Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice.

Sester, David P., Sagulenko, Vitaliya, Thygesen, Sara J., Cridland, Jasmyn A., Loi, Yen Siew, Cridland, Simon O., Masters, Seth L., Genske, Ulrich, Hornung, Veit, Andoniou, Christopher E., Sweet, Matthew J., Degli-Esposti, Mariapia A., Schroder, Kate and Stacey, Katryn J. (2015) Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice.. Journal of Immunology, 195 3: 1233-1241. doi:10.4049/jimmunol.1402859

Author Sester, David P.
Sagulenko, Vitaliya
Thygesen, Sara J.
Cridland, Jasmyn A.
Loi, Yen Siew
Cridland, Simon O.
Masters, Seth L.
Genske, Ulrich
Hornung, Veit
Andoniou, Christopher E.
Sweet, Matthew J.
Degli-Esposti, Mariapia A.
Schroder, Kate
Stacey, Katryn J.
Title Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice.
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2015-06-26
Year available 2015
Sub-type Article (original research)
DOI 10.4049/jimmunol.1402859
Volume 195
Issue 3
Start page 1233
End page 1241
Total pages 9
Place of publication Bethesda, MD United States
Publisher American Association of Immunologists
Language eng
Formatted abstract
Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1β 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-1β 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-1β 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 03 Jul 2015, 19:57:18 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences