Researchers have implicated the pro-inflammatory cytokine interleukin-1 (IL-1) in a wide variety of diseases such as osteoarthritis, rheumatoid arthritis (RA), diabetes, and obesity. Steven Abramson, MD, the Frederick H. King Professor of Internal Medicine, professor of pathology, and chair of the Department of Medicine at NYU Langone Health, has long studied how IL-1 can propagate and exacerbate the disease process. That research effort has more recently expanded to include investigations into how the anti-inflammatory IL-1 receptor antagonist, IL-1Ra, can counter IL-1 and modulate the inflammatory response. Based on intriguing findings about how certain gene variants may influence osteoarthritis risk and severity, a new National Institutes of Health (NIH) research grant will help Dr. Abramson and collaborators seek out IL-1related targets for inflammatory disease prevention and treatment.

To help clarify the inflammatory process, Dr. Abramson and collaborators including Mukundan G. Attur, PhD, associate professor of medicine, and Jonathan Samuels, MD, associate professor of medicine, examined several variants of the IL-1Raencoding IL1RN gene in the knee joints and cells of osteoarthritis and rheumatoid arthritis patients. In particular, a haplotype designated TTG predicted which at-risk patients would go on to develop knee osteoarthritis and was associated with more severe radiographic osteoarthritis as well as new onset RA. Its a marker of both severity and increased risk for incident osteoarthritis, Dr. Abramson says.

Their 2019 study in osteoarthritis patients, published in Annals of the Rheumatic Diseases, suggested that the IL1RN TTG haplotype produced less IL-1Ra protein. So one explanation for the finding is that these people with the gene are deficient in the endogenous inhibitor of IL-1, which is driving the disease, Dr. Abramson says. Conversely, a separate haplotype called CTA yields more IL-1Ra protein production and may be protective.

In collaboration with Jef D. Boeke, PhD, professor of biochemistry and molecular pharmacology and director of the Institute for Systems Genetics, a new NIH grant may help clarify how each gene haplotype modulates inflammation, influences the associated gene regulatory networks, and contributes to the mechanics of disease pathogenesis. In particular, the research will focus on a haplotype block, or a section of DNA including multiple genes adjacent to the IL1RN gene. The researchers hope to learn whether any of the neighboring genes have inflammatory properties of their own, a synergistic effect on IL1RN, or even a more dominant effect on the underlying inflammatory pathway. One reason to do that is if youre developing a drug, you might find that one of these other genes is a better target than IL1RN, Dr. Abramson says.

One key to the unique research effort is Dr. Boekes expertise in using CRISPR-Cas9 gene editing technology to construct a series of what his lab calls assemblons, or precisely altered haplotype blocks. Led by Dr. Attur, the collaborators will then transfect embryonic stem cells with the manipulated DNA and use in vitro assays to gauge the effects of the putative risk and protective IL1RN haplotypes. The genetic manipulation is very technical. But if we can succeed, it allows us to really define the role of these haplotypes, not just in osteoarthritis but in other IL-1driven diseases, Dr. Abramson says.

After differentiating the engineered embryonic stem cells into macrophage cells, the researchers will measure production of the IL-1Ra protein. Well also be stimulating the macrophages in an inflammatory way and looking at the profile of inflammatory mediators that they produce, Dr. Abramson says. Experiments may reveal whether stimulated macrophages that carry the protective IL1RN CTA haplotype, for example, produce more IL1-Ra protein and fewer pro-inflammatory mediators such as IL-1, cyclooxygenase-2 (COX-2), and tumor necrosis factor (TNF). In the same way, sequential knockouts of other genes in the assemblon may clarify their own contributions to each haplotypes effects.

If the researchers can zero in on the principal drivers of disease through their in vitro experiments, they plan to inject the engineered embryonic stem cells into mice models of osteoarthritis and RA. The in vivo studies of the gene regulatory network may help determine how specific gene variants influence disease outcomes.

The research could have broad implications for understanding IL-1associated inflammatory diseases and for personalizing antiIL-1 therapies. It might be that in personalized medicine, antiIL-1 treatments will be more effective in patients who have a deficiency of IL-1 receptor antagonist, Dr. Abramson says. A patient who produces abundant IL-1Ra, on the other hand, may not benefit from receiving more of it as a therapy. Alternatively, the research may suggest that the IL1RN haplotypes are exerting their influence mainly by modulating other genes with key roles in the disease pathogenesis. It may be that they will emerge as targets that people hadnt even thought about in those diseases, he says.

Link:
New Research Grant Seeks to Clarify the Role Genes Play in Modulating Inflammation - NYU Langone Health

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