Macrophage migration inhibitory factor drives pathology in a mouse model of spondyloarthritis and is associated with human disease,Science Translational Medicine

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Macrophage migration inhibitory factor drives pathology in a mouse model of spondyloarthritis and is associated with human disease
Science Translational Medicine ( IF 15.8 ) Pub Date : 2021-10-20 , DOI: 10.1126/scitranslmed.abg1210
Akihiro Nakamura _{1,

2,

3,

4} , Fanxing Zeng _{1,

2} , Sayaka Nakamura _{1,

2} , Kyle T Reid _{5,

6} , Eric Gracey _{7,

8} , Melissa Lim _{1,

2} , Lin Leng ₉ , Sungsin Jo ₁₀ , Ye-Soo Park ₁₁ , Masaki Kusuda _{1,

2} , Rohan Machhar _{1,

2} , Shaghayegh F Boroojeni _{1,

2,

4} , Brian Wu _{1,

2} , Evgeny Rossomacha _{1,

2} , Tae-Hwan Kim ₁₀ , Francesco Ciccia ₁₂ , Jason S Rockel _{1,

2} , Mohit Kapoor _{1,

2} , Robert D Inman _{1,

2,

3,

5} , Igor Jurisica _{1,

2,

13,

14} , Sarah Q Crome _{5,

6} , Richard Bucala ₉ , Nigil Haroon _{1,

2,

3,

4}

Affiliation

Schroeder Arthritis Institute, University Health Network, Toronto, Ontario M5T 0S8, Canada.
Krembil Research Institute, University Health Network, Toronto, Ontario M5T 0S8, Canada.
Division of Rheumatology, Toronto Western Hospital, University Health Network, Toronto, Ontario M5T 2S8, Canada.
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
Unit Molecular Immunology and Inflammation, Inflammation Research Institute, VIB-Ghent University, 9000 Ghent, Belgium.
Department of Rheumatology, Universitair Ziekenhuis Ghent, University of Gent, 9000 Ghent, Belgium.
Section of Rheumatology, Allergy and Immunology, Yale School of Medicine, New Haven, CT 06510, USA.
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Republic of Korea.
Department of Orthopaedic Surgery, Guri Hospital, Hanyang University College of Medicine, Guri 11293, Republic of Korea.
Department of Precision Medicine, University della Campania L. Vanvitelli, 80131 Naples, Italy.
Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Institute of Neuroimmunology, Slovak Academy of Sciences, 85410 Bratislava, Slovakia.

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 (T_reg) acquisition of a T_H17 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_H17 phenotype. These results indicate that MIF is a crucial regulator and a potential therapeutic target in type 3 immunity-mediated arthritis.

中文翻译：

巨噬细胞迁移抑制因子驱动脊柱关节炎小鼠模型的病理学并与人类疾病有关

脊柱关节炎 (SpA) 是一种 3 型免疫介导的炎症性关节炎，是一种系统性风湿性疾病，主要影响关节、脊柱、肠道、皮肤和眼睛。巨噬细胞迁移抑制因子 (MIF) 是一种促炎细胞因子，但 MIF 在 SpA 中的病理作用尚不清楚。在这里，我们观察到 MIF 及其受体 CD74 的表达在 curdlan（β-葡聚糖）处理的 SKG 小鼠（一种 SpA 的小鼠模型）的血液和组织中增加。我们发现，在 curdlan 治疗的 SKG 小鼠中，中性粒细胞显着扩增并产生 MIF，并且与健康个体相比，来自 SpA 患者的人类中性粒细胞分泌更高浓度的 MIF。虽然Mif ( Mif ^-/-) 显着抑制 SpA 特征的严重性，炎症性中性粒细胞的过继转移在 curdlan 治疗的Mif ^-/- SKG 小鼠中诱导 SpA 病理学；相反，用抗 Gr-1 抗体阻断中性粒细胞的功能可抑制 curdlan 诱导的 SpA 样表型。我们还确定全身 MIF 过表达足以在 3 型免疫增强的 SKG 小鼠中诱导 SpA 样临床特征，而用 MIF 拮抗剂治疗的 SKG 小鼠预防或减弱 curdlan 诱导的 SpA 表现。从机制上讲，我们发现 MIF 通过促进人和小鼠 T 调节细胞 (T _reg ) 获得 T _{H来增强 3 型免疫。}17 细胞样表型，包括体外白细胞介素 17 (IL-17) 和 IL-22 的上调。SpA 患者的血液和滑液中的T _{regs具有病理性 T}_H 17 表型。这些结果表明，MIF 是 3 型免疫介导关节炎的关键调节剂和潜在治疗靶点。

更新日期：2021-10-21

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