Article
Inflammatory arthritis elicits an interferon gamma response in neutrophils shared across species
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Authors
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Ricardo Grieshaber Bouyer
- Klinik für Hämatologie, Onkologie und Rheumatologie, Universitätsklinikum Heidelberg, Heidelberg
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Olha Halyabar
- Division of Immunology, Boston Children’s Hospital, Boston
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Felix Radtke
- Klinik für Hämatologie, Onkologie und Rheumatologie, Universitätsklinikum Heidelberg, Heidelberg
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Anais Levescot
- Institut IMAGINE-INSERM 1163, Université Paris Descartes-Sorbonne Paris Cité, Paris
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Kacie Hoyt
- Division of Immunology, Boston Children’s Hospital, Boston
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Lauren Henderson
- Division of Immunology, Boston Children’s Hospital, Boston
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Hanns-Martin Lorenz
- Klinik für Hämatologie, Onkologie und Rheumatologie, Universitätsklinikum Heidelberg, Heidelberg
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Peter A. Nigrovic
- Division of Immunology, Boston Children’s Hospital, Boston
| Published: | September 14, 2021 |
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Outline
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Introduction: Neutrophils are immune first responders and often the most abundant lineage in arthritic synovial fluid. We sought to characterize the changes that occur in neutrophils as they migrate from blood to joint and to identify related programs of protein and transcriptional shifts that are shared between humans and mice.
Methods: Using mass cytometry and bulk RNA sequencing, we phenotyped neutrophils from healthy peripheral blood, arthritic peripheral blood, and arthritic synovial fluid. Findings were compared with data from blood and joint fluid from mice undergoing K/BxN serum transfer arthritis.
Results: Transcriptomic profiles of circulating neutrophils from healthy and arthritic donors were markedly similar. By contrast, joint neutrophils differed in more than 1,300 differentially expressed genes. Gene sets enriched in synovial fluid neutrophils included, expectedly, tumor necrosis factor and interleukin-6 response but also, somewhat less expected, response to interferon gamma. Upregulated genes included CXCR4, CD274 (PD-L1) and HLA class II genes. Comparison with data from arthritic mice showed remarkable overlap, including upregulation of CD9, CCRL2, CXCR4 and CD274 shared across species. Downregulated transcripts shared across species included MMP8 and LCN2, encoding secondary granule proteins.
Mass cytometry of human neutrophils identified multiple gradients of surface marker expression consistent with developmental and activation sequences. In blood, neutrophils from healthy controls and patients with inflammatory arthritis were phenotypically similar. Comparison between blood and synovial fluid, including in 8 contemporaneous blood/synovial fluid pairs, identified a consistent set of changes including downregulation of the IL-8 receptor CXCR1 and upregulation of the CXCL12 receptor CXCR4. A set of proteins related to interferon gamma response were again induced in neutrophils in synovial fluid, including PD-L1, CD32, CD64 and HLA-DR.
Conclusion: Transcriptome and protein expression measurements identify a network of changes that characterize the circulating and synovial neutrophil compartments, including a conserved set of transcriptional and protein changes associated with an interferon gamma response shared across species.
Disclosures: None declared
