IL33-induced neutrophil extracellular traps (NETs) mediate a positive feedback loop for synovial inflammation and NET amplification in rheumatoid arthritis
2
조회
0
다운로드
0
인용
0
참고문헌
초록
This study investigated the mechanisms driving the induction and sustained presence of neutrophil extracellular traps (NETs) in the synovial microenvironment of rheumatoid arthritis (RA). Synovial tissue and fluid samples were collected from patients with RA and osteoarthritis (OA), and NET levels and cytokine concentrations were measured using a cytometric bead array and enzyme-linked immunosorbent assay (ELISA). The ability of interleukin-33 (IL-33) to induce NET formation was evaluated using quantitative assays, immunofluorescence staining, live-cell imaging, and electron microscopy. Coincubation experiments of NETs with fibroblast-like synovial cells (FLSs) were conducted, and a modified Transwell migration assay was designed to assess neutrophil migration. The role of IL-33 and NETs in RA progression was further investigated using a collagen antibody-induced arthritis (CAIA) mouse model. The results revealed an increase in NETs and IL-33 levels in the synovial fluid of RA patients, with a significant positive correlation between them. NET formation assays confirmed that IL-33 activates neutrophils to produce NETs and that neutrophils from RA patients exhibit increased responsiveness to IL-33 stimulation. Both in vitro and in vivo evidence has demonstrated that NETs stimulate FLSs to secrete IL-33 and the chemokine CXCL8 via Toll-like receptor 9, promoting further neutrophil recruitment and increasing NET production within the RA synovium. This study reveals a novel positive feedback loop involving NETs and FLSs that is mediated by IL-33 that increases NET accumulation in RA. Targeting IL-33 or NET formation and amplification may offer new therapeutic strategies for managing RA.
Abstract
This study investigated the mechanisms driving the induction and sustained presence of neutrophil extracellular traps (NETs) in the synovial microenvironment of rheumatoid arthritis (RA). Synovial tissue and fluid samples were collected from patients with RA and osteoarthritis (OA), and NET levels and cytokine concentrations were measured using a cytometric bead array and enzyme-linked immunosorbent assay (ELISA). The ability of interleukin-33 (IL-33) to induce NET formation was evaluated using quantitative assays, immunofluorescence staining, live-cell imaging, and electron microscopy. Coincubation experiments of NETs with fibroblast-like synovial cells (FLSs) were conducted, and a modified Transwell migration assay was designed to assess neutrophil migration. The role of IL-33 and NETs in RA progression was further investigated using a collagen antibody-induced arthritis (CAIA) mouse model. The results revealed an increase in NETs and IL-33 levels in the synovial fluid of RA patients, with a significant positive correlation between them. NET formation assays confirmed that IL-33 activates neutrophils to produce NETs and that neutrophils from RA patients exhibit increased responsiveness to IL-33 stimulation. Both in vitro and in vivo evidence has demonstrated that NETs stimulate FLSs to secrete IL-33 and the chemokine CXCL8 via Toll-like receptor 9, promoting further neutrophil recruitment and increasing NET production within the RA synovium. This study reveals a novel positive feedback loop involving NETs and FLSs that is mediated by IL-33 that increases NET accumulation in RA. Targeting IL-33 or NET formation and amplification may offer new therapeutic strategies for managing RA.
참고문헌 (49)
- Smolen, J. S., "Rheumatoid arthritis", Lancet, 388, pp.2023~2038 (2016)
- Viatte, S., "Genetics of rheumatoid arthritis susceptibility, severity, and treatment response", Semin. Immunopathol, 39, pp.395~408 (2017)
- Scherer, H. U., "The etiology of rheumatoid arthritis", J. Autoimmun, 110, pp.102400~ (2020)
- Smith, M. H., "What Is Rheumatoid Arthritis?", JAMA, 327, pp.1194~ (2022)
- Darrah, E., "Rheumatoid arthritis and citrullination", Curr. Opin. Rheumatol, 30, pp.72~78 (2018)
- Makrygiannakis, D., "Citrullination is an inflammation-dependent process", Ann. Rheum. Dis, 65, pp.1219~1222 (2006)
- Spengler, J., "Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid", Arthritis Rheumatol, 67, pp.3135~3145 (2015)
- O’Neil, L. J., "Neutrophils in Rheumatoid Arthritis : Breaking Immune Tolerance and Fueling Disease", Trends Mol. Med, 25, pp.215~227 (2019)
- Burgener, S. S., "Neutrophil Extracellular Traps in Host Defense", Cold Spring Harb. Perspect. Biol, 12, pp.a037028~ (2020)
- Wigerblad, G., "Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases", Nat. Rev. Immunol, 23, pp.274~288 (2023)
- Hidalgo, A., "Neutrophil extracellular traps : from physiology to pathology", Cardiovasc. Res, 118, pp.2737~2753 (2022)
- Herre, M., "Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases", Physiological Rev, 103, pp.277~312 (2023)
- Khandpur, R., "NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis", Sci. Transl. Med, 5, pp.178ra140~ (2013)
- Wang, W., "Increased levels of neutrophil extracellular trap remnants in the serum of patients with rheumatoid arthritis", Int. J. Rheum. Dis, 21, pp.415~421 (2018)
- Carmona-Rivera, C., "Neutrophil extracellular traps mediate articular cartilage damage and enhance cartilage component immunogenicity in rheumatoid arthritis", JCI insight, 5, pp.e139388~ (2020)
- O’Neil, L. J., "Neutrophil extracellular trap-associated carbamylation and histones trigger osteoclast formation in rheumatoid arthritis", Ann. Rheum. Dis, 82, pp.630~638 (2023)
- Aletaha, D., "2010 Rheumatoid arthritis classification criteria : an American College of Rheumatology", European League Against Rheumatism collaborative initiative, 2010, pp.62, 2569~2581
- Rausch Osthoff, A. K., "2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis", Ann. Rheum. Dis, 77, pp.1251~1260 (2018)
- Johnson, T. M., "Measures of Rheumatoid Arthritis Disease Activity", Arthritis Care Res, 72, pp.4~26 (2020)
- Khachigian, L. M., "Collagen antibody-induced arthritis", Nat. Protoc, 1, pp.2512~2516 (2006)
- Jia, J., "Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis", Nat. Commun, 13, pp.6804~ (2022)
- Ouyang, T., "Potential mechanistic roles of Interleukin-33 in rheumatoid arthritis", Int. Immunopharmacol, 123, pp.110770~ (2023)
- Dwyer, G. K., "Emerging Functions of IL-33 in Homeostasis and Immunity", Annu. Rev. Immunol, 40, pp.15~43 (2022)
- Nygaard, G., "Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes", Nat. Rev. Rheumatol, 16, pp.316~333 (2020)
- Fitzgerald, K. A., "Toll-like Receptors and the Control of Immunity", Cell, 180, pp.1044~1066 (2020)
- Liu, O., "Adipose-mesenchymal stromal cells suppress experimental Sjögren syndrome by IL-33-driven expansion of ST2(+)regulatory T cells", iScience, 24, pp.102446~ (2021)
- An, Z., "Neutrophil extracellular traps induced by IL-8 aggravate atherosclerosis via activation NF-κB signaling in macrophages", Cell Cycle, 18, pp.2928~2938 (2019)
- Cecchi, I., "Neutrophils: Novel key players in Rheumatoid Arthritis. Current and future therapeutic targets", Autoimmun. Rev, 17, pp.1138~1149 (2018)
- Cayrol, C., "Interleukin-33(IL-33) : A nuclear cytokine from the IL-1family", Immunological Rev, 281, pp.154~168 (2018)
- Hong, Y. S., "Measurement of interleukin-33(IL-33)and IL-33 receptors(sST2and ST2L)in patients with rheumatoid arthritis", J. Korean Med. Sci, 26, pp.1132~1139 (2011)
- Talabot-Ayer, D., "Distinct serum and synovial fluid interleukin(IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis", Jt. Bone Spine, 79, pp.32~37 (2012)
- Matsuyama, Y., "Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis", J. Rheumatol, 37, pp.18~25 (2010)
- Sundnes, O., "Rapid systemic surge of IL-33 after severe human trauma : a prospective observational study", Mol. Med, 27, pp.29~ (2021)
- Cayrol, C., "Interleukin-33(IL-33) : A critical review of its biology and the mechanisms involved in its release as a potent extracellular cytokine", Cytokine, 156, pp.155891~ (2022)
- Chen, Z., "Anti-inflammatory and immuneregulatory cytokines in rheumatoid arthritis", Nat. Rev. Rheumatol, 15, pp.9~17 (2019)
- Verri, W. A. Jr., "IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy", Ann. Rheum. Dis, 69, pp.1697~1703 (2010)
- Xu, D., "IL-33 exacerbates antigen-induced arthritis by activating mast cells", Proc. Natl. Acad. Sci. USA, 105, pp.10913~10918 (2008)
- Li, Y., "Blocking Interleukin-33 Alleviates the Joint Inflammation and Inhibits the Development of Collagen-Induced Arthritis in Mice", J. Immunol. Res, 2020, pp.4297354~ (2020)
- Palmer, G., "Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis", Arthritis Rheumatism, 60, pp.738~749 (2009)
- Biton, J., "In Vivo Expansion of Activated Foxp3+ Regulatory T Cells and Establishment of a Type 2 Immune Response upon IL-33 Treatment Protect against Experimental Arthritis", J. Immunol, 197, pp.1708~1719 (2016)
- You, S., "The Tumor-Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine", Arthritis Rheumatol, 70, pp.637~652 (2018)
- Carmona-Rivera, C., "Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis", Sci. Immunol, 2, pp.eaag3358~ (2017)
- Saber, M. M., "TLR9 : A friend or a foe", Life Sci, 307, pp.120874~ (2022)
- Corsiero, E., "NETosis as Source of Autoantigens in Rheumatoid Arthritis", Front. Immunol, 7, pp.485~ (2016)
- Carmona-Rivera, C., "Neutrophils in Inflammatory Bone Diseases", Curr. Osteoporos. Rep, 22, pp.280~289 (2024)
- Hong, J., "Interleukin-33 and ST2 Signaling in Tumor Microenvironment", J. Interferon Cytokine Res, 39, pp.61~71 (2019)
- Dong, Y., "IL-33 in Rheumatic Diseases", Front. Med, 8, pp.739489~ (2021)
- Lefrançais, E., "IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G", Proc. Natl. Acad. Sci. USA, 109, pp.1673~1678 (2012)
- Georgakis, S., "NETs decorated with bioactive IL-33 infiltrate inflamed tissues and induce IFN-α production in patients with SLE", JCI insight, 6, pp.e147671~ (2021)