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- Title
Macrophage migration inhibitory factor drives pathology in a mouse model of spondyloarthritis and is associated with human disease.
- Authors
Nakamura, Akihiro; Zeng, Fanxing; Nakamura, Sayaka; Reid, Kyle T.; Gracey, Eric; Lim, Melissa; Leng, Lin; Jo, Sungsin; Park, Ye-Soo; Kusuda, Masaki; Machhar, Rohan; Boroojeni, Shaghayegh F.; Wu, Brian; Rossomacha, Evgeny; Kim, Tae-Hwan; Ciccia, Francesco; Rockel, Jason S.; Kapoor, Mohit; Inman, Robert D.; Jurisica, Igor
- Abstract
keyimage.jpg A driver of spondyloarthritis: Spondyloarthritis is a systemic inflammatory disease characterized by damage to the joints, spine, gut, skin, and eyes. In this study, Nakamura et al. investigated the role of macrophage migration inhibitory factor (MIF) produced by neutrophils in driving spondyloarthritis. The authors found that genetic deletion of MIF reduced disease severity in curdlan-treated SKG mice, a mouse model of spondyloarthritis, whereas adoptive transfer of proinflammatory, MIF-producing neutrophils enhanced disease. Mechanistically, MIF induced a pathogenic TH17 phenotype in regulatory T cells. Pharmacological inhibition of MIF reversed the TH17 phenotype in regulatory T cells, suggesting that MIF inhibitors merit further consideration as treatments for spondyloarthritis. Spondyloarthritis (SpA), a type 3 immunity-mediated inflammatory arthritis, is a systemic rheumatic disease that primarily affects the joints, spine, gut, skin, and eyes. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine, yet MIF's pathological role in SpA is unknown. Here, we observed that the expression of MIF and its receptor CD74 is increased in blood and tissues of curdlan (β-glucan)–treated SKG mice, a mouse model of SpA. We found that neutrophils substantially expanded and produced MIF in curdlan-treated SKG mice and that human neutrophils from SpA patients secreted higher concentrations of MIF compared to healthy individuals. Although genetic deletion of Mif (Mif−/−) substantially suppressed the severity of SpA features, adoptive transfer of inflammatory neutrophils induced SpA pathology in curdlan-treated Mif−/− SKG mice; in contrast, blocking the function of neutrophils with anti–Gr-1 antibody suppressed the curdlan-induced SpA-like phenotype. We also determined that systemic MIF overexpression was sufficient to induce SpA-like clinical features in SKG mice with enhanced type 3 immunity, whereas SKG mice treated with a MIF antagonist prevented or attenuated curdlan-induced SpA manifestations. Mechanistically, we identified that MIF intensifies type 3 immunity by boosting human and mouse T regulatory cell (Treg) acquisition of a TH17 cell–like phenotype, including the up-regulation of interleukin-17 (IL-17) and IL-22 in vitro. Tregs in blood and synovial fluids from SpA patients have a pathologic TH17 phenotype. These results indicate that MIF is a crucial regulator and a potential therapeutic target in type 3 immunity-mediated arthritis.
- Subjects
MACROPHAGE migration inhibitory factor; LABORATORY mice; REGULATORY T cells; SYNOVIAL fluid; T cells; NEUTROPHILS; ANIMAL disease models
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 616, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abg1210