07.16 Nlrp1 mutations cause autoinflammatory diseases in human: implication of the nlrp1 inflammasome?

Background Inflammation is a vital and complex process in response to diverse tissue damaging stimuli such as trauma, injury and pathogen. NLRP1, NLRP3 and NLRC4 belonging to the intracellular proteins Nod like receptor family, are capable of sensing the inflammatory inducers and trigger the assembly of a large complex called the inflammasome. By inducing the caspase-1 activation, inflammasome plays a crucial role in the release of IL-1β and IL-18, two critical cytokines of the initial steps of inflammatory responses. Whereas mutations in NLRP3 and NLRC4 have been linked to two rare monogenic systemic autoinflammatory diseases (SAIDs), several polymorphisms in the NLRP1 gene have been associated extensively to an increased risk of autoimmune disorders (e.g. vitiligo, psoriasis, type 1 diabetes, and rheumatoid arthritis). We identified for the first time two distinct NLRP1 mutations in patients displaying a novel SAID combining autoinflammation and autoimmunity. We named this disease NAIAD, for NLRP1-associated autoinflammation arthritis and dyskeratosis. The aim of our study was to unravel how mutation in NLRP1 impaired its function and triggered autoinflammation. Materials and methods Peripheral blood mononuclear cells from patients were analysed to identify the immunologic components involved in these novel diseases, using flow cytometry. The pathogenic effect of the NLRP1 mutations in inflammation was investigated using in vitro functional assays in transfected HEK293T. Results The level of caspase-1, IL-18 and IL-1β in serum samples from patients was increased as compared to controls and asymptomatic parents. Moreover, patient’s cells displayed constitutive production of IL-1β. Functional studies in HEK293T revealed that the NLRP1 mutations resulted in a constitutive activation of the NLRP1 inflammasome. Conclusions We demonstrated that two mutations in the NLRP1 gene are involved in autoinflammation in human. This novel disease could be a novel inflammasomopathy combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity.