N-GSDMD Trafficking to Neutrophil Organelles Facilitates IL-1β Release Independently of Plasma Membrane Pores and Pyroptosis
Overview
Authors
Affiliations
Gasdermin-D (GSDMD) in inflammasome-activated macrophages is cleaved by caspase-1 to generate N-GSDMD fragments. N-GSDMD then oligomerizes in the plasma membrane (PM) to form pores that increase membrane permeability, leading to pyroptosis and IL-1β release. In contrast, we report that although N-GSDMD is required for IL-1β secretion in NLRP3-activated human and murine neutrophils, N-GSDMD does not localize to the PM or increase PM permeability or pyroptosis. Instead, biochemical and microscopy studies reveal that N-GSDMD in neutrophils predominantly associates with azurophilic granules and LC3 autophagosomes. N-GSDMD trafficking to azurophilic granules causes leakage of neutrophil elastase into the cytosol, resulting in secondary cleavage of GSDMD to an alternatively cleaved N-GSDMD product. Genetic analyses using ATG7-deficient cells indicate that neutrophils secrete IL-1β via an autophagy-dependent mechanism. These findings reveal fundamental differences in GSDMD trafficking between neutrophils and macrophages that underlie neutrophil-specific functions during inflammasome activation.
Neutrophils: a new target for postoperative cognitive dysfunction.
Cheng J, Gao J, Li J, Tian H Apoptosis. 2025; .
PMID: 40042745 DOI: 10.1007/s10495-025-02098-w.
Huang J, Yin L, Niu M, Geng Z, Zuo L, Li J Nan Fang Yi Ke Da Xue Xue Bao. 2025; 45(2):261-268.
PMID: 40031970 PMC: 11875862. DOI: 10.12122/j.issn.1673-4254.2025.02.07.
The spectrum of lysosomal stress and damage responses: from mechanosensing to inflammation.
Scott O, Saran E, Freeman S EMBO Rep. 2025; .
PMID: 40016424 DOI: 10.1038/s44319-025-00405-9.
GSDMD-mediated pyroptosis: molecular mechanisms, diseases and therapeutic targets.
Li Y, Guo B Mol Biomed. 2025; 6(1):11.
PMID: 39994107 PMC: 11850691. DOI: 10.1186/s43556-025-00249-8.
Targeting secretory autophagy in solid cancers: mechanisms, immune regulation and clinical insights.
Li X, Zhao H Exp Hematol Oncol. 2025; 14(1):12.
PMID: 39893499 PMC: 11786567. DOI: 10.1186/s40164-025-00603-0.