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

Journal: cellular & molecular immunology

Authors:  Akihiro Nakamura^{1,2,3,4,5,6,*}, Sungsin Jo^7,8, Sayaka Nakamura^9,10, Mansi K Aparnathi^9,10, Shaghayegh Foroozan Boroojeni^9,10,11, Mariia Korshko^9,10, Ye-Soo Park¹², Himanshi Gupta^9,10, Sandra Vijayan^9,10, Jason S Rockel^9,10, Mohit Kapoor^9,10,13, Igor Jurisica^9,10,14,15, Tae-Hwan Kim^7,16, Nigil Haroon^17,18,19,*

Affiliations

 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 Schroeder Arthritis Institute, University Health Network, Toronto, ON, M5T 0S8, Canada.

 ¹⁰ Krembil Research Institute, University Health Network, Toronto, ON, M5T 0S8, Canada.

 ¹¹ Institute of Medical Science, Temerty Faculty of Medicine of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.

 ¹² Department of Orthopedic Surgery, Guri Hospital, Hanyang University College of Medicine, Guri, 11293, Republic of Korea.

 ¹³ Department of Surgery and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5T 1P5, Canada.

 ¹⁴ Departments of Medical Biophysics and Comp. Science and Faculty of Dentistry, University of Toronto, Toronto, ON, M5G 1L7, Canada.

 ¹⁵ Institute of Neuroimmunology, Slovak Academy of Sciences, 85410, Bratislava, Slovakia.

 ¹⁶ Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, 04763, Republic of Korea.

 ¹⁷ Schroeder Arthritis Institute, University Health Network, Toronto, ON, M5T 0S8, Canada. 

 ¹⁸ Krembil Research Institute, University Health Network, Toronto, ON, M5T 0S8, Canada. 

 ¹⁹ Institute of Medical Science, Temerty Faculty of Medicine of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. 

 *  Correspondence

Abstract:

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.

Keywords: Endochondral ossification, Hypoxia-inducible factor-1 alpha, Interleukin-23, Macrophage migration inhibitory factor, Neutrophil, Spondyloarthritis.

DOI: 10.1038/s41423-024-01183-5

​Published: 05 June 2024