Evidence map›Paper›PMID 41089701›Full record

ArticleFrontiers in immunology2025

Analysis of GSDMD-N abnormality promoting neutrophil NETs mediated RA disease through NLRP3-dependent pathway.

Yali Sang, Huiyang Liu, Bingle Li, Lingyan Zhu, Yongfu Wang, Li Bai

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Article in Frontiers in immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

6 authors.

Yali Sang *The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science & Technology, Baotou, China.
Huiyang Liu *Department of Rheumatology and Immunology, the First Affiliated Hospital of Baotou Medical College, Baotou, China.
Bingle LiThe First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science & Technology, Baotou, China.
Lingyan ZhuDepartment of Rheumatology and Immunology, the First Affiliated Hospital of Baotou Medical College, Baotou, China.
Yongfu WangDepartment of Rheumatology and Immunology, the First Affiliated Hospital of Baotou Medical College, Baotou, China.
Li BaiThe Central Lab, the First Affiliated Hospital of Baotou Medical College (Inner Mongolia Autoimmune Key Laboratory), Baotou, China.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Introduction: Rheumatoid arthritis (RA) is characterized by persistent synovitis and progressive joint damage. Mounting evidence implicates neutrophil extracellular traps (NETs) formation (NETosis) in RA pathogenesis, yet the upstream regulatory nodes remain incompletely defined. We aimed to elucidate the role of the NLRP3 inflammasome in regulating GSDMD-dependent NETosis and to evaluate whether inhibiting NLRP3 or Gasdermin D (GSDMD) alleviates RA pathology. Methods: Neutrophils and synovial tissues from patients with RA and osteoarthritis (OA) were analyzed for NLRP3, GSDMD, and NET-related markers by immunofluorescence, Western blot, and qPCR. A collagen-induced arthritis (CIA) mouse model was used to test the effects of pharmacological inhibition of NLRP3 or blockade of GSDMD pore formation on joint swelling, bone destruction, and synovial inflammation. Transcriptomic sequencing was performed to identify differentially expressed genes following inhibition of GSDMD pore formation. Ionomycin was used to induce ROS-independent NETosis in vitro. Results: The RA group exhibited elevated NLRP3/GSDMD expression and increased NET markers relative to OA controls. In CIA mice, inhibition of NLRP3 or blockade of GSDMD pore formation mitigated joint swelling, reduced bone erosion, and attenuated synovial inflammation. Transcriptomic profiling identified 12 core genes-enriched for heat-shock proteins and histone variants-with significant differential expression after GSDMD pore inhibition. Ionomycin stimulation enhanced ROS-independent NET formation and was accompanied by increased NLRP3 expression and promoted cleavage of GSDMD into its active N-terminal fragment (GSDMD-N). Conversely, suppressing NLRP3 activation or preventing GSDMD pore formation effectively inhibited this process. Discussion: These data position the NLRP3 inflammasome as a pivotal upstream regulator of GSDMD-dependent NETosis in RA. Targeting this axis-via inhibition of NLRP3 or blockade of GSDMD pore formation-ameliorates inflammatory joint pathology in vivo and constrains NETosis in vitro. Collectively, our findings support the NLRP3-GSDMD pathway as a promising therapeutic avenue for RA.

Indexed as

Arthritis, RheumatoidExtracellular TrapsIntracellular Signaling Peptides and ProteinsNeoplasm ProteinsNeutrophilsNLR Family, Pyrin Domain-Containing 3 ProteinPhosphate-Binding ProteinsAnimalsArthritis, ExperimentalDisease Models, AnimalFemaleGasderminsHumansInflammasomesMaleMiceGasderminsGSDMD protein, humanGsdmd protein, mouseInflammasomesIntracellular Signaling Peptides and ProteinsNeoplasm ProteinsNLR Family, Pyrin Domain-Containing 3 ProteinNLRP3 protein, humanPhosphate-Binding ProteinsGSDMDNEtosisneutrophilsNLRP3 inflammasomerheumatoid arthritis

Identifiers

PMID41089701
PMCPMC12515664

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