Increased Neutrophil Extracellular Trap Formation in Oligoarticular, Polyarticular Juvenile Idiopathic Arthritis and Enthesitis-related Arthritis: Biomarkers for Diagnosis and Disease Activity

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Aug 26

PMID 39185410

Authors

Hongxia Tang

Yucheng Zhong

Yali Wu

Yanmei Huang

Yi Liu

Jing Chen

Ting Xi

Yini Wen

Ting He

Shanshan Yang

Fan Liu

Runji Xiong

Runming Jin

Affiliations

Soon will be listed here.

Abstract

Objective: Neutrophil extracellular traps (NETs) are important factors in initiating and perpetuating inflammation. However, the role of NETs in different subtypes of juvenile idiopathic arthritis (JIA) has been rarely studied. Therefore, we aimed to explore the ability of JIA-derived neutrophils to release NETs and the effect of TNF-α (tumor necrosis factor-alpha) inhibitors on NET formation both and , and evaluate the associations of NET-derived products with clinical and immune-related parameters.

Methods: The ability of neutrophils to release NETs and the effect of adalimumab on NET formation was assessed via stimulation and inhibition studies. Plasma NET-derived products were detected to assess the incidence of NET formation . Furthermore, flow cytometry and western blotting were used to detect NET-associated signaling components in neutrophils.

Results: Compared to those derived from HCs, neutrophils derived from patients with oligoarticular-JIA, polyarticular-JIA and enthesitis-related arthritis were more prone to generate NETs spontaneously and in response to TNF-α or PMA . Excessive NET formation existed in peripheral circulation of JIA patients, and elevated plasma levels of NET-derived products (cell-free DNA and MPO-DNA complexes) could accurately distinguish JIA patients from HCs and were positively correlated with disease activity. Multiple linear regression analysis showed that erythrocyte sedimentation rate and TNF-α levels were independent variables and were positively correlated with cell-free DNA concentration. Notably, TNF-α inhibitors could effectively prevent NET formation both and . Moreover, the phosphorylation levels of NET-associated kinases in JIA-derived neutrophils were markedly increased.

Conclusion: Our data suggest that NETs might play pathogenic roles and may be involved in TNF-α-mediated inflammation in JIA. Circulating NET-derived products possess potential diagnostic and disease monitoring value. Furthermore, the preliminary results related to the molecular mechanisms of NET formation in JIA patients provide a theoretical basis for NET-targeted therapy.

References

Kahlenberg J, Carmona-Rivera C, Smith C, Kaplan M . Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol. 2012; 190(3):1217-26. PMC: 3552129. DOI: 10.4049/jimmunol.1202388. View

McCurdy D, Parsa M . Updates in Juvenile Idiopathic Arthritis. Adv Pediatr. 2021; 68:143-170. DOI: 10.1016/j.yapd.2021.05.014. View

Consolaro A, Giancane G, Schiappapietra B, Davi S, Calandra S, Lanni S . Clinical outcome measures in juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2016; 14(1):23. PMC: 4836071. DOI: 10.1186/s12969-016-0085-5. View

Martini A, Lovell D, Albani S, Brunner H, Hyrich K, Thompson S . Juvenile idiopathic arthritis. Nat Rev Dis Primers. 2022; 8(1):5. DOI: 10.1038/s41572-021-00332-8. View

Keshari R, Jyoti A, Dubey M, Kothari N, Kohli M, Bogra J . Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition. PLoS One. 2012; 7(10):e48111. PMC: 3482178. DOI: 10.1371/journal.pone.0048111. View

Wigerblad G, Kaplan M . Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases. Nat Rev Immunol. 2022; 23(5):274-288. PMC: 9579530. DOI: 10.1038/s41577-022-00787-0. View

Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight J . NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013; 5(178):178ra40. PMC: 3727661. DOI: 10.1126/scitranslmed.3005580. View

Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss D . Neutrophil extracellular traps kill bacteria. Science. 2004; 303(5663):1532-5. DOI: 10.1126/science.1092385. View

Yipp B, Petri B, Salina D, Jenne C, Scott B, Zbytnuik L . Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med. 2012; 18(9):1386-93. PMC: 4529131. DOI: 10.1038/nm.2847. View

10.

Ravindran M, Khan M, Palaniyar N . Neutrophil Extracellular Trap Formation: Physiology, Pathology, and Pharmacology. Biomolecules. 2019; 9(8). PMC: 6722781. DOI: 10.3390/biom9080365. View

11.

Carmona-Rivera C, Kaplan M . Detection of SLE antigens in neutrophil extracellular traps (NETs). Methods Mol Biol. 2014; 1134:151-61. PMC: 4123114. DOI: 10.1007/978-1-4939-0326-9_11. View

12.

Hakkim A, Fuchs T, Martinez N, Hess S, Prinz H, Zychlinsky A . Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol. 2010; 7(2):75-7. DOI: 10.1038/nchembio.496. View

13.

Thimmappa P, Nair A, Najar M, Mohanty V, Shastry S, Prasad T . Quantitative phosphoproteomics reveals diverse stimuli activate distinct signaling pathways during neutrophil activation. Cell Tissue Res. 2022; 389(2):241-257. PMC: 9287233. DOI: 10.1007/s00441-022-03636-7. View

14.

Branzk N, Lubojemska A, Hardison S, Wang Q, Gutierrez M, Brown G . Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol. 2014; 15(11):1017-25. PMC: 4236687. DOI: 10.1038/ni.2987. View

15.

Petty R, Southwood T, Manners P, Baum J, Glass D, Goldenberg J . International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004; 31(2):390-2. View

16.

Linhares-Lacerda L, Ramos Temerozo J, Ribeiro-Alves M, Azevedo E, Mojoli A, Nascimento M . Neutrophil extracellular trap-enriched supernatants carry microRNAs able to modulate TNF-α production by macrophages. Sci Rep. 2020; 10(1):2715. PMC: 7026108. DOI: 10.1038/s41598-020-59486-2. View

17.

Tillack K, Breiden P, Martin R, Sospedra M . T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses. J Immunol. 2012; 188(7):3150-9. DOI: 10.4049/jimmunol.1103414. View

18.

Jarvis J, Petty H, Tang Y, Frank M, Tessier P, Dozmorov I . Evidence for chronic, peripheral activation of neutrophils in polyarticular juvenile rheumatoid arthritis. Arthritis Res Ther. 2006; 8(5):R154. PMC: 1779452. DOI: 10.1186/ar2048. View

19.

Ohyama A, Osada A, Kawaguchi H, Kurata I, Nishiyama T, Iwai T . Specific Increase in Joint Neutrophil Extracellular Traps and Its Relation to Interleukin 6 in Autoimmune Arthritis. Int J Mol Sci. 2021; 22(14). PMC: 8303722. DOI: 10.3390/ijms22147633. View

20.

Heshin-Bekenstein M, Baron S, Schulert G, Shusterman A, Fidel V, Ben-Shahar Y . Neutrophils extracellular traps formation may serve as a biomarker for disease activity in oligoarticular juvenile idiopathic arthritis: a pilot study. Arthritis Res Ther. 2023; 25(1):135. PMC: 10388488. DOI: 10.1186/s13075-023-03104-9. View