Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

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.

Leaky Gut As a Danger Signal for Autoimmune Diseases

“…The most extensively characterized NLRs are associated with inflammasome formation (135, 136). Loss of NLRP3 and AIM2 inflammasome function was found to significantly contribute to lupus pathogenesis (137). Interestingly, both of these inflammasomes were found compromised in NZB mice, a lupus-prone model.…”

Absent in melanoma 2 proteins in the development of cancer

“…Constitutive levels of Aim2 mRNA and protein are lower in immune cells from the New Zealand black (NZB) strain (and NZB-derived B6.Nba2 congenic strain of mice) of female mice as compared with age and sex-matched C57BL/6 (B6) strain of mice [24,25]. Steady-state levels of Aim2 mRNA and protein were detectable in bone marrow-derived macrophages (BMDMs) from the B6 female mice and treatment of cells with IFN-a appreciably increased the levels in time-dependent manner [26].…”

AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity

“…Furthermore, several proteins produced in the cell have the ability to inhibit activation of the AIM2 inflammasome [14,[36][37][38][39][40][41][42][43]. These include the PYD-containing proteins POP1 [39] and POP3 [36] in human cells and the bipartite protein containing two HIN domains, p202, in mouse cells [14, [40][41][42][43]. Here, we summarize the latest research on the regulation of AIM2 inflammasome, and its role in pathogen recognition after infection, cancer, and autoimmunity.…”