Ageing and interferon gamma response drive the phenotype of neutrophils in the inflamed joint. Issue 6 (15th February 2022)

• Record Type: Journal Article
• Authors: Grieshaber-Bouyer, Ricardo; Exner, Tarik; Hackert, Nicolaj S; Radtke, Felix A; Jelinsky, Scott A; Halyabar, Olha; Wactor, Alexandra; Karimizadeh, Elham; Brennan, Joseph; Schettini, Jorge; Jonsson, Helena; Rao, Deepak A; Henderson, Lauren A; Müller-Tidow, Carsten; Lorenz, Hanns-Martin; Wabnitz, Guido; Lederer, James A; Hadjipanayis, Angela; Nigrovic, Peter A
• Is Part Of: Annals of the rheumatic diseases. Volume 81:Issue 6(2022)
• Page Start: 805
• Page End: 814
• Publication Date: 2022-02-15
• Subjects: arthritis -- rheumatoid -- arthritis -- juvenile -- arthritis -- synovial fluid; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2021-221866
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objective: Neutrophils are typically the most abundant leucocyte in arthritic synovial fluid. We sought to understand changes that occur in neutrophils as they migrate from blood to joint. Methods: We performed RNA sequencing of neutrophils from healthy human blood, arthritic blood and arthritic synovial fluid, comparing transcriptional signatures with those from murine K/BxN serum transfer arthritis. We employed mass cytometry to quantify protein expression and sought to reproduce the synovial fluid phenotype ex vivo in cultured healthy blood neutrophils. Results: Blood neutrophils from healthy donors and patients with active arthritis showed largely similar transcriptional signatures. By contrast, synovial fluid neutrophils exhibited more than 1600 differentially expressed genes. Gene signatures identified a prominent response to interferon gamma (IFN-γ), as well as to tumour necrosis factor, interleukin-6 and hypoxia, in both humans and mice. Mass cytometry confirmed that healthy and arthritic donor blood neutrophils are largely indistinguishable but revealed a range of neutrophil phenotypes in synovial fluid defined by downregulation of CXCR1 and upregulation of FcγRI, HLA-DR, PD-L1, ICAM-1 and CXCR4. Reproduction of key elements of this signature in cultured blood neutrophils required both IFN-γ and prolonged culture. Conclusions: Circulating neutrophils from patients with arthritis resemble those from healthy controls, but joint fluid cells exhibit a network of changes, conserved across species, that implicate IFN-γ response and ageing as complementary drivers of the synovial fluid neutrophil phenotype.