Pyroptosis: Cellular Signaling of Inflammatory Cell Death

Yazarlar

Özet

Pyroptosis is a highly inflammatory form of programmed cell death characterized by cell swelling, membrane rupture, and release of pro-inflammatory mediators such as IL-1β and IL-18. Distinct from apoptosis, pyroptosis is primarily mediated by gasdermin family proteins, particularly Gasdermin D (GSDMD), which forms membrane pores upon activation. Signaling occurs via canonical pathways involving caspase-1 and inflammasomes (e.g., NLRP3) or non-canonical pathways via caspases-4/5/11 in response to intracellular LPS. Tight regulatory mechanisms, including endogenous inhibitors and feedback loops, control pyroptosis to prevent excessive inflammation. This review focuses on the cellular mechanism of pyroptosis and its inhibitors.

Referanslar

Evavold CL, Kagan JC. How Inflammasomes Inform Adaptive Immunity. Journal of Molecular Biology. 2017;430:217. https://doi.org/10.1016/j.jmb.2017.09.019.

Liu Y, Pan R, Ouyang Y, et al. Pyroptosis in health and disease: mechanisms, regulation and clinical perspective. Signal Transduction and Targeted Therapy. 2024;9. https://doi.org/10.1038/s41392-024-01958-2.

Cui J, Zhao S, Li Y, et al. Regulated cell death: discovery, features and implications for neurodegenerative diseases. Cell Communication and Signaling. 2021;19. https://doi.org/10.1186/s12964-021-00799-8.

Zahid A, Ismail H, Jin T. Molecular and structural aspects of gasdermin family pores and insights into gasdermin-elicited programmed cell death. Biochemical Society Transactions. 2021;49:2697. https://doi.org/10.1042/bst20210672.

Zeng C, Wang R, Tan H. Role of Pyroptosis in Cardiovascular Diseases and its Therapeutic Implications. International Journal of Biological Sciences. 2019;15:1345. https://doi.org/10.7150/ijbs.33568.

Zhao H, Fu X, Zhang Y, et al. The Role of Pyroptosis and Autophagy in the Nervous System. Molecular Neurobiology. 2023;61:1271. https://doi.org/10.1007/s12035-023-03614-2.

Dai Z, Liu W-C, Chen X, et al. Gasdermin D-mediated pyroptosis: mechanisms, diseases, and inhibitors. Frontiers in Immunology. 2023;14. https://doi.org/10.3389/fimmu.2023.1178662.

Ji F, Shi C, Shu Z, et al. Nanomaterials Enhance Pyroptosis-Based Tumor Immunotherapy. International Journal of Nanomedicine. 2024:5545. https://doi.org/10.2147/ijn.s457309.

Hao W, Feng C. Research progress on pyroptosis and its effect on the central nervous system. Neurobiology of Disease. 2023.188. https://doi.org/10.1016/j.nbd.2023.106333

Tsuchiya K, Nakajima S, Hosojima S, et al. Caspase-1 initiates apoptosis in the absence of gasdermin D. Nature Communications. 2019;10. https://doi.org/10.1038/s41467-019-09753-2.

Napodano C, Carnazzo V, Basile V, et al. NLRP3 Inflammasome Involvement in Heart, Liver, and Lung Diseases—A Lesson from Cytokine Storm Syndrome. International Journal of Molecular Sciences. 2023;24:16556. https://doi.org/10.3390/ijms242316556.

Kolb JP, Oguin TH, Oberst A, et al. Programmed Cell Death and Inflammation: Winter Is Coming. Trends in Immunology. 2017;38:705. https://doi.org/10.1016/j.it.2017.06.009.

Wu Y, Zhang J, Yu S, et al. Cell pyroptosis in health and inflammatory diseases. Cell Death Discovery. 2022;8. https://doi.org/10.1038/s41420-022-00998-3.

Beckwith KS, Beckwith MS, Ullmann S, et al. Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection. Nature Communications. 2020;11. https://doi.org/10.1038/s41467-020-16143-6.

Loveless R, Bloomquist RF, Teng Y. Pyroptosis at the forefront of anticancer immunity. Journal of Experimental & Clinical Cancer Research. 2021;40. https://doi.org/10.1186/s13046-021-02065-8.

Kim JK, Jung H-J, Hyun M, et al. Resistance of hypervirulent Klebsiella pneumoniae to cathepsin B-mediated pyroptosis in murine macrophages. Frontiers in Immunology. 2023;14. https://doi.org/10.3389/fimmu.2023.1207121.

Yu P, Zhang X, Liu N, et al. Pyroptosis: mechanisms and diseases. Signal Transduction and Targeted Therapy. 2021;6. https://doi.org/10.1038/s41392-021-00507-5.

Li N, Zhang L, Wang X, et al. Exploring exercise-driven inhibition of pyroptosis: novel insights into treating diabetes mellitus and its complications. Frontiers in Endocrinology. 2023;14. https://doi.org/10.3389/fendo.2023.1230646.

Chen T, Jin L, Li J, et al. Pyroptosis mediates osteoporosis via the inflammation immune microenvironment. Frontiers in Immunology. 2024;15. https://doi.org/10.3389/fimmu.2024.1371463.

Wang S, Wang H, Feng C, et al. The regulatory role and therapeutic application of pyroptosis in musculoskeletal diseases. Cell Death Discovery. 2022;8. https://doi.org/10.1038/s41420-022-01282-0.

Li F-J, Starrs L, Mathur A, et al. Interferon signalling and non-canonical inflammasome activation promote host protection against multidrug-resistant Acinetobacter baumannii. Communications Biology. 2024;7. https://doi.org/10.1038/s42003-024-07204-3.

Braud A, Lipsker D. Schnitzler Syndrome: Insights into Its Pathogenesis, Clinical Manifestations, and Current Management. Biomolecules. 2024;14:646. https://doi.org/10.3390/biom14060646.

Bulté D, Rigamonti C, Romano APM, et al. Inflammasomes: Mechanisms of Action and Involvement in Human Diseases. Cells. 2023;12:1766. https://doi.org/10.3390/cells12131766.

Zheng L, Duan Y, He P, et al. Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death. Cellular & Molecular Biology Letters. 2024;29. https://doi.org/10.1186/s11658-024-00602-9.

Xiao F, Li H, Yang B, et al. Disulfidptosis: A new type of cell death. APOPTOSIS. 2024. https://doi.org/10.1007/s10495-024-01989-8.

Liang H, Wang B, Wang J, et al. Pyolysin of Trueperella pyogenes Induces Pyroptosis and IL-1β Release in Murine Macrophages Through Potassium/NLRP3/Caspase-1/Gasdermin D Pathway. Frontiers in Immunology. 2022;13. https://doi.org/10.3389/fimmu.2022.832458.

Vigneswaran N, Wu J, S. Nagaraj N, et al. Differential susceptibility of metastatic and primary oral cancer cells to TRAIL-induced apoptosis. International Journal of Oncology. 2005. https://doi.org/10.3892/ijo.26.1.103.

Christgen S, Place DE, Kanneganti T. Toward targeting inflammasomes: insights into their regulation and activation. Cell Research. 2020;30:315. https://doi.org/10.1038/s41422-020-0295-8.

Ahn H, Kim J, Kang SG, et al. Mercury and arsenic attenuate canonical and non-canonical NLRP3 inflammasome activation. Scientific Reports. 2018;8. https://doi.org/10.1038/s41598-018-31717-7.

Astorga J, Gasaly N, Dubois-Camacho K, et al. The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD. Frontiers in Immunology. 2022;13. https://doi.org/10.3389/fimmu.2022.1028953.

Govindarajan V, Vaccari JP de R, Keane RW. Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets. Journal of Neuroinflammation. 2020;17. https://doi.org/10.1186/s12974-020-01944-9.

Dubey S, Turnbull C, Pandey A, et al. Molecular mechanisms and regulation of inflammasome activation and signaling: sensing of pathogens and damage molecular patterns. Cellular and Molecular Immunology. 2025. https://doi.org/10.1038/s41423-025-01354-y.

Xu X-L, Wu X, Yue G, et al. The role of Nod-like receptor protein 3 inflammasome activated by ion channels in multiple diseases. Molecular and Cellular Biochemistry. 2022;478:1397. https://doi.org/10.1007/s11010-022-04602-1.

Krawczyk PA, Laub M, Kozik P. To Kill But Not Be Killed: Controlling the Activity of Mammalian Pore-Forming Proteins. Frontiers in Immunology. 2020;11. https://doi.org/10.3389/fimmu.2020.601405.

Liu H, Liu H, Huang G, et al. The roles of pyroptosis in genitourinary diseases. International Urology and Nephrology 2023;56:1515. https://doi.org/10.1007/s11255-023-03894-6.

Lieberman J, Wu H, Kagan JC. Gasdermin D activity in inflammation and host defense. Science Immunology. 2019;4. https://doi.org/10.1126/sciimmunol.aav1447.

Alba E de. Structure, interactions and self-assembly of ASC-dependent inflammasomes. Archives of Biochemistry and Biophysics. 2019;670:15. https://doi.org/10.1016/j.abb.2019.05.023.

Kovacs SB, Miao EA. Gasdermins: Effectors of Pyroptosis. Trends in Cell Biology. 2017;27:673. https://doi.org/10.1016/j.tcb.2017.05.005.

Li Y, Guo B. GSDMD-mediated pyroptosis: molecular mechanisms, diseases and therapeutic targets. Molecular Biomedicine. 2025;6. https://doi.org/10.1186/s43556-025-00249-8.

Gao X, Wang C, Shen X, et al. Pyroptosis burden is associated with anti-TNF treatment outcome in inflammatory bowel disease: new insights from bioinformatics analysis. Scientific Reports. 2023;13. https://doi.org/10.1038/s41598-023-43091-0.

Swanson KV, Deng M, Ting JP ‐Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology. 2019;19:477. https://doi.org/10.1038/s41577-019-0165-0.

Wang Y, Peng J, Xie X, et al. Gasdermin E-mediated programmed cell death: An unpaved path to tumor suppression. Journal of Cancer. 2021;12:5241. https://doi.org/10.7150/jca.48989.

Jiang X, Zhang X, Cai X, et al. NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation. Science Advances. 2024;10. https://doi.org/10.1126/sciadv.adi9284.

Boersma B, Möller K, Wehl L, et al. Inhibition of IL-1β release from macrophages targeted with necrosulfonamide-loaded porous nanoparticles. Journal of Controlled Release. 2022;351:989. https://doi.org/10.1016/j.jconrel.2022.09.063.

Hu X, Chen H, Xu H, et al. Role of Pyroptosis in Traumatic Brain and Spinal Cord Injuries. International Journal of Biological Sciences. 2020;16:2042. https://doi.org/10.7150/ijbs.45467.

Kopp A, Hagelueken G, Jamitzky I, et al. Pyroptosis inhibiting nanobodies block Gasdermin D pore formation. Nature Communications. 2023;14. https://doi.org/10.1038/s41467-023-43707-z.

Rathkey JK, Zhao J, Liu Z, et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Science Immunology. 2018;3. https://doi.org/10.1126/sciimmunol.aat2738.

Ge Y, Chen Y, Guo C, et al. Pyroptosis and Intervertebral Disc Degeneration: Mechanistic Insights and Therapeutic Implications. Journal of Inflammation Research. 2022:5857. https://doi.org/10.2147/jir.s382069.

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9 Şubat 2026

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