2. Academic Validation
  3. Activated autophagy drives the adaptive response to LPS-evoked lung pyroptosis in adolescent mice

Activated autophagy drives the adaptive response to LPS-evoked lung pyroptosis in adolescent mice

  • Toxicol Appl Pharmacol. 2026 Jan:506:117650. doi: 10.1016/j.taap.2025.117650.
Hao Li 1,  Hua Wang 2,  Ye-Xin Luo 3,  Tian-Tian Wang 3,  Kong-Wen Ouyang 3,  Xin-Mei Zheng 3,  Xin-Xin Zhang 3,  Qing Ling 3,  Yong-Wei Xiong 4,  De-Xiang Xu 3,  Hua-Long Zhu 5,  Hua Wang 6
Affiliations

Affiliations

  • 1 Department of Preventive Medicine, School of Public Health, Wannan Medical College, Wuhu, Anhui Province 241002, China; Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
  • 2 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China; Department of Respiratory Medicine, Anhui Provincial Children's Hospital, Hefei, Anhui 230000, PR China. Electronic address: [email protected].
  • 3 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
  • 4 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei 230032, China.
  • 5 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei 230032, China. Electronic address: [email protected].
  • 6 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei 230032, China. Electronic address: [email protected].
PMID: 41285320 DOI: 10.1016/j.taap.2025.117650
Abstract

The disease of lipopolysaccharide (LPS)-induced acute lung injury (ALI) is prevalent among clinical respiratory patients. The LPS adaptive response is a phenomenon whereby prior exposure to a low dose of LPS results in insensitivity to a subsequent high-dose challenge. However, the LPS adaptive response and its mechanism in mice with LPS-induced ALI remains limited. In this study, CD-1 male mice received a low-dose LPS (0.1 mg/kg) pretreatment for 24 h before high-dose LPS (5 mg/kg) challenge. Pretreatment with low-dose LPS mitigates the effects of high-dose LPS-induced lung Pyroptosis and ALI. Low-dose LPS pretreatment also blocked high-dose LPS-induced activation of NLRC4 inflammasome in the lung. Interestingly, low-dose LPS pretreatment further increased the level of autophagy-related proteins in the lung with high-dose LPS treatment, suggesting that Autophagy was further activated after low-dose LPS pretreatment. It is also important to note that 3-methyladenine is a specific inhibitor of Autophagy, blocks the adaptive response to LPS-evoked Pyroptosis and ALI. Inversely, rapamycin, an Autophagy Inducer, promotes adaptive response to LPS-evoked Pyroptosis and ALI. Mechanistically, activated Autophagy drives the adaptive response to LPS-evoked lung Pyroptosis in mice via promoting p62-dependent degradation of NLRC4. Collectively, our results indicate that low-dose LPS pretreatment activates Autophagy to degrade NLRC4 by p62 dependent manner, thereby protecting against Pyroptosis and ALI induced by high-dose of LPS.

Keywords

Acute lung injury; Adaptive response; Autophagy; LPS; NLRC4; Pyroptosis.

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