title: An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice.
abstract: The NLRP3 inflammasome plays a critical role in host defense by facilitating caspase I activation and maturation of IL-1β and IL-18, whereas dysregulation of inflammasome activity results in autoinflammatory disease. Factors regulating human NLRP3 activity that contribute to the phenotypic heterogeneity of NLRP3-related diseases have largely been inferred from the study of Nlrp3 mutant mice. By generating a mouse line in which the NLRP3 locus is humanized by syntenic replacement, we show the functioning of the human NLRP3 proteins in vivo, demonstrating the ability of the human inflammasome to orchestrate immune reactions in response to innate stimuli. Humanized mice expressing disease-associated mutations develop normally but display acute sensitivity to endotoxin and develop progressive and debilitating arthritis characterized by granulocytic infiltrates, elevated cytokines, erosion of bones, and osteoporosis. This NLRP3-dependent arthritis model provides a platform for testing therapeutic reagents targeting the human inflammasome.
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Snouwaert
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: MyTrang
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Repenning
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dye
authors.affiliation: Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Livingston
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Kovarova
authors.affiliation: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Moy
authors.affiliation: Department of Orthopedic Surgery and Pediatrics, Duke University, Durham, NC 27705, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Brigman
authors.affiliation: Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Ted A
authors.initials: TA
authors.lastname: Bateman
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: bkoller@correspondence.unc.edu.
authors.forename: Beverly H
authors.initials: BH
authors.lastname: Koller
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D058847:Inflammasomes / Q000235:genetics; D007592:Joint Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics* / Q000473:pathology
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse
keywords: IL-18; Muckle-Wells syndrome; NOMID; arthritis; autoinflammatory; cryopyrinopathies; endotoxic shock; familial cold autoinflammatory syndrome; inflammasome; meningitis; syntenic replacement