ORIGINAL RESEARCH article
Front. Immunol.
Sec. Immunological Tolerance and Regulation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1631152
This article is part of the Research TopicStriking the Balance: The Role of Regulatory Pathways and the Microbiome in Inflammation and Immune ToleranceView all articles
Impaired NLRP3 inflammasome signaling diverts pyroptotic to apoptotic caspase activation in macrophages
Provisionally accepted
Ying-qing GanYuan-wen CaiXiu-wen Liang
Fu-li ShiNuo SunYa-Ping LiRong XuBo Hu
Qing-bing Zha
Xian-Hui HeTaksui Wong
Jin-hua Li
Dong-Yun Ouyang*- Jinan University, Guangzhou, China
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NLRP3 (NLR family pyrin domain-containing 3) inflammasome is a first line of defense of innate immunity, mediating caspase-1-dependent pyroptosis and cytokine release upon danger signaling. Intervention of NLRP3 innate surveillance may cause defects in this signaling pathway, while the host has evolved alternative ways to combat such intervention. Yet it remains incompletely understood whether NLRP3 sensing of danger signaling can divert pyroptosis to other forms of cell death in circumstances of impaired NLRP3 signaling. In this study, we adopted two macrophage models (delayed delivery of triggering signaling and caspase-1 deficiency) to mimic defects in NLRP3 signaling to address this issue. We found that the NLRP3/ASC platform preferentially recruited caspase-1 rather than caspase-8 in lipopolysaccharide (LPS)-primed macrophages timely triggered with nigericin. However, when the triggering signal (nigericin) was delayed, the recruitment diverted to caspase-8, leading to apoptotic caspase activation. Furthermore, in caspase-1-deficient macrophages, nigericin triggering diverted NLRP3-ASC-caspase-1-driven pyroptosis to caspase-8/-9/-3 activation and GSDME-mediated secondary necrosis. Unexpectedly, VX-765 (a caspase-1 inhibitor) exhibited a pan-caspase inhibitor-like effect, suppressing caspase-8/-9/-3 activation and GSDME cleavage in a dose-dependent manner. Mitochondrial damage was observed in both WT and caspase-1-deficient cells upon nigericin stimulation, suggesting mitochondrial injury being an upstream event in this process. Collectively, our data indicate that NLRP3 inflammasome is poised to divert pyroptotic to apoptotic caspase activation for combating danger signaling when conventional pathway is impaired, highlighting a complex interaction between various forms of cell death pathways.
Keywords: NLRP3 inflammasome, apoptosome, caspase-8, LPS tolerance, pyroptosis, Apoptosis
Received: 19 May 2025; Accepted: 02 Oct 2025.
Copyright: © 2025 Gan, Cai, Liang, Shi, Sun, Li, Xu, Hu, Zha, He, Wong, Li and Ouyang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dong-Yun Ouyang, dongyun1967@aliyun.com
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