Caffeic acid, but not ferulic acid, inhibits macrophage pyroptosis by directly blocking gasdermin D activation

Author:

Liu Mingjiang123ORCID,Liu Dandan2,Yu Chenglong2,Fan Hua hao4ORCID,Zhao Xin2,Wang Huiwen2,Zhang Chi2,Zhang Minxia2,Bo Ruonan23,He Shasha1,Wang Xuerui1,Jiang Hui5,Guo Yuhong1,Li Jingui23,Xu Xiaolong1,Liu Qingquan1

Affiliation:

1. Beijing Key Laboratory of Basic Research With Traditional Chinese Medicine on Infectious Diseases Beijing Hospital of Traditional Chinese Medicine Capital Medical University Beijing China

2. College of Veterinary Medicine Yangzhou University Yangzhou China

3. Jiangsu Co‐innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses Yangzhou China

4. Beijing University of Chemical Technology Beijing China

5. Beijing Chest Hospital Capital Medical University Beijing China

Abstract

AbstractRegulated pyroptosis is critical for pathogen elimination by inducing infected cell rupture and pro‐inflammatory cytokines secretion, while overwhelmed pyroptosis contributes to organ dysfunction and pathological inflammatory response. Caffeic acid (CA) and ferulic acid (FA) are both well‐known antioxidant and anti‐inflammatory phenolic acids, which resemble in chemical structure. Here we found that CA, but not FA, protects macrophages from both Nigericin‐induced canonical and cytosolic lipopolysaccharide (LPS)‐induced non‐canonical pyroptosis and alleviates LPS‐induced mice sepsis. It significantly improved the survival of pyroptotic cells and LPS‐challenged mice and blocked proinflammatory cytokine secretion. The anti‐pyroptotic effect of CA is independent of its regulations in cellular lipid peroxidation, mitochondrial function, or pyroptosis‐associated gene transcription. Instead, CA arrests pyroptosis by directly associating with gasdermin D (GSDMD) and blocking its processing, resulting in reduced N‐GSDMD pore construction and less cellular content release. In LPS‐induced septic mice, CA inhibits GSDMD activation in peritoneal macrophages and reduces the serum levels of interleukin‐1β and tumor necrosis factor‐α as the known pyroptosis inhibitors, disulfiram and dimethyl fumarate. Collectively, these findings suggest that CA inhibits pyroptosis by targeting GSDMD and is a potential candidate for curbing the pyroptosis‐associated disease.

Funder

National Natural Science Foundation of China

Priority Academic Program Development of Jiangsu Higher Education Institutions

Publisher

Wiley

Subject

Cell Biology,Biochemistry (medical),Genetics (clinical),Computer Science Applications,Drug Discovery,Genetics,Oncology,Immunology and Allergy

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. The gasdermin family: emerging therapeutic targets in diseases;Signal Transduction and Targeted Therapy;2024-04-08

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