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Compromised NLRP 3 and AIM 2 inflammasome function in autoimmune NZB /W F1 mouse macrophages
Author(s) -
Thygesen Sara J,
Takizawa Karli E,
Robertson Avril A B,
Sester David P,
Stacey Katryn J
Publication year - 2019
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/imcb.12193
Subject(s) - inflammasome , aim2 , autoimmunity , immunology , pyrin domain , inflammation , biology , caspase 1 , antibody
Inflammasomes are protein complexes activated by infection and cellular stress that promote caspase‐1 activation and subsequent inflammatory cytokine processing and cell death. It has been anticipated that inflammasome activity contributes to autoimmunity. However, we previously showed that macrophages from autoimmune New Zealand Black ( NZB ) mice lack NLRP 3 inflammasome function, and their absent in melanoma 2 ( AIM 2) inflammasome responses are compromised by high expression of the AIM 2 antagonist protein p202. Here we found that the point mutation leading to lack of NLRP 3 expression occurred early in the NZB strain establishment, as it is shared with the related obese strain New Zealand Obese, but not with the unrelated New Zealand White ( NZW ) strain. The first cross progeny of NZB and NZW mice develop more severe lupus nephritis than the NZB strain. We have compared AIM 2 and NLRP 3 inflammasome function in macrophages from NZB , NZW , and NZB /W F1 mice. The NZW parental strain showed strong inflammasome function, whereas the NZB /W F1 have haploinsufficient expression of NLRP 3 and show reduced NLRP 3 and AIM 2 inflammasome responses, particularly at low stimulus strength. It remains to be established whether the low inflammasome function could contribute to loss of tolerance and the onset of autoimmunity in NZB and NZB /W F1. However, with amplifying inflammatory stimuli through the course of disease, the NLRP 3 response in the NZB /W F1 may be sufficient to contribute to kidney damage at later stages of disease.