-platelet aggregates: features increasingly associated with CVD risk. These findings suggest that dysregulated purinergic signaling may contribute to systemic immune activation in psoriasis. Importantly, anti-TNF therapy was associated with normalization of these parameters, pointing toward a potential immunomodulatory mechanism by which such treatment may help reduce CVD risk. These observations highlight a novel intersection between inflammation, purinergic signaling, and monocyte-platelet activation, which may contribute to the increased CVD risk in psoriasis.