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Cell Mol Immunol. 2019 Jun 13. doi: 10.1038/s41423-019-0235-z. [Epub ahead of print]

Macrophages are the primary effector cells in IL-7-induced arthritis.

Author information

1
Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA.
2
Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
3
Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, 60515, USA.
4
Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, 43210, USA.
5
Division of Allergy, Clinical Immunology and Rheumatology, The University of Kansas Medical Center, Kansas City, KS, 66160, USA.
6
Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, 481096, USA.
7
Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA. shahrara@uic.edu.
8
Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA. shahrara@uic.edu.

Abstract

Synovial macrophages are crucial in the development of joint inflammation and bone damage; however, the pathways that control macrophage remodeling in inflammatory M1 cells or bone-eroding osteoclasts are not fully understood. We determined that elevated IL-7R/CD127 expression is the hallmark of rheumatoid arthritis (RA) M1 macrophages and that these cells are highly responsive to interleukin-7 (IL-7)-driven osteoclastogenesis. We established that lipopolysaccharide (LPS), interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα), the classic M1 macrophage mediators, enhance IL-7R expression in RA and murine macrophages. The local expression of IL-7 provokes arthritis, predominantly through escalating the number of F480+iNOS+ cells rather than CD3+ T cells. Ectopic LPS injection stabilizes IL-7-induced arthritis by increasing myeloid IL-7R expression, in part via IFNγ induction. Hence, in RAG-/- mice, IL-7-mediated arthritis is suppressed because of the reduction in myeloid IL-7R expression due to the lack of IFNγ. Moreover, the amelioration of IL-7-induced arthritis by anti-TNF therapy is due to a decrease in the number of cells in the unique F480+iNOS+IL-7R+CCL5+ subset, with no impact on the F480+Arginase+ cell or CD3+ T cell frequency. Consistent with the preclinical findings, the findings of a phase 4 study performed with RA patients following 6 months of anti-TNF therapy revealed that IL-7R expression was reduced without affecting the levels of IL-7. This study shifts the paradigm by discovering that IL-7-induced arthritis is dependent on F480+iNOS+IL-7R+CCL5+ cell function, which activates TH-1 cells to amplify myeloid IL-7R expression and disease severity.

PMID:
31197255
DOI:
10.1038/s41423-019-0235-z

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