TNF Induces Neutrophil Elastase/Gasdermin D-mediated Neutrophil Extracellular Traps in Axial Spondyloarthritis

Yehao Li and Xiang Peng, Department of Rheumatology and Immunology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China

Meeting: ACR Convergence 2023

Keywords: Cell Death, immunology, neutrophils, spondyloarthritis

Session Information

Date: Tuesday, November 14, 2023

Title: (1776–1795) Spondyloarthritis Including Psoriatic Arthritis – Basic Science Poster

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Emerging studies have shown that neutrophil extracellular traps (NETs) are increased and associated with the disease activity in patients with axial spondyloarthritis (axSpA). However, the molecular mechanism underlying the release of NETs remains unclear in axSpA. In this study, we aimed to investigate the role of TNF/neutrophil elastase (NE)/Gasdermin D (GSDMD) in the release of NETs in axSpA.

Methods: The expression of GSDMD in the neutrophils of axSpA patients was analyzed by Western blot and immunofluorescence. The role of NE/GSDMD in the NETs release of axSpA patients was tested. Furthermore, the effect of TNF on NE/GSDMD-mediated NETs was analyzed.

Results: Compared with the healthy controls, increased expression of GSDMD and the N-terminal fragment of GSDMD (GSDMD-N) were detected in the neutrophils of axSpA patients. In addition, higher expression of GSDMD-N was found to be associated with the increased NETs structures in axSpA, which was blocked by either GSDMD or NE inhibitor. Furthermore, TNF induced the release of NETs through the NE/GSDMD pathway.

Conclusion: These results demonstrated that TNF/NE/GSDMD pathway plays a critical role in the NETs release in axSpA, which reveals that NE/GSDMD may serve as novel potential targets for inhibiting NETs to treat axSpA.

Figure 1 Increased expression of GSDMD in the neutrophils of axSpA patients and associates with NETs release. A. Western blot shows that the expressions of GSDMD and GSDMD-N were increased in the neutrophils of axSpA patients. B. Immunofluorescence images show that higher expression of GSDMD-N was found to be associated with the increased NETs structures in axSpA patients. C. Immunofluorescence images show that GSDMD inhibitor (disulfiram, DSF) or NE inhibitor (NEi) inhibited the NETs release and NEi inhibited the expression of GSDMD-N in axSpA patients.

Figure 2 TNF induced the release of NETs through the NE/GSDMD pathway. A. Western blot shows that TNF induced the NETs release dose-dependently. B. Western blot shows that TNF stimulation increased the expression of GSDMD and GSDMD-N. C. GSDMD inhibitor disulfiram inhibited TNF-induced NETs release. D. Western blot shows that TNF stimulation increased the expression of NE. E. Western blot shows that NE inhibitor (NEi) inhibited TNF-induced GSDMD-N expression.

Disclosures: Y. Li: None; X. Peng: None.

To cite this abstract in AMA style:

Li Y, Peng X. TNF Induces Neutrophil Elastase/Gasdermin D-mediated Neutrophil Extracellular Traps in Axial Spondyloarthritis [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/tnf-induces-neutrophil-elastase-gasdermin-d-mediated-neutrophil-extracellular-traps-in-axial-spondyloarthritis/. Accessed .

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