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Abstract Number: 605

Macrophage Migration Inhibitory Factor Is a Critical Regulator in a Mouse Model of Spondyloarthritis

Akihiro Nakamura1, Fanxing Zeng 1, Sayaka Nakamura 1, Richard Bucala 2 and Nigil Haroon 3, 1University Health Network, Toronto, Canada, 2Yale University School of Medicine, New Haven, CT, 3Toronto Western Hospital, Krembil Research Institute, University of Toronto, Toronto, ON, Canada

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Spondylarthritis

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Session Information

Date: Sunday, November 10, 2019

Session Title: Spondyloarthritis Including Psoriatic Arthritis – Clinical Poster I: Axial Spondyloarthritis, Clinical Features

Session Type: Poster Session (Sunday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Spondyloarthritis (SpA) is a chronic rheumatic disease characterized by severe inflammation in the spine, peripheral joints, intestine, skin and eyes. Although current treatment modalities including tumor-necrosis-factor (TNF) and interleukin (IL)-17 blockers could control inflammation, up to 40% of SpA patients don’t adequately response to any medications or lose their efficacies, resulting in severe pain, increased cardiovascular risk and deteriorating mental health. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that exhibits pro-inflammatory effects. MIF has functions in the regulation of immune responses and has been implicated in various inflammatory conditions. We recently discovered that serum levels of MIF were significantly elevated in Ankylosing Spondylitis (AS) patients compared to healthy controls. However, the specific role of MIF in SpA is largely unknown.

Methods: Curdlan (β-glucan) or MIF-plasmid (mini-circle) treated SKG mice (8-10 weeks) were used as SpA mouse models. The expression of MIF in serum or tissues was measured by ELISA, quantitative PCR (qPCR), western blotting, immunohistochemistry (IHC) and/or immunofluorescence (IF). MIF knockout (KO) SKG mice were generated as MIF deficiency mice. MIF inhibitor (MIF098) was used to block the function of MIF in SpA mouse models to assess the therapeutic or prophylactic effects in a curdlan-treated SpA mouse model. Populations of immunological cells were assessed by flow cytometry. Anti-Gr-1 monoclonal antibody (mAb) or isotype control mAb was used to block the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) or monocytic MDSCs (mMDSCs). Clinical scores, histopathology and microCT imaging were used to assess the severity of inflammation in the various tissues of the mouse models.

Results: The expression of MIF and its receptor CD74 were significantly up-regulated in serum, spleen, ileum, sacroiliac and ankle joints of curdlan-treated SKG mice. MIF-overexpressed SKG mice injected with MIF-plasmid remarkably induced major SpA clinical features including colitis, psoriasis and arthritis in the axial and peripheral joints, while MIFKO SKG mice or blocking the function of MIF with MIF inhibitor (MIF098) dramatically suppressed or attenuated these manifestations, with decreased populations of Th17 and increased regulatory T (Treg) cells. We have also identified the cell populations (PMN-MDSCs and mMDSCs) substantially producing MIF in the disease condition. Interestingly, adopted transfer of these cells into non-disease control mice clearly exhibits SpA phenotype including arthritis, blepharitis and psoriasis. Furthermore, blocking the function of those cells with anti-Gr-1 antibody suppresses the SpA phenotype.

Conclusion: These results indicate that MIF is a crucial regulator of inflammation and may be a promising therapeutic target in SpA.


Disclosure: A. Nakamura, None; F. Zeng, None; S. Nakamura, None; R. Bucala, MIFCOR, Inc., 9; N. Haroon, Abbive, Amgen, Janssen, Eli Lilly, Novartis AG, UCB Pharma, 5, 8, Abbvie, 5, 8, Amgen, 5, 8, Eli Lilly, 5, 8, Janssen, 5, 8, Merck, 5, 8, Novartis, 5, 8, UCB Pharma, 5, 8.

To cite this abstract in AMA style:

Nakamura A, Zeng F, Nakamura S, Bucala R, Haroon N. Macrophage Migration Inhibitory Factor Is a Critical Regulator in a Mouse Model of Spondyloarthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/macrophage-migration-inhibitory-factor-is-a-critical-regulator-in-a-mouse-model-of-spondyloarthritis/. Accessed January 28, 2023.
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