@article{8740568,
  abstract     = {{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 ((beta-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 (T-reg) acquisition of a T(H)17 cell-like phenotype, including the up-regulation of interleukin-17 (IL-17) and IL-22 in vitro. T-regs in blood and synovial fluids from SpA patients have a pathologic T(H)17 phenotype. These results indicate that MIF is a crucial regulator and a potential therapeutic target in type 3 immunity-mediated arthritis.}},
  articleno    = {{eabg1210}},
  author       = {{Nakamura, Akihiro and Zeng, Fanxing and Nakamura, Sayaka and Reid, Kyle T. and Gracey, Eric and Lim, Melissa and Leng, Lin and Jo, Sungsin and Park, Ye-Soo and Kusuda, Masaki and Machhar, Rohan and Boroojeni, Shaghayegh F. and Wu, Brian and Rossomacha, Evgeny and Kim, Tae-Hwan and Ciccia, Francesco and Rockel, Jason S. and Kapoor, Mohit and Inman, Robert D. and Jurisica, Igor and Crome, Sarah Q. and Bucala, Richard and Haroon, Nigil}},
  issn         = {{1946-6234}},
  journal      = {{SCIENCE TRANSLATIONAL MEDICINE}},
  keywords     = {{T-CELL SELECTION,SUPPRESSOR-CELLS,ANKYLOSING-SPONDYLITIS,AUTOIMMUNE ARTHRITIS,SYNOVIAL-FLUID,DECTIN-1,DIFFERENTIATION,INDUCTION,PATHWAY,MIF}},
  language     = {{eng}},
  number       = {{616}},
  pages        = {{17}},
  title        = {{Macrophage migration inhibitory factor drives pathology in a mouse model of spondyloarthritis and is associated with human disease}},
  url          = {{http://doi.org/10.1126/scitranslmed.abg1210}},
  volume       = {{13}},
  year         = {{2021}},
}

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