Induction of multiple subroutines of regulated necrosis in murine macrophages by natural BH3-mimetic gossypol

坏死性下垂 上睑下垂 炎症体 棉酚 坏死 程序性细胞死亡 裂谷1 碘化丙啶 细胞凋亡 肿瘤坏死因子α 细胞生物学 化学 生物 免疫学 生物化学 炎症 遗传学
作者
Mei-Yan Zhong,Yuanting Huang,Bo Zeng,Lihui Xu,Chun-Su Zhong,Jiahao Qiu,Xun-jia Ye,Mingye Chen,Bo Hu,Dong-Yun Ouyang,Xian-Hui He
出处
期刊:Acta Biochimica et Biophysica Sinica [Oxford University Press]
卷期号:54 (1): 64-76 被引量:6
标识
DOI:10.3724/abbs.2021004
摘要

Macrophages are critical sentinel cells armed with multiple regulated necrosis pathways, including pyroptosis, apoptosis followed by secondary necrosis, and necroptosis, and are poised to undergo distinct form(s) of necrosis for tackling dangers of pathogenic infection or toxic exposure. The natural BH3-mimetic gossypol is a toxic phytochemical that can induce apoptosis and/or pyroptotic-like cell death, but what exact forms of regulated necrosis are induced remains largely unknown. Here we demonstrated that gossypol induces pyroptotic-like cell death in both unprimed and lipopolysaccharide-primed mouse bone marrow-derived macrophages (BMDMs), as evidenced by membrane swelling and ballooning accompanied by propidium iodide incorporation and lactic acid dehydrogenase release. Notably, gossypol simultaneously induces the activation of both pyroptotic and apoptotic (followed by secondary necrosis) pathways but only weakly activates the necroptosis pathway. Unexpectedly, gossypol-induced necrosis is independent of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as neither inhibitor for the NLRP3 pathway nor NLRP3 deficiency protects the macrophages from the necrosis. Furthermore, necrotic inhibitors or even pan-caspase inhibitor alone does not or only partly inhibit such necrosis. Instead, a combination of inhibitors composed of pan-caspase inhibitor IDN-6556, RIPK3 inhibitor GSK'872 and NADPH oxidase inhibitor GKT137831 not only markedly inhibits the necrosis, with all apoptotic and pyroptotic pathways being blocked, but also attenuates gossypol-induced peritonitis in mice. Lastly, the activation of the NLRP3 pathway and apoptotic caspase-3 appears to be independent of each other. Collectively, gossypol simultaneously induces the activation of multiple subroutines of regulated necrosis in macrophages depending on both apoptotic and inflammatory caspases.
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