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

• DOI: 10.3724/abbs.2021004
• Publication Date: 2021-12-22T07:03:32Z
• Authors: Meiyan Zhong; Yuanting Huang; Bo Zeng; Lihui Xu; Chunsu Zhong; Jiahao Qiu; Xunjia Ye; Mingye Chen; Bo Hu; Dongyun Ouyang; Xianhui He
• Keywords: Pyroptosis; Gossypol; RIPK1; Propidium iodide

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