School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, 4072, Australia.
Immunol Cell Biol. 2019 Jan;97(1):17-28. doi: 10.1111/imcb.12193. Epub 2018 Aug 19.
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 NLRP3 inflammasome function, and their absent in melanoma 2 (AIM2) inflammasome responses are compromised by high expression of the AIM2 antagonist protein p202. Here we found that the point mutation leading to lack of NLRP3 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 AIM2 and NLRP3 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 NLRP3 and show reduced NLRP3 and AIM2 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 NLRP3 response in the NZB/W F1 may be sufficient to contribute to kidney damage at later stages of disease.
炎症小体是一种被感染和细胞应激激活的蛋白复合物，可促进半胱天冬酶-1 的激活以及随后的炎症细胞因子加工和细胞死亡。人们曾预计炎症小体的活性有助于自身免疫。然而，我们之前曾表明，来自自身免疫性新西兰黑（NZB）小鼠的巨噬细胞缺乏 NLRP3 炎症小体功能，其缺失黑色素瘤 2（AIM2）炎症小体反应由于高表达 AIM2 拮抗剂蛋白 p202 而受到损害。在这里，我们发现导致 NLRP3 表达缺失的点突变发生在 NZB 株建立的早期，因为它与相关的肥胖株新西兰肥胖（New Zealand Obese）共享，但与不相关的新西兰白（New Zealand White，NZW）株不共享。NZB 和 NZW 小鼠的第一代杂交后代比 NZB 株发展出更严重的狼疮肾炎。我们比较了来自 NZB、NZW 和 NZB/W F1 小鼠的巨噬细胞中的 AIM2 和 NLRP3 炎症小体功能。NZW 亲本株表现出强烈的炎症小体功能，而 NZB/W F1 则表现出 NLRP3 的单倍不足表达，并表现出 NLRP3 和 AIM2 炎症小体反应减少，尤其是在低刺激强度下。NLRP3 炎症小体功能降低是否会导致 NZB 和 NZB/W F1 自身免疫的耐受丧失和自身免疫的发生，还有待确定。然而，随着疾病过程中炎症刺激的放大，NZB/W F1 中的 NLRP3 反应可能足以在疾病的后期阶段导致肾脏损伤。
