Inhibition of Gasdermin D-dependent Pyroptosis Attenuates the Progression of Silica-induced Pulmonary Inflammation and Fibrosis

Overview

Journal Acta Pharm Sin B

Publisher Elsevier

Specialty Pharmacology

Date 2022 May 9

PMID 35530143

Authors

Meiyue Song

Jiaxin Wang

Youliang Sun

Junling Pang

XiaoNa Li

Yuan Liu

Yitian Zhou

Peiran Yang

Tianhui Fan

Ying Liu

Zhaoguo Li

Xianmei Qi

Baicun Li

Xinri Zhang

Jing Wang

Chen Wang

Affiliations

Soon will be listed here.

Abstract

Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide, but the molecular basis underlying its development remains unclear. An accumulating body of evidence supports gasdermin D (GSDMD)-mediated pyroptosis as a key component in the development of various pulmonary diseases. However, there is little experimental evidence connecting silicosis and GSDMD-driven pyroptosis. In this work, we investigated the role of GSDMD-mediated pyroptosis in silicosis. Single-cell RNA sequencing of healthy and silicosis human and murine lung tissues indicated that GSDMD-induced pyroptosis in macrophages was relevant to silicosis progression. Through microscopy we then observed morphological alterations of pyroptosis in macrophages treated with silica. Measurement of interleukin-1 release, lactic dehydrogenase activity, and real-time propidium iodide staining further revealed that silica induced pyroptosis of macrophages. Additionally, we verified that both canonical (caspase-1-mediated) and non-canonical (caspase-4/5/11-mediated) signaling pathways mediated silica-induced pyroptosis activation, and . Notably, knockout mice exhibited dramatically alleviated silicosis phenotypes, which highlighted the pivotal role of pyroptosis in this disease. Taken together, our results demonstrated that macrophages underwent GSDMD-dependent pyroptosis in silicosis and inhibition of this process could serve as a viable clinical strategy for mitigating silicosis.

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References

Hamilton Jr R, Thakur S, Holian A . Silica binding and toxicity in alveolar macrophages. Free Radic Biol Med. 2008; 44(7):1246-58. PMC: 2680955. DOI: 10.1016/j.freeradbiomed.2007.12.027. View

Sollberger G, Choidas A, Burn G, Habenberger P, Di Lucrezia R, Kordes S . Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci Immunol. 2018; 3(26). DOI: 10.1126/sciimmunol.aar6689. View

Peeters P, Eurlings I, Perkins T, Wouters E, Schins R, Borm P . Silica-induced NLRP3 inflammasome activation in vitro and in rat lungs. Part Fibre Toxicol. 2014; 11:58. PMC: 4243278. DOI: 10.1186/s12989-014-0058-0. View

Chen X, He W, Hu L, Li J, Fang Y, Wang X . Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res. 2016; 26(9):1007-20. PMC: 5034106. DOI: 10.1038/cr.2016.100. View

Xia S, Zhang Z, Magupalli V, Pablo J, Dong Y, Vora S . Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature. 2021; 593(7860):607-611. PMC: 8588876. DOI: 10.1038/s41586-021-03478-3. View

Evavold C, Ruan J, Tan Y, Xia S, Wu H, Kagan J . The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages. Immunity. 2017; 48(1):35-44.e6. PMC: 5773350. DOI: 10.1016/j.immuni.2017.11.013. View

Shi J, Gao W, Shao F . Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. Trends Biochem Sci. 2016; 42(4):245-254. DOI: 10.1016/j.tibs.2016.10.004. View

Sauler M, Bazan I, Lee P . Cell Death in the Lung: The Apoptosis-Necroptosis Axis. Annu Rev Physiol. 2018; 81:375-402. PMC: 6598441. DOI: 10.1146/annurev-physiol-020518-114320. View

Liang Q, Cai W, Zhao Y, Xu H, Tang H, Chen D . Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis. Pharmacol Res. 2020; 158:104884. DOI: 10.1016/j.phrs.2020.104884. View

10.

Yang J, Zhao Y, Zhang P, Li Y, Yang Y, Yang Y . Hemorrhagic shock primes for lung vascular endothelial cell pyroptosis: role in pulmonary inflammation following LPS. Cell Death Dis. 2016; 7(9):e2363. PMC: 5059873. DOI: 10.1038/cddis.2016.274. View

11.

Perlman D, Maier L . Occupational Lung Disease. Med Clin North Am. 2019; 103(3):535-548. DOI: 10.1016/j.mcna.2018.12.012. View

12.

Rathkey J, Zhao J, Liu Z, Chen Y, Yang J, Kondolf H . Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci Immunol. 2018; 3(26). PMC: 6462819. DOI: 10.1126/sciimmunol.aat2738. View

13.

Luan J, Chen W, Fan J, Wang S, Zhang X, Zai W . GSDMD membrane pore is critical for IL-1β release and antagonizing IL-1β by hepatocyte-specific nanobiologics is a promising therapeutics for murine alcoholic steatohepatitis. Biomaterials. 2019; 227:119570. DOI: 10.1016/j.biomaterials.2019.119570. View

14.

Hoffman H, Wanderer A . Inflammasome and IL-1beta-mediated disorders. Curr Allergy Asthma Rep. 2010; 10(4):229-35. PMC: 2892083. DOI: 10.1007/s11882-010-0109-z. View

15.

Kim R, Pinkerton J, Essilfie A, Robertson A, Baines K, Brown A . Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma. Am J Respir Crit Care Med. 2017; 196(3):283-297. DOI: 10.1164/rccm.201609-1830OC. View

16.

Barnes H, Goh N, Leong T, Hoy R . Silica-associated lung disease: An old-world exposure in modern industries. Respirology. 2019; 24(12):1165-1175. DOI: 10.1111/resp.13695. View

17.

Broz P, Pelegrin P, Shao F . The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2019; 20(3):143-157. DOI: 10.1038/s41577-019-0228-2. View

18.

Cheng K, Xiong S, Ye Z, Hong Z, Di A, Tsang K . Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest. 2017; 127(11):4124-4135. PMC: 5663346. DOI: 10.1172/JCI94495. View

19.

Kovarova M, Hesker P, Jania L, Nguyen M, Snouwaert J, Xiang Z . NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice. J Immunol. 2012; 189(4):2006-16. PMC: 3635067. DOI: 10.4049/jimmunol.1201065. View

20.

Chao K, Kulakova L, Herzberg O . Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein. Proc Natl Acad Sci U S A. 2017; 114(7):E1128-E1137. PMC: 5321033. DOI: 10.1073/pnas.1616783114. View