HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model  

作　　者：Akihiro Nakamura Sungsin Jo Sayaka Nakamura Mansi K.Aparnathi Shaghayegh Foroozan Boroojeni Mariia Korshko Ye-Soo Park Himanshi Gupta Sandra Vijayan Jason S.Rockel Mohit Kapoor Igor Jurisica Tae-Hwan Kim Nigil Haroon 

机构地区：[1]Schroeder Arthritis Institute,University Health Network,Toronto,ON,M5T 0S8,Canada [2]Krembil Research Institute,University Health Network,Toronto,ON,M5T 0S8,Canada [3]Institute of Medical Science,Temerty Faculty of Medicine of Medicine,University of Toronto,Toronto,ON,M5S 1A8,Canada [4]Department of Medicine,Division of Rheumatology,Queen’s University,Kingston,ON,K7L,2V6,Canada [5]Translational Institute of Medicine,School of Medicine,Queen’s University,Kingston,ON,K7L 2V6,Canada [6]Division of Rheumatology,Kingston Health Science Centre,Kingston,ON,K7L 2V6,Canada [7]Hanyang University Institute for Rheumatology Research(HYIRR),Seoul,04763,Republic of Korea [8]Department of Biology,College of Natural Sciences,Soonchunhyang University,Asan,31538,Republic of Korea [9]Department of Orthopedic Surgery,Guri Hospital,Hanyang University College of Medicine,Guri,11293,Republic of Korea [10]Department of Surgery and Department of Laboratory Medicine and Pathobiology,University of Toronto,Toronto,ON,M5T 1P5,Canada [11]Departments of Medical Biophysics and Comp.Science and Faculty of Dentistry,University of Toronto,Toronto,ON,M5G 1L7,Canada [12]Institute of Neuroimmunology,Slovak Academy of Sciences,85410,Bratislava,Slovakia [13]Department of Rheumatology,Hanyang University Hospital for Rheumatic Diseases,Seoul,04763,Republic of Korea

出　　处：《Cellular & Molecular Immunology》2024年第7期770-786,共17页中国免疫学杂志（英文版）

基　　金：supported by grants to NH from the Canadian Institute of Health Research(CIHR)and Arthritis Society(Canada);AN is a recipient of a CIHR fellowship,Spondyloarthritis Research and Treatment Network(SPARTAN)fellowship,Spondyloarthritis Research Consortium of Canada(SPARCC)fellowship,Edward Christie Stevens fellowship;S.Fenwick Research fellowship,and Krembil Research Institute fellowship(Canada);IJ was supported in part by funding from the Natural Sciences Research Council(NSERC#203475);Canada Foundation for Innovation(CFI#225404,#30865);Ontario Research Fund(RDI#34876,RE010-020);IBM and Ian Lawson van Toch Fund.THK was supported by funding from the National Research Foundation(NRF)of Korea(NRF-2021R1A6A1A03038899);the Korea Healthy Industry Development Institute(HI23C0661).

摘　　要：The hallmarks of spondyloarthritis(SpA)are type 3 immunity-driven inflammation and new bone formation(NBF).Macrophage migration inhibitory factor(MIF)was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity,yet MIF-interacting molecules and networks remain elusive.Herein,we identified hypoxia-inducible factor-1 alpha(HIF1A)as an interacting partner molecule of MIF that drives SpA pathologies,including inflammation and NBF.HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG(curdlan-SKG)mice compared to the respective controls.Under hypoxic conditions in which HIF1A was stabilized,human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23,an upstream type 3 immunity-related cytokine.Similar to MIF,systemic overexpression of IL-23 induced SpA pathology in SKG mice,while the injection of a HIF1A-selective inhibitor(PX-478)into curdlan-SKG mice prevented or attenuated SpA pathology,as indicated by a marked reduction in the expression of MIF and IL-23.Furthermore,genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF,despite the presence of psoriasis-like dermatitis and blepharitis.We also found that MIF-and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice.These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification.Together,these results provide supporting evidence for an MIF/HIF1A regulatory network,and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.

关 键 词：Endochondral ossification Hypoxia-inducible factor-1 alpha INTERLEUKIN-23 Macrophage migration inhibitory factor NEUTROPHIL SPONDYLOARTHRITIS 

分 类 号：R392[医药卫生—免疫学]