Neutrophilic Inflammation in Spondyloarthritis

To test whether MIF overexpression without Curdlan was sufficient to induce this phenotype, they used a plasmid to express MIF and found similar disease manifestations. Conversely, MIF knockout led to clinical improvements in weight, arthritis, dermatitis and blepharitis. Pharmacological inhibition of MIF with a MIF antagonist, MIF098, similarly prevented and reversed these spondyloarthritis-like manifestations.

Dr. Haroon posed the question: What is the cellular source of MIF? Using human peripheral blood cells, they found that almost all cell types produce MIF, but it is significantly higher in granulocytes and in Curdlan-injected SKG mice neutrophils.

With the neutrophil now in focus, they performed comparative total RNA-sequencing on neutrophils from MIF positive and MIF knock out mice and identified DTL (denticleless E3 ubiquitin protein ligase homolog), which is a negative inhibitor of IL-23/24 production. In MIF knockout mice, DTL expression was increased, leading to greater inhibition of IL-23. This led them to hypothesize that overexpression of DTL could be therapeutic in spondyloarthritis.

To demonstrate the importance of neutrophil mediated MIF production, they isolated neutrophils capable of MIF production and transferred them into MIF knockout mice, and which led to the development of spondyloarthritis-like manifestations.

Spondyloarthritis is unique for its tissue specificity, so they wondered which proteins MIF was interacting with at the tissue level. This inquiry led them to the discovery of HIF1alpha, which is significantly increased in production in Curdlan treated mice. Blocking of HIF1alpha (with PX-748) led to improvement of symptoms including arthritis, dermatitis and blepharitis, and decreased production of pro-inflammatory cytokines. Blocking HIF1alpha was also able to prevent new bone formation in Curdlan treated SKG mice.¹¹

In summary, the MIF-HIF axis seems to be mediated through neutrophils and has an important role in symptom development in a pre-clinical axial spondyloarthritis model. Neutrophils are activated and expanded in the tissues, lead to production of inflammatory cytokines, such as MIF, IL-1 and IL-23, and warrant continued study to uncover novel therapeutic targets.

Michael Cammarata, MD, RhMSUS, is an assistant professor of medicine at the Johns Hopkins University School of Medicine, Baltimore.

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