IL33-induced neutrophil extracellular traps (NETs) mediate a positive feedback loop for synovial inflammation and NET amplification in rheumatoid arthritis

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. Rheumatoid arthritis is a disease where the body’s defense system wrongly attacks the joints, leading to swelling and pain. This research explores the role of neutrophil extracellular traps in RA. NETs are net-like structures released by a type of white blood cell to catch harmful germs but in RA, NETs can harm the body’s own tissues. The team collected samples from 120 RA patients, comparing them with samples from osteoarthritis patients and healthy people. They studied how certain proteins, particularly IL-33, affect NET formation in RA patients’ joints. They found that IL-33 greatly increases NET production, suggesting a cycle where IL-33 and NETs continue the inflammation in RA. This highlights IL-33’s potential as a target for RA treatment, providing new understanding of this disabling disease. Future treatments might aim to break this cycle to ease RA symptoms. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.