Original articles
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. Inhibition of gasdermin D-dependent pyroptosis attenuates the progression of silica-induced pulmonary inflammation and fibrosis[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1213-1224

Inhibition of gasdermin D-dependent pyroptosis attenuates the progression of silica-induced pulmonary inflammation and fibrosis
Meiyue Songa, Jiaxin Wangb, Youliang Sunc, Junling Panga, Xiaona Lia, Yuan Liud,e,f, Yitian Zhouf,g, Peiran Yanga, Tianhui Fana, Ying Liua, Zhaoguo Lih, Xianmei Qia, Baicun Lia, Xinri Zhangi, Jing Wanga, Chen Wanga,d,e
a. State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100730, China;
b. Tsinghua-Peking Center for Life Sciences, Department of Biology, College of Medicine, Tsinghua University, Beijing 100084, China;
c. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China;
d. Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China;
e. National Clinical Research Center for Respiratory Diseases, Beijing 100029, China;
f. Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China;
g. Peking Union Medical College, MD Program, Beijing 100730, China;
h. Department of Respiratory, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China;
i. Department of Pulmonary and Critical Care Medicine, the First Hospital of Shanxi Medical University, Taiyuan 030001, China
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-1β 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, in vivo and in vitro. Notably, Gsdmd 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.
Key words:    Silicosis    Gasdermin D    Pyroptosis    Macrophage    Pulmonary fibrosis   
Received: 2021-06-28     Revised: 2021-08-12
DOI: 10.1016/j.apsb.2021.10.006
Funds: This study was supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS; Nos. 2021-1-I2M-049 and 2018-I2M-1-001, China), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (Nos. 2019RC330001 and 2021RC310002, China) and National Natural Science Foundation of China (No. 82090010). Special thanks to Prof. Feng Shao for his generous experimental assistance.
Corresponding author: Xinri Zhang,E-mai:ykdzxr61@163.com;Jing Wang,E-mai:wangjing@ibms.pumc.edu.cn     Email:ykdzxr61@163.com;wangjing@ibms.pumc.edu.cn
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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

References:
[1] Leung CC, Yu ITS, Chen W. Silicosis. Lancet 2012;379:2008-2018
[2] Perlman DM, Maier LA. Occupational lung disease. Med Clin North Am 2019;103:535-548
[3] Rushton L. The global burden of occupational disease. Curr Environ Health Rep 2017;4:340-348
[4] Barnes H, Goh NSL, Leong TL, Hoy R. Silica-associated lung disease: an old-world exposure in modern industries. Respirology 2019;24:1165-1175
[5] Hamilton RF, Thakur SA, Holian A. Silica binding and toxicity in alveolar macrophages. Free Radic Biol Med 2008;44:1246-1258
[6] Guo J, Gu N, Chen J, Shi T, Zhou Y, Rong Y, et al. Neutralization of interleukin-1 beta attenuates silica-induced lung inflammation and fibrosis in C57BL/6 mice. Arch Toxicol 2013;87:1963-1973
[7] Hoffman HM, Wanderer AA. Inflammasome and IL-1β-mediated disorders. Curr Allergy Asthma Rep 2010;10:229-235
[8] Batista SJ, Still KM, Johanson D, Thompson JA, OBrien CA, Lukens JR, et al. Gasdermin-D-dependent IL-1α release from microglia promotes protective immunity during chronic Toxoplasma gondii infection. Nat Commun 2020;11:3687
[9] Evavold CL, Ruan J, Tan Y, Xia S, Wu H, Kagan JC. The Pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages. Immunity 2018;48:35-44
[10] He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res 2015;25:1285-1298
[11] Luan J, Chen W, Fan J, Wang S, Zhang X, Zai W, et al. 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 2020;227:119570
[12] Xia S, Zhang Z, Magupalli VG, Pablo JL, Dong Y, Vora SM, et al. Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature 2021;593:607-611
[13] Shi J, Gao W, Shao F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci 2017;42:245-254
[14] Sauler M, Bazan IS, Lee PJ. Cell death in the lung: the apoptosis-necroptosis axis. Annu Rev Physiol 2019;81:375-402
[15] Broz P, Pelegrin P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol 2020;20:143-157
[16] Orning P, Lien E, Fitzgerald KA. Gasdermins and their role in immunity and inflammation. J Exp Med 2019;216:2453-2465
[17] Liang Q, Cai W, Zhao Y, Xu H, Tang H, Chen D, et al. Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis. Pharmacol Res 2020;158:104884
[18] Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, et al. Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma. Am J Respir Crit Care Med 2017;196:283-297
[19] Panganiban RA, Sun M, Dahlin A, Park H-R, Kan M, Himes BE, et al. A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis. J Allergy Clin Immunol 2018;142:1469-78.e2
[20] Kovarova M, Hesker PR, Jania L, Nguyen M, Snouwaert JN, Xiang Z, et al. NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice. J Immunol 2012;189:2006-2016
[21] Yang J, Zhao Y, Zhang P, Li Y, Yang Y, Yang Y, et al. Hemorrhagic shock primes for lung vascular endothelial cell pyroptosis: role in pulmonary inflammation following LPS. Cell Death Dis 2016;7:e2363
[22] Cao Z, Song M, Liu Y, Pang J, Li Z, Qi X, et al. A novel pathophysiological classification of silicosis models provides some new insights into the progression of the disease. Ecotoxicol Environ Saf 2020;202:110834
[23] Chen X, He WT, Hu L, Li J, Fang Y, Wang X, et al. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res 2016;26:1007-1020
[24] Szapiel SV, Elson NA, Fulmer JD, Hunninghake GW, Crystal RG. Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse. Am Rev Respir Dis 1979;120:893-899
[25] King EJ. Silicosis. Lect Sci Basis Med 1952;2:108-138
[26] Peeters PM, Perkins TN, Wouters EFM, Mossman BT, Reynaert NL. Silica induces NLRP3 inflammasome activation in human lung epithelial cells. Part Fibre Toxicol 2013;10:3
[27] Davis BK, Wen H, Ting JPY. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 2011;29:707-735
[28] Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol 2013;13:397-411
[29] Lu F, Lan Z, Xin Z, He C, Guo Z, Xia X, et al. Emerging insights into molecular mechanisms underlying pyroptosis and functions of inflammasomes in diseases. J Cell Physiol 2020;235:3207-3221
[30] Elliott EI, Sutterwala FS. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol Rev 2015;265:35-52
[31] Peeters PM, Eurlings IMJ, Perkins TN, Wouters EF, Schins RPF, Borm PJA, et al. Silica-induced NLRP3 inflammasome activation in vitro and in rat lungs. Part Fibre Toxicol 2014;11:58
[32] Liang F, Zhang F, Zhang L, Wei W. The advances in pyroptosis initiated by inflammasome in inflammatory and immune diseases. Inflamm Res 2020;69:159-166
[33] Zaslona Z, Flis E, Wilk MM, Carroll RG, Palsson-McDermott EM, Hughes MM, et al. Caspase-11 promotes allergic airway inflammation. Nat Commun 2020;11:1055
[34] Chao KL, 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:E1128-E1137
[35] Ying Y, Mao Y, Yao M. NLRP3 inflammasome activation by microRNA-495 promoter methylation may contribute to the progression of acute lung injury. Mol Ther Nucleic Acids 2019;18:801-814
[36] Cheng KT, Xiong S, Ye Z, Hong Z, Di A, Tsang KM, et al. Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest 2017;127:4124-4135
[37] Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 2018;25:486-541
[38] Rathkey JK, Zhao J, Liu Z, Chen Y, Yang J, Kondolf HC, et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci Immunol 2018;3:eaat2738
[39] Sollberger G, Choidas A, Burn GL, Habenberger P, Di Lucrezia R, Kordes S, et al. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci Immunol 2018;3:eaar6689
[40] Pandeya A, Li L, Li Z, Wei Y. Gasdermin D (GSDMD) as a new target for the treatment of infection. Medchemcomm 2019;10:660-667
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