Inflammasome adaptor and effectors in Cryopyrinopathies and crystal arthropathies

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 DESCRIPTION (provided by applicant): Inflammasomes are protein complexes that facilitate the maturation and secretion of the pro-inflammatory cytokines interleukin (IL) -1ß and IL-18, which are important for innate immune responses. Nevertheless, for maintaining homeostasis balance and temporary inflammasome activation is essential, since uncontrolled and excessive cytokine production has been linked to rheumatic and other inflammatory diseases. The first step of inflammasome activation is the sensing of pathogens and cellular danger signals by pattern recognition receptors (PRRs) and the NOD-like receptor containing a pyrin domain (NLRP) 3 is one of them. Upon activation, NLRP3 recruits the adaptor ASC and the effector caspase-1, which subsequently processes IL-1¿ and IL-18 into their biologically active forms. However, recently the mitochondrial MAVS protein has been proposed to also function as an inflammasome adaptor and caspases-11 and -8 were implicated as alternative effectors for NLRP3 inflammasomes during bacterial infections. Nevertheless, their contribution and relevance to NLRP3 inflammasome activation in rheumatic and inflammatory diseases has not been investigated yet. The proper function of NLRP3 is crucial for human health, since defects in the NLRP3 inflammasome regulation are associated with several inflammatory diseases, including Cryopyrinopathies and crystal arthropathies. While hereditary mutations render NLRP3 constitutively active in Cryopyrinopathies, an excess of danger signals in the form of monosodium urate (MSU) crystal precipitates in the joint triggers NLRP3 inflammasome activation and an acute local inflammatory response that causes gouty arthritis. Hence, in both diseases the uncontrolled activation of NLRP3 leads to excessive IL-1ß production. Consequently, blocking IL-1ß improves disease symptoms and patient outcomes. However, IL-1ß is crucial for innate immune responses and elimination of IL- 1ß altogether can also impair host defense. Thus, it is crucial to gain a detailed understanding of the NLRP3 inflammasomes regulation in Cryopyrinopathies and crystal arthropathies in order to develop specific NLRP3 inflammasome targeted therapies. I propose to study the function of MAVS and caspases-11 and -8 in NLRP3 inflammasome linked Muckle-Wells syndrome (MWS), which is a Cryopyrinopathy, and MSU crystal-induced gout by utilizing in vivo mouse models. I expect that the results from this study will have widespread implications for future therapies of MWS and gout but also for other NLRP3-associated diseases and will concurrently contribute to a better understanding of the complex molecular mechanisms involved in NLRP3 inflammasome biology. My long-term career goal is to build an academic research group focused on understanding immunologic mechanisms underlying the development of rheumatic and inflammatory diseases. I belief that this proposal is an ideal training vehicle for a K01 Mentored Scientist Development Award, as I will become proficient in mouse models of rheumatic and inflammatory diseases, as well as translational immunology, thereby developing my own niche as I begin to establish an independent academic career.