Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation

• Psoriasis is linked to systemic inflammation and cardiovascular comorbidities, but studies of the underlying cellular mechanisms are lacking. The NLRP3 inflammasome is genetically associated with psoriasis, and its activation is increasingly linked with cardiovascular disease. In this study, we show that patients with psoriasis exhibited higher plasma levels of inflammasome-generated IL-1ß and IL-18, without any correlation to skin lesion severity. Increased constitutive expression of the inflammasome sensors NLRP3, NLRP1, and AIM2 was found in peripheral blood cells of the patients and also of those with mild disease, and this was accompanied by an increased caspase-1 reactivity in the myeloid blood subsets. TNF-a was found to activate selectively the NLRP3 inflammasome without the requirement for a priming signal. TNF-a was found to signal through the TNFR?caspase-8?caspase-1 alternative inflammasome pathway, which proceeds independently of pyroptosis. Patients who received anti-TNF therapy had normalized plasma IL-1ß and IL-18 levels as well as normalized caspase-1 reactivity. This was in contrast to the patients treated with methotrexate who exhibited persistent, increased caspase-1 reactivity. Thus, we show that the TNF-a-mediated activation of NLRP3 inflammasomes in patients with psoriasis may contribute to systemic inflammation. Anti-TNF therapy normalized inflammasome function, suggesting a mechanism for the cardiovascular risk?reducing effect.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

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