The role of macrophage-derived MIF in rheumatoid arthritis-associated lung disease: My educative summer of research

The role of macrophage-derived MIF in rheumatoid arthritis-associated lung disease: My educative summer of research

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BY:Jared Riviere
Supervisor: Dr. Nigil Haroon

 

This summer I was lucky enough to complete a SURP project under the guidance of my supervisor Dr. Nigil Haroon. While our lab’s focuses on studying the pathways of ankylosing spondylitis, the subject of my project was lung fibrosis, a complication in about 40% of Rheumatoid arthritis (RA) cases3.

In fibrotic lung disease, inflammatory cells accumulate in the lung and produce excessive extra-cellular matrix, damaging airspaces4. Lung disease in RA cases is a major contributor to mortality, and many of its mechanisms remain unknown.  As such, there have been few therapeutic advancements for severe cases in the past half-century. Moreover, several commonly-prescribed antirheumatic drugs have shown potential to exacerbate pulmonary dysfunction2. Evolving new treatment options for patients with RA-associated lung fibrosis is certainly a high priority.

To address the need for new therapeutic interventions, my project focused on the cytokine macrophage migration inhibitory factor (MIF). MIF is implicated in immuno-inflammatory diseases including rheumatoid arthritis and is dramatically increased in the fibrotic lungs of curdlan-injected SKG mice, an established RA model1. In contrast, MIF knockout (MIFKO) mice receiving curdlan injections develop relatively little fibrosis. Preliminary data suggests that macrophages in the SKG fibrotic lung may be the major source of MIF, which led me to investigate the role of macrophage-derived MIF in RA-associated lung fibrosis.

We cultured macrophages isolated from curdlan- injected SKG mice lungs for 24 h and added their culture media to cultures of lung fibroblasts from healthy SKG mice. Our control fibroblasts received normal culture media. We measured inflammatory markers by western blot, qPCR, and Immunofluorescence. Additionally, the MIF concentration in macrophage culture media and bronchoalveolar lavage fluid (BALF) of curdlan-injected SKG mice was measured with ELISA.

Curdlan-injected SKG mice BALF and macrophage-culture media showed elevated MIF concentrations compared to controls. Fibroblasts cultured with macrophage-culture media had substantially increased expression of fibrosis-related markers αSMA and type I collagen, confirmed by western blot and immunofluorescence. The expression of CD74, the MIF receptor, was also elevated in the macrophage treatment. On the other hand, there were no differences in the expression of these markers when fibroblasts were cultured in media from MIFKO macrophage cultures. Collectively, these observations suggest that macrophage-derived MIF is causing fibroblasts to differentiate into myofibroblasts. We concluded that macrophage-derived MIF contributes to the fibrotic changes in the lungs of RA mouse model. In the future, blocking MIF may be a potential therapeutic strategy for RA-associated lung fibrosis.

The most important thing I learned this summer was how important teamwork can be in the lab. At the beginning of this program I thought I had to be as independent as possible to become a competent researcher, but I quickly learned that the people around me were priceless resources to help achieve this goal. In addition to the time they spent teaching me the ins and outs of the lab, they provided models of discipline and professionalism that I could strive to emulate. I am sure I will carry much that they taught me for rest of my career.

 

 

References

  1. Kim KW, Kim HR. Macrophage migration inhibitory factor: a potential therapeutic target for rheumatoid arthritis. Korean J Intern Med. 2016 Jul;31(4):634–642.
  2. Redente EF, Aguilar MA, Black BP, Edelman BL, Bahadur AN, Humphries SM, et al. Nintedanib reduces pulmonary fibrosis in a model of rheumatoid arthritis-associated interstitial lung disease. Am J Physiol Lung Cell Mol Physiol. 2018 Mar;314(6):L998–L1009
  3. Roschmann RA, Rothenberg RJ. Pulmonary fibrosis in rheumatoid arthritis: A review of clinical features and therapy. Semin Arthritis Rheum. 1987 Feb;16(3):174–185
  4. Shiomi A, Usui T, Ishikawa Y, Shimizu M, Murakami K, Mimori T. GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice. J Immunol. 2014 Jul;93(2):849–859