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Although NLRP3 is activated by many pathogens, it only appears to be critical for host defense for a limited number of specific infections. NLRP3 is however strongly associated with the initiation and pathology of many inflammatory diseases. If NLRP3 function is largely redundant for host defense, but drives a number of inflammatory diseases, this raises the important question of why evolution has elected to maintain NLRP3 function. We propose that the primary physiological functions of NLRP3 in health are to engage pathways to clear noxious substances (e.g. protein aggregates and crystals), and to regulate metabolism. We discuss the newly identified functions for NLRP3 in metabolic homeostasis, and how NLRP3 beneficial functions in homeostasis may become detrimental during the onset of inflammatory and metabolic diseases. A common feature of most NLRP3-driven diseases is that they are associated with ageing or metabolic excess, and indeed, <jats:italic>Nlrp3<\/jats:italic> deficiency promotes \u2018healthspan\u2019 in ageing mice. This suggests that beneficial functions of NLRP3 in youth may become increasingly countered by NLRP3-dependent pathology as an individual ages, and we propose a general model by which ageing or nutrient excess may provide a tipping point to switch NLRP3 function from beneficial to pathological. The physiological role of NLRP3 in healthy individuals remains incompletely understood and future research will need to address this if NLRP3 is to become a successful therapeutic target for the clinical management of inflammatory diseases.<\/jats:p>","DOI":"10.1038\/cddiscovery.2016.19","type":"journal-article","created":{"date-parts":[[2016,4,5]],"date-time":"2016-04-05T10:38:24Z","timestamp":1459852704000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Questions and controversies in innate immune research: what is the physiological role of NLRP3?"],"prefix":"10.1038","volume":"2","author":[{"given":"RC","family":"Coll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LAJ","family":"O\u2019Neill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Schroder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,4]]},"reference":[{"key":"BFcddiscovery201619_CR1","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1038\/ng756","volume":"29","author":"HM Hoffman","year":"2001","unstructured":"Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD . 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