Skin Application of Inflammasome Inhibitor MCC950 Prevents Psoriasis-like Cutaneous Manifestations and Associated Systemic Inflammation.

Psoriasis is a chronic, systemic inflammatory disease associated with cardiovascular and metabolic comorbidities. It is driven by a sustained immune response in the skin, orchestrated by keratinocytes and both innate and adaptive immune cells. The initial phase of the pathology remains largely unclear. It likely involves the activation of dendritic cells by stress signals from keratinocytes with the NLRP3 inflammasome potentially acting as a key innate sensor. Here we investigate the effects of the topical administration of the selective NLRP3 inhibitor MCC950, in the imiquimod-induced psoriasis-like inflammation model with the aim to achieve the inhibition of both cutaneous and systemic manifestations. Topical MCC950 effectively suppressed NLRP3 inflammasome activation by preventing pro-caspase-1 cleavage and generation of the active p20 subunit in the skin. Gene expression analysis showed that inhibition of NLRP3 suppressed the expression of psoriasis hallmark genes, including Il17, Tnf, S100a8/a9 and Il1b. Furthermore, network analysis identified NLRP3 as a central hub in the psoriasis-associated inflammatory module, supporting the concept that inflammasome inhibition dampens multiple downstream inflammatory pathways. In psoriasis-like condition, MCC950 reduced the skin infiltration of CD3