Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice.
David P SesterVitaliya SagulenkoSara J ThygesenJasmyn A CridlandYen Siew LoiSimon O CridlandSeth L MastersUlrich GenskeVeit HornungChristopher E AndoniouMatthew J SweetMariapia A Degli-EspostiKate SchroderKatryn J StaceyPublished in: Journal of immunology (Baltimore, Md. : 1950) (2015)
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.
Keyphrases
- cell death
- induced apoptosis
- candida albicans
- cell cycle arrest
- nlrp inflammasome
- binding protein
- multiple sclerosis
- protein protein
- systemic lupus erythematosus
- high fat diet induced
- poor prognosis
- wild type
- amino acid
- biofilm formation
- type diabetes
- adipose tissue
- metabolic syndrome
- insulin resistance
- endoplasmic reticulum stress
- rheumatoid arthritis
- gene expression
- oxidative stress
- disease activity
- skeletal muscle
- signaling pathway
- escherichia coli
- multidrug resistant
- gram negative
- drug induced
- quantum dots