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Homozygous: Mice showed reduced IL-1β secretion from LPS-primed macrophages, bone marrow-derived macrophages, and bone marrow-derived dendritic cells after stimulation with nigericin, ATP, or alum as well as after E. coli or C. rodentium infection. Mice also exhibited impaired NLRP3-dependent IL-18 production and pyroptosis of LPS-primed macrophages simulated with nigericin, ATP, or alum as well as after E. coli or C. rodentium infection. When challenged with monosodium urate crystals (MSU), some mice exhibited reduced NLRP3-dependent recruitment of total cells, neutrophils, and F4/80 positive monocytes/macrophages to the peritoneal cavity. When exposed to IL-1β-driven experimental autoimmune encephalitis, some mice exhibited reduced disease severity compared to wild-type mice as well as reduced recruitment of lymphocytes (CD4, CD8, TCR??, CD19+ B cells), monocytes/microglia, and NK cells to the spinal cord. Cyclic AMP levels were increased in the macrophages compared to wild-type macrophages after LPS-priming and nigericin stimulation. NLRP3 inflammasome activation was partially impaired in the macrophages due to a defective cAMP response. Mice weighed an average of 30% less than their wild-type littermates at two months of age; comparable to wild-type at birth. Mice exhibited an abnormal gait and slight paresis of the limbs. Mice exhibited infertility.
Heterozygous: Mice showed reduced IL-1β secretion from LPS-primed macrophages, bone marrow-derived macrophages, and bone marrow-derived dendritic cells after stimulation with nigericin, ATP, or alum as well as after E. coli or C. rodentium infection. Mice also exhibited impaired NLRP3-dependent IL-18 production and pyroptosis of LPS-primed macrophages simulated with nigericin, ATP, or alum as well as after E. coli or C. rodentium infection.
Shi H, Wang Y, Li X, Zhan X, Tang M, Fina M, Su L, Pratt D, Bu CH, Hildebrand S, Lyon S, Scott L, Quan J, Sun Q, Russell J, Arnett S, Jurek P, Chen D, Kravchenko VV, Mathison JC, Moresco EMY, Monson NL, Ulevitch RJ, Beutler B. NLRP3 Activation and Mitosis are Mutually Exclusive Events Coordinated by NEK7, a New Inflammasome Component. Nature Immunology. 2015 (Reference).
Shi H, Wang Y, Murray AR, Beutler B. Record for Cuties. MUTAGENETIX, B. Beutler and colleagues, Center for the Genetics of Host Defense, UT Southwestern, Dallas, TX.
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