Pyroptosis is a form of cell death associated with inflammation. In the maintenance of airway homeostasis, pyroptosis goes through activation and assembly of Inflammasome. The pyroptosis pathway is mediated by caspase which activates the pore-forming effect of substrate gasdermin family members. It eventually leads to lysis and release of the cell contents and then induces an inflammatory response. In this process, it participates in airway homeostasis regulation by affecting airway immunity, airway epithelial structure and airway microbiota. Therefore, we discussed the correlation between airway immunity, airway epithelial structure, airway microbiota and the mechanism of pyroptosis to describe the role of pyroptosis in airway homeostasis regulation which is of great significance for understanding the occurrence and treatment of airway inflammatory diseases.

Department of Respiratory Disease and Critical Care Medicine Shanghai Public Health Clinical Center Fudan University Shanghai China and

Zobrazit více v PubMed

Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541. doi: 10.1038/s41418-017-0012-4. PubMed DOI PMC

Liu Y, Fang Y, Chen X, Wang Z, Liang X, Zhang T, Liu M, et al. Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci Immunol. 2020;5:eaax7969. doi: 10.1126/sciimmunol.aax7969. PubMed DOI

Long FQ, Kou CX, Li K, Wu J, Wang QQ. MiR-223-3p inhibits rTp17-induced inflammasome activation and pyroptosis by targeting NLRP3. J Cell Mol Med. 2020;24:14405–14414. doi: 10.1111/jcmm.16061. PubMed DOI PMC

Wang Y, Liu Y, Liu Q, Zheng Q, Dong X, Liu X, Gao W, Bai X, Li Z. Caspase-1-dependent pyroptosis of peripheral blood mononuclear cells is associated with the severity and mortality of septic patients. Biomed Res Int. 2020;2020:9152140. doi: 10.1155/2020/9152140. PubMed DOI PMC

Zhang MY, Jiang YX, Yang YC, Liu JY, Huo C, Ji XL, Qu YQ. Cigarette smoke extract induces pyroptosis in human bronchial epithelial cells through the ROS/NLRP3/caspase-1 pathway. Life Sci. 2021;269:119090. doi: 10.1016/j.lfs.2021.119090. PubMed DOI

Raneros AB, Bernet CR, Flórez AB, Suarez-Alvarez B. An epigenetic insight into NLRP3 inflammasome activation in inflammation-related processes. Biomedicines. 2021;9:1614. doi: 10.3390/biomedicines9111614. PubMed DOI PMC

Roshanravan N, Alamdari NM, Jafarabadi MA, Mohammadi A, Shabestari BR, Nasirzadeh N, Asghari S, et al. Effects of oral butyrate and inulin supplementation on inflammation-induced pyroptosis pathway in type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Cytokine. 2020;131:155101. doi: 10.1016/j.cyto.2020.155101. PubMed DOI

Huang Y, Jiang H, Chen Y, Wang X, Yang Y, Tao J, Deng X, et al. Tranilast directly targets NLRP3 to treat inflammasome-driven diseases. EMBO Mol Med. 2018;10:e8689. doi: 10.15252/emmm.201708689. PubMed DOI PMC

Hu JJ, Liu X, Xia S, Zhang Z, Zhang Y, Zhao J, Ruan J, et al. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol. 2020;21:736–745. doi: 10.1038/s41590-020-0669-6. PubMed DOI PMC

Blasco MT, Gomis RR. PD-L1 controls cancer pyroptosis. Nat Cell Biol. 2020;22:1157–1159. doi: 10.1038/s41556-020-00582-w. PubMed DOI

Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, Meng R, et al. Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem. 2010;285:9792–9802. doi: 10.1074/jbc.M109.082305. PubMed DOI PMC

Qiu T, Pei P, Yao X, Jiang L, Wei S, Wang Z, Bai J, et al. Taurine attenuates arsenic-induced pyroptosis and nonalcoholic steatohepatitis by inhibiting the autophagic-inflammasomal pathway. Cell Death Dis. 2018;9:946. doi: 10.1038/s41419-018-1004-0. PubMed DOI PMC

Wu LM, Wu SG, Chen F, Wu Q, Wu CM, Kang CM, He X, et al. Atorvastatin inhibits pyroptosis through the lncRNA NEXN-AS1/NEXN pathway in human vascular endothelial cells. Atherosclerosis. 2020;293:26–34. doi: 10.1016/j.atherosclerosis.2019.11.033. PubMed DOI

Zhuo L, Chen X, Sun Y, Wang Y, Shi Y, Bu L, Xia W, Han J, Chen D, Li X. Rapamycin inhibited pyroptosis and reduced the release of IL-1β and IL-18 in the septic response. Biomed Res Int. 2020;2020:5960375. doi: 10.1155/2020/5960375. PubMed DOI PMC

Rathinam VAK, Zhao Y, Shao F. Innate immunity to intracellular LPS. Nat Immunol. 2019;20:527–533. doi: 10.1038/s41590-019-0368-3. PubMed DOI PMC

Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–791. doi: 10.4049/jimmunol.0901363. PubMed DOI PMC

Rubartelli A. Redox control of NLRP3 inflammasome activation in health and disease. J Leukoc Biol. 2012;92:951–958. doi: 10.1189/jlb.0512265. PubMed DOI

Wimmer K, Sachet M, Oehler R. Circulating biomarkers of cell death. Clin Chim Acta. 2020;500:87–97. doi: 10.1016/j.cca.2019.10.003. PubMed DOI

de Vasconcelos NM, Van Opdenbosch N, Van Gorp H, Parthoens E, Lamkanfi M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ. 2019;26:146–161. doi: 10.1038/s41418-018-0106-7. PubMed DOI PMC

Tang R, Xu J, Zhang B, Liu J, Liang C, Hua J, Meng Q, Yu X, Shi S. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol. 2020;13:110. doi: 10.1186/s13045-020-00946-7. PubMed DOI PMC

Wang Y, Kanneganti TD. From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways. Comput Struct Biotechnol J. 2021;19:4641–4657. doi: 10.1016/j.csbj.2021.07.038. PubMed DOI PMC

Zheng M, Karki R, Vogel P, Kanneganti TD. Caspase-6 is a key regulator of innate immunity, inflammasome activation, and host defense. Cell. 2020;181:674–687.e13. doi: 10.1016/j.cell.2020.03.040. PubMed DOI PMC

Aglietti RA, Estevez A, Gupta A, Ramirez MG, Liu PS, Kayagaki N, Ciferri C, Dixit VM, Dueber EC. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc Natl Acad Sci U S A. 2016;113:7858–7863. doi: 10.1073/pnas.1607769113. PubMed DOI PMC

Ming-Yong L, Xia-Lian Z, Bi-Xia Z, Lei S, Wei W, Wei H, Song-Lin Q, et al. Adrenomedullin alleviates the pyroptosis of Leydig cells by promoting autophagy via the ROS-AMPK-mTOR axis. Cell Death Dis. 2019;10:489. doi: 10.1038/s41419-019-1728-5. PubMed DOI PMC

Wang Y, Gao W, Shi X, Ding J, Liu W, He H, Wang K, Shao F. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547:99–103. doi: 10.1038/nature22393. PubMed DOI

de Vasconcelos NM, Vliegen G, Gonçalves A, De Hert E, Martín-Pérez R, Van Opdenbosch N, Jallapally A, et al. DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages. Life Sci Alliance. 2019;2:e201900313. doi: 10.26508/lsa.201900313. PubMed DOI PMC

Santa Cruz Garcia AB, Schnur KP, Malik AB, Mo GCH. Gasdermin D pores are dynamically regulated by local phosphoinositide circuitry. Nat Commun. 2022;13:52. doi: 10.1038/s41467-021-27692-9. PubMed DOI PMC

Joosten LA, Netea MG, Dinarello CA. Interleukin-1β in innate inflammation, autophagy and immunity. Semin Immunol. 2013;25:416–424. doi: 10.1016/j.smim.2013.10.018. PubMed DOI

Dinarello CA, Novick D, Kim S, Kaplanski G. Interleukin-18 and IL-18 binding protein. Front Immunol. 2013;4:289. doi: 10.3389/fimmu.2013.00289. PubMed DOI PMC

Goto T. Airway microbiota as a modulator of lung cancer. Int J Mol Sci. 2020;21:3044. doi: 10.3390/ijms21093044. PubMed DOI PMC

Yin T, Jeong JH, Hardcastle TF, Biswas K, Douglas RG. A scoping review of longitudinal airway microbiota studies. Expert Rev Respir Med. 2021;15:1187–1195. doi: 10.1080/17476348.2021.1924061. PubMed DOI

Hilty M, Burke C, Pedro H, Cardenas P, Bush A, Bossley C, Davies J, Ervine A, et al. Disordered microbial communities in asthmatic airways. PLoS One. 2010;5:e8578. doi: 10.1371/journal.pone.0008578. PubMed DOI PMC

Kang R, Zeng L, Zhu S, Xie Y, Liu J, Wen Q, Cao L, et al. Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis. Cell Host Microbe. 2018;24:97–108.e4. doi: 10.1016/j.chom.2018.05.009. PubMed DOI PMC

Kesavardhana S, Malireddi RKS, Kanneganti TD. Caspases in cell death, inflammation, and pyroptosis. Annu Rev Immunol. 2020;38:567–595. doi: 10.1146/annurev-immunol-073119-095439. PubMed DOI PMC

Roux CM, Rolán HG, Santos RL, Beremand PD, Thomas TL, Adams LG, Tsolis RM. Brucella requires a functional Type IV secretion system to elicit innate immune responses in mice. Cell Microbiol. 2007;9:1851–1869. doi: 10.1111/j.1462-5822.2007.00922.x. PubMed DOI

Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol. 2006;7:318–325. doi: 10.1038/ni1305. PubMed DOI

Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535:153–158. doi: 10.1038/nature18629. PubMed DOI PMC

Liu L, Sun B. Neutrophil pyroptosis: new perspectives on sepsis. Cell Mol Life Sci. 2019;76:2031–2042. doi: 10.1007/s00018-019-03060-1. PubMed DOI PMC

Lupfer C, Kanneganti TD. The expanding role of NLRs in antiviral immunity. Immunol Rev. 2013;255:13–24. doi: 10.1111/imr.12089. PubMed DOI PMC

Man SM, Karki R, Kanneganti TD. AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity. Eur J Immunol. 2016;46:269–280. doi: 10.1002/eji.201545839. PubMed DOI PMC

Akhter A, Caution K, Abu Khweek A, Tazi M, Abdulrahman BA, Abdelaziz DH, Voss OH, et al. Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization. Immunity. 2012;37:35–47. doi: 10.1016/j.immuni.2012.05.001. PubMed DOI PMC

Uwamahoro N, Verma-Gaur J, Shen HH, Qu Y, Lewis R, Lu J, Bambery K, et al. The pathogen Candida albicans hijacks pyroptosis for escape from macrophages. mBio. 2014;5:e00003–e14. doi: 10.1128/mBio.00003-14. PubMed DOI PMC

Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, et al. Corrigendum: Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature. 2017;544:124. doi: 10.1038/nature22066. PubMed DOI

Boal-Carvalho I, Mazel-Sanchez B, Silva F, Garnier L, Yildiz S, Bonifacio JP, Niu C, et al. Influenza A viruses limit NLRP3-NEK7-complex formation and pyroptosis in human macrophages. EMBO Rep. 2020;21:e50421. doi: 10.15252/embr.202050421. PubMed DOI PMC

Ramos HJ, Lanteri MC, Blahnik G, Negash A, Suthar MS, Brassil MM, Sodhi K, et al. IL-1β signaling promotes CNS-intrinsic immune control of West Nile virus infection. PLoS Pathog. 2012;8:e1003039. doi: 10.1371/journal.ppat.1003039. PubMed DOI PMC

Hellings PW, Steelant B. Epithelial barriers in allergy and asthma. J Allergy Clin Immunol. 2020;145:1499–1509. doi: 10.1016/j.jaci.2020.04.010. PubMed DOI PMC

Hewitt RJ, Lloyd CM. Regulation of immune responses by the airway epithelial cell landscape. Nat Rev Immunol. 2021;21:347–362. doi: 10.1038/s41577-020-00477-9. PubMed DOI PMC

Rathinam VAK, Chan FK. Inflammasome, inflammation, and tissue homeostasis. Trends Mol Med. 2018;24:304–318. doi: 10.1016/j.molmed.2018.01.004. PubMed DOI PMC

Schwarzer R, Jiao H, Wachsmuth L, Tresch A, Pasparakis M. FADD and caspase-8 regulate gut homeostasis and inflammation by controlling MLKL- and GSDMD-mediated death of intestinal epithelial cells. Immunity. 2020;52:978–993.e6. doi: 10.1016/j.immuni.2020.04.002. PubMed DOI

Subramanian S, Geng H, Tan XD. Cell death of intestinal epithelial cells in intestinal diseases. Sheng Li Xue Bao. 2020;72:308–324. PubMed PMC

Tsai YM, Chiang KH, Hung JY, Chang WA, Lin HP, Shieh JM, Chong IW, Hsu YL. Der f1 induces pyroptosis in human bronchial epithelia via the NLRP3 inflammasome. Int J Mol Med. 2018;41:757–764. doi: 10.3892/ijmm.2017.3310. PubMed DOI PMC

Das S, Miller M, Beppu AK, Mueller J, McGeough MD, Vuong C, Karta MR, et al. GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation. Proc Natl Acad Sci U S A. 2016;113:13132–13137. doi: 10.1073/pnas.1610433113. PubMed DOI PMC

Das S, Miller M, Broide DH. Chromosome 17q21 Genes ORMDL3 and GSDMB in asthma and immune diseases. Adv Immunol. 2017;135:1–52. doi: 10.1016/bs.ai.2017.06.001. PubMed DOI

Yokoyama S, Cai Y, Murata M, Tomita T, Yoneda M, Xu L, Pilon AL, Cachau RE, Kimura S. A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death. Elife. 2018;7:e37854. doi: 10.7554/eLife.37854. PubMed DOI PMC

Kim K, Kim HJ, Binas B, Kang JH, Chung IY. Inflammatory mediators ATP and S100A12 activate the NLRP3 inflammasome to induce MUC5AC production in airway epithelial cells. Biochem Biophys Res Commun. 2018;503:657–664. doi: 10.1016/j.bbrc.2018.06.057. PubMed DOI

Zhuang J, Cui H, Zhuang L, Zhai Z, Yang F, Luo G, He J, et al. Bronchial epithelial pyroptosis promotes airway inflammation in a murine model of toluene diisocyanate-induced asthma. Biomed Pharmacother. 2020;125:109925. doi: 10.1016/j.biopha.2020.109925. PubMed DOI

Sharma L, Feng J, Britto CJ, Dela Cruz CS. Mechanisms of epithelial immunity evasion by respiratory bacterial pathogens. Front Immunol. 2020;11:91. doi: 10.3389/fimmu.2020.00091. PubMed DOI PMC

Wu DM, He M, Zhao YY, Deng SH, Liu T, Zhang T, Zhang F, Wang YY, Xu Y. Increased susceptibility of irradiated mice to Aspergillus fumigatus infection via NLRP3/GSDMD pathway in pulmonary bronchial epithelia. Cell Commun Signal. 2022;20:98. doi: 10.1186/s12964-022-00907-2. PubMed DOI PMC

Pouwels SD, Heijink IH, ten Hacken NH, Vandenabeele P, Krysko DV, Nawijn MC, van Oosterhout AJ. DAMPs activating innate and adaptive immune responses in COPD. Mucosal Immunol. 2014;7:215–226. doi: 10.1038/mi.2013.77. PubMed DOI

Akbari O, DeKruyff RH, Umetsu DT. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol. 2001;2:725–731. doi: 10.1038/90667. PubMed DOI

Alpan O, Bachelder E, Isil E, Arnheiter H, Matzinger P. ‘Educated’ dendritic cells act as messengers from memory to naive T helper cells. Nat Immunol. 2004;5:615–622. doi: 10.1038/ni1077. PubMed DOI

Mayer AK, Dalpke AH. Regulation of local immunity by airway epithelial cells. Arch Immunol Ther Exp (Warsz) 2007;55:353–362. doi: 10.1007/s00005-007-0041-7. PubMed DOI

Kotb M. Bacterial pyrogenic exotoxins as superantigens. Clin Microbiol Rev. 1995;8:411–426. doi: 10.1128/CMR.8.3.411. PubMed DOI PMC

Zhou Z, He H, Wang K, Shi X, Wang Y, Su Y, Wang Y, et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science. 2020;368:eaaz7548. doi: 10.1126/science.aaz7548. PubMed DOI

Peng Z, Wang P, Song W, Yao Q, Li Y, Liu L, Li Y, Zhou S. GSDME enhances Cisplatin sensitivity to regress non-small cell lung carcinoma by mediating pyroptosis to trigger antitumor immunocyte infiltration. Signal Transduct Target Ther. 2020;5:159. doi: 10.1038/s41392-020-00274-9. PubMed DOI PMC

van de Veerdonk FL, Joosten LA, Shaw PJ, Smeekens SP, Malireddi RK, van der Meer JW, Kullberg BJ, Netea MG, Kanneganti TD. The inflammasome drives protective Th1 and Th17 cellular responses in disseminated candidiasis. Eur J Immunol. 2011;41:2260–2268. doi: 10.1002/eji.201041226. PubMed DOI PMC

Paces J, Strizova Z, Smrz D, Cerny J. COVID-19 and the immune system. Physiol Res. 2020;69:379–388. doi: 10.33549/physiolres.934492. PubMed DOI PMC

Yap JKY, Moriyama M, Iwasaki A. Inflammasomes and pyroptosis as therapeutic targets for COVID-19. J Immunol. 2020;205:307–312. doi: 10.4049/jimmunol.2000513. PubMed DOI PMC

Andersson U, Yang H, Harris H. Extracellular HMGB1 as a therapeutic target in inflammatory diseases. Expert Opin Ther Targets. 2018;22:263–277. doi: 10.1080/14728222.2018.1439924. PubMed DOI

Yang H, Liu H, Zeng Q, Imperato GH, Addorisio ME, Li J, He M, et al. Inhibition of HMGB1/RAGE-mediated endocytosis by HMGB1 antagonist box A, anti-HMGB1 antibodies, and cholinergic agonists suppresses inflammation. Mol Med. 2019;25:13. doi: 10.1186/s10020-019-0081-6. PubMed DOI PMC

Frey A, Lunding LP, Ehlers JC, Weckmann M, Zissler UM, Wegmann M. More than just a barrier: The immune functions of the airway epithelium in asthma pathogenesis. Front Immunol. 2020;11:761. doi: 10.3389/fimmu.2020.00761. PubMed DOI PMC

Huang Y, Zhang G, Zhu Q, Wu X, Wu L. Role of cytokines released during pyroptosis in non-small cell lung cancer. Cancer Manag Res. 2021;13:7399–7409. doi: 10.2147/CMAR.S330232. PubMed DOI PMC

Tang R, Xu J, Zhang B, Liu J, Liang C, Hua J, Meng Q, Yu X, Shi S. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol. 2020;13:110. doi: 10.1186/s13045-020-00946-7. PubMed DOI PMC

Hyperbaric Oxygen Promotes Chronic Wound Healing in Sprague-Dawley Rats by Inhibiting Pyroptosis

Heat Stroke Induces Pyroptosis in Spermatogonia via the cGAS-STING Signaling Pathway