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

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.

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Acknowledgements

The authors would like to acknowledge the help of members of the Schroeder Arthritis Institute (Toronto). Figure 8 was created with BioRender (BioRender.com).

Funding

This article was 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), and IBM and Ian Lawson van Toch Fund. THK was supported by funding from the National Research Foundation (NRF) of Korea (NRF-2021R1A6A1A03038899) and the Korea Healthy Industry Development Institute (HI23C0661). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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AN and NH conceived the study and designed the experiments. AN and SN performed mouse genotyping, assessments of clinical and histological scores, and in vivo mouse injections (PBS, curdlan, CTL PLM, IL-23 PLM, MIF PLM, PX-478, CTL vehicle, anti-Ly6G mAb, and isotype IgG mAb). MKA, SFB, and M Korshko administered PX-478 to IL-23 PLM-injected SKG mice and performed in vitro coculture experiments using PCs and neutrophil supernatants during the revision. AN, SJ, and SV performed the IHC, IF, qPCR, ELISA, and in vitro experiments on the mouse samples. SJ, YSP, and THK performed IHC and immunoblotting for human spinal cord samples. AN and SN performed tissue dissection, cell isolation, and data acquisition for flow cytometry. HG performed the SO/FG staining of the mouse samples. IJ performed analyses of the PPI network and TFs associated with HIF1A. JSR and M Kapoor helped with data analysis for microCT and histopathology for mouse samples. AN, SJ, SN, JSR, M Kapoor, IJ, THK, and NH primarily performed the analyses and interpretation of all the datasets. Each author was involved in drafting the article and revising it critically for important intellectual content.

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Correspondence to Akihiro Nakamura or Nigil Haroon.

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Competing interests

AN and NH have filed a US provisional patent (METHODS OF TREATING SPONDYLOARTHRITIS AND SYMPTOMS THEREOF; No. 63/106,859). AN has received speaker honorarium and/or consultant fees from AbbVie, JAMP, and Novartis. NH has received consulting fees from AbbVie, Amgen, Eli Lilly, Janssen, Merck, Novartis and UCB.

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Nakamura, A., Jo, S., Nakamura, S. et al. HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model. Cell Mol Immunol 21, 770–786 (2024). https://doi.org/10.1038/s41423-024-01183-5

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