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Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice


Sester, DP; Sagulenko, V; Thygesen, SJ; Cridland, JA; Loi, YS; Cridland, SO; Masters, SL; Genske, U; Hornung, V; Andoniou, CE; Sweet, MJ; Degli-Esposti, MA; Schroder, K; Stacey, KJ
2015-06-26
Journal of Immunology
Journal Article in press
Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1beta and cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. The New Zealand Black (NZB) mouse develops anti-erythrocyte Abs and is a model of autoimmune hemolytic anemia. These mice also develop anti-nuclear Abs typical of lupus. In this article, we show that NZB macrophages have deficient inflammasome responses to a DNA virus and fungal infection. Absent in melanoma 2 (AIM2) inflammasome responses are compromised in NZB by high expression of the AIM 2 antagonist protein p202, and consequently NZB cells had low IL-1beta output in response to both transfected DNA and mouse CMV infection. Surprisingly, we also found that a second inflammasome system, mediated by the NLR family, pyrin domain containing 3 (NLRP3) initiating protein, was completely lacking in NZB cells. This was due to a point mutation in an intron of the Nlrp3 gene in NZB mice, which generates a novel splice acceptor site. This leads to incorporation of a pseudoexon with a premature stop codon. The lack of full-length NLRP3 protein results in NZB being effectively null for Nlrp3, with no production of bioactive IL-1beta in response to NLRP3 stimuli, including infection with Candida albicans. Thus, this autoimmune strain harbors two inflammasome deficiencies, mediated through quite distinct mechanisms. We hypothesize that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoantibodies.
ASI
Inflammation
10.4049/jimmunol.1402859
26116505
Refer to copyright notice on published article.

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Creation Date 2015-07-15 02:16:03 Last Modified 2016-04-20 12:18:47