New Study Published in Nature Finds Genetic Pathway for Autoimmune Inflammation Relevant to Multiple Disease Processes
August 15, 2024
A recent multicenter collaborative study published in Nature, titled “A Disease-Associated Gene Desert Directs Macrophage Inflammation Through ETS2” provides a significant advancement in our understanding of the molecular mechanisms of inflammatory bowel disease (IBD), but also how the same inflammatory pathway modulates the inflammatory response in other autoimmune disorders, including Takayasu arteritis and ankylosing spondylitis.
Contributing to the research study from the UPMC Division of Rheumatology and Clinical Immunology was Amr H. Sawalha, MD. Dr. Sawalha is professor of Pediatrics, Medicine, and Immunology at the University of Pittsburgh School of Medicine. He holds the Vincent Londino Endowed Chair and is director of the Division of Pediatric Rheumatology at UPMC Children’s Hospital of Pittsburgh. Dr. Sawalha is director of the Lupus Center of Excellence that spans the clinical and research enterprises of UPMC and the University of Pittsburgh.
Dr. Sawalha’s research program focuses on the genetic and epigenetic contributions to the pathogenesis of systemic autoimmune and inflammatory diseases. His team applies state-of-the-art genomic, epigenomic, and bioinformatics methodologies, and subsequent functional studies using both in vitro and in vivo systems to identify and characterize genetic loci and pathways involved in the pathogenesis of immune-mediated diseases.
"Our lab initially observed the link between the gene desert on chromosome 21q22 and ETS2 in a previous study we published on Takayasu arteritis,” says Dr. Sawalha. “This new collaborative research has functionally characterized the genetic effect in a way that is highly relevant to multiple immune-mediated diseases, including IBD and Takayasu arteritis. The findings highlight the importance of ETS2 as a central regulator of inflammation, one that may be amenable for targeted therapeutic interventions, including from existing drugs."
Study Overview and Main Findings
The research identified ETS2 as a primary regulator of inflammation in macrophages. The research team found that a specific region on chromosome 21q22, which was previously linked to multiple autoimmune diseases, interacts with the ETS2 gene, increasing its expression. This finding was confirmed through gene editing techniques that showed deleting this region significantly reduced ETS2 expression, which highlights its central role in the inflammatory response of innate immune system cells.
By overexpressing ETS2 in resting, nonactivated macrophages, the researchers were able to create a similar type of inflammatory state seen in diseases associated with chromosome 21q22. The induced inflammatory state in the resting macrophages showed upregulation of key inflammatory mediators and cytokines like tumor necrosis factor (TNF) and interleukin-23 (IL-23), showing how ETS2 activation promotes inflammation.
It is important to note that the genetic and molecular functional data from the research suggest that the ETS2 pathway is relevant not only to IBD but also to other autoimmune diseases. This shared pathway shows the broader significance of ETS2 regulation in autoimmune inflammatory conditions.
By disrupting the ETS2 activation in inflammatory macrophages, the research team found broad changes in gene expression which decreased the production of several inflammatory molecules but also altered cytokine production, phagocytosis, and reactive oxygen species (ROS) production. Inhibiting ETS2 also influenced macrophage metabolism through changes in glycolysis and oxidative phosphorylation.
The Role of MEK Inhibitors as Potential Therapeutic
A significant finding of the study was the team’s identification of a class of small molecules called MEK inhibitors that can reduce the activity of ETS2. MEK inhibitors block the MEK enzyme, part of a signaling pathway that activates various cellular processes, including inflammation. By inhibiting this pathway, MEK inhibitors effectively decrease the inflammatory response mediated by ETS2.
The study's experiments showed that treating macrophages with MEK inhibitors resulted in reduced production of inflammatory molecules, mirroring the effects of lowering ETS2 activity. This finding suggests that MEK inhibitors could be a promising therapeutic strategy for treating autoimmune diseases characterized by excessive inflammation if they can be targeted specifically at the population of macrophages driving the inflammatory response.
“While there are currently MEK inhibitors on the market as cancer therapeutics, we need to find a way to specifically target only the macrophage activity in order to avoid downstream toxicities of systemic disruption of the MEK pathway, a pathway that is essential in other physiologic processes,” says Dr. Sawalha.
Clinical Implications for Potential Therapeutic Development
The discovery of ETS2 as a key regulator of inflammation has important clinical implications for understanding and finding new treatment options for immune-mediated conditions like IBD and Takayasu arteritis. The identification of small molecules that can modulate the ETS2 pathway provides a possible new approach for drug development. Additionally, the relevance of the ETS2 pathway across multiple autoimmune diseases means that successful therapies that target this pathway could benefit a wide range of patients with immune-mediated conditions driven by ETS2.
Read the complete open access paper using the reference link below.
Study Reference
Stankey CT, Bourges C, Haag LM, et al. A Disease-Associated Gene Desert Directs Macrophage Inflammation Through ETS2. Nature. 2024 05 June. 630: 447-456. Open Access.
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