The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been demonstrated to drive the induction and progression of spondyloarthritis (SpA) in mice and to be associated with human disease, according to the findings of an international study led by researchers at the University of Toronto in Ontario, Canada.
The study further showed that MIF is a key upstream regulator of type 3 immunity, indicating that it may represent a therapeutic target for immunity-mediated inflammatory diseases like SpA, the authors reported in Science Translational Medicine.
"Our study has identified the key roles of MIF in initiation and progression of SpA through modulating type 3 immunity in an SpA mouse model," said study leader Nigil Haroon, a researcher at the Schroeder Arthritis Institute in Toronto and associate professor of rheumatology with the University Health Network.
SpA is a chronic rheumatic disease characterized by inflammation and abnormal new bone formation (NBF) and enthesitis, or inflammation of the spine and peripheral joint connective tissues, but which can also affect the gut, skin and eyes.
"Tumor necrosis factor (TNF) and IL-17 inhibitors have been approved for SpA treatment, but up to 40% of patients fail to respond," said Haroon.
Moreover, "controlling SpA-associated symptoms including psoriasis, colitis and uveitis is difficult with currently available treatments."
Compared with healthy controls, MIF levels have been shown to be higher in the serum and synovial fluid of ankylosing spondylitis patients, in whom elevated baseline serum MIF concentrations predict radiographic disease progression.
These findings suggest that MIF may drive both inflammation and NBF in SpA, although its precise role in SpA initiation or progression remains largely unknown.
Major inflammatory contributors in SpA include T helper 17 (TH17) cells and lymphoid cells producing IL-17 and IL-22 in joint tissues.
Naive CD4+ T cells differentiate into subpopulations, such as TH17 and regulatory T cells (Tregs), with Treg dysfunction being thought to contribute to SpA pathogenesis, although the exact mechanisms remain unclear.
In the Science Translational Medicine study, the authors investigated the contribution of MIF to SpA pathogenesis and MIF's potential as a therapeutic target in curdlan-treated SKG mice, which are well-established models of SpA.
"The expression of MIF and its receptor, CD74, were both significantly increased in the blood and tissues of these mouse models," noted Haroon.
The researchers then found that neutrophils not only substantially expanded and produced MIF in these mice, but also that human neutrophils from SpA patients secreted higher concentrations of MIF compared to healthy controls.
Although Mif genetic knockout (KO) was shown to suppress the severity of SpA features, adoptive transfer of inflammatory neutrophils induced SpA pathology in Mif KO SKG mice.
"Spondylitis and peripheral arthritis, as well as inflammation of the eyes and skin, were all significantly lower in the Mif KO mice," Haroon told BioWorld Science.
"After identifying neutrophils as one of the main sources of MIF, we wanted to see whether neutrophils from diseased mice alone could induce disease in otherwise healthy SKG mice," he explained.
Indeed, "even without curlan induction, neutrophils from diseased mice were shown to be able to trigger SpA in the SKG mice."
Conversely, blocking neutrophil function with an antibody was demonstrated to suppress the curdlan-induced SpA-like phenotype.
Systemic MIF overexpression was also shown to induce SpA-like clinical features in SKG mice with enhanced type 3 immunity, whereas SKG mice treated with a MIF antagonist had attenuated curdlan-induced SpA symptoms.
"MIF overexpression was achieved using genetic means, whereas MIF antagonism was with MIF-098, a small-molecule inhibitor that binds to the enzymatic binding site of MIF," said Haroon.
The researchers demonstrated that, mechanistically, MIF enhanced type 3 immunity by boosting both human and mouse Treg acquisition of a TH17 cell-like phenotype, including in vitro upregulation of the cytokines IL-17 and IL-22.
Moreover, Tregs in blood and synovial fluids from SpA patients were shown to have a pathologic TH17 phenotype.
This is a significant finding, "as Treg cells have an active role in controlling excess inflammation and autoimmune processes in order to prevent self damage," said Haroon.
"However, we found that MIF can drive these cells to the proinflammatory phenotype that causes SpA," he told BioWorld Science.
These findings collectively indicate that MIF is a crucial regulator and potential therapeutic target in type 3 immunity-mediated arthritis, which has implications for clinical drug development.
"The beauty of this study concerns the potential for immediate translation, since MIF inhibitors are already available for use in humans, with clinical trials of various MIF inhibitor having been conducted in various diseases," said Haroon.
Importantly, in these studies, "no major adverse events have been observed that would preclude studying these agents in SpA," he said.
Therefore, "our next steps will involve pursuing the development of MIF inhibition for clinical application and a more in-depth investigation of the finer mechanisms of MIF-mediated bone changes, with such studies being already underway."