Summary
Using a database of cellular signatures and a combination of gene editing tools, expression assays and advanced sequencing techniques the authors elucidate in their work how a specific genetic locus on chromosome 21 (chr21q22) influences macrophage-mediated inflammation through the ETS2 pathway. A common variation of this gene locos on chromosome 21 predisposes for several autoinflammatory diseases including Takayasu arteritis (TAK), inflammatory bowel disease, primary sclerosing cholangitis and ankylosing spondylitis. ETS2 is part of the ETS (E26 transformation-specific) family of transcription factors, which are involved in regulating a wide range of cellular processes, including cell proliferation, differentiation, and apoptosis, especially in macrophages. Overexpression of ETS2 was found to be associated with an upregulation of multiple drug targets such as TNF and IL-23.

The investigators particularly focused on identifying single nucleotide polymorphisms (SNPs) within the enhancer regions that influence ETS2 and their role in inflammatory macrophages. By using a variety of techniques like CRISPR-Cas9 genome editing, expression assays, chromatin immunoprecipitation sequencing (ChIP-seq), and single-cell RNA sequencing, they aimed to uncover the functional consequences of genetic variations in the chr21q22 region.

The study identified several enhancer elements within the chr21q22 locus that are essential for regulating ETS2 expression and downstream inflammatory genes in macrophages. Deleting these enhancers significantly reduced ETS2 levels, leading to a dampened inflammatory response. Specific SNPs within these enhancers were found to alter transcription factor binding, thus modulating ETS2 activity and macrophage activation.

Furthermore, the authors identified MEK inhibitors as a class of small molecules that can modulate the ETS2 pathway and simultaneously affecting multiple cytokines, including TNF and IL-23. They validated the anti-inflammatory activity of these MEK inhibitors in vitro and ex vivo. Specifically, they examined the expression of ETS2-regulated genes in Crohn’s disease patient biopsies and inflammatory macrophages from primary sclerosing cholangitis (PSC) liver tissue, demonstrating the potential therapeutic application of MEK inhibitors in diseases associated with the chr21q22 locus. However, prolonged use of MEK inhibitors may cause several side effects due to their impact on various tissues. Therefore, directly targeting ETS2 or delivering MEK inhibitors specifically to macrophages using antibody-drug conjugates could offer a safer method to reduce ETS2-driven inflammation.

Impact on Patient Treatment and Future Perspectives
This study highlights the pivotal role of the ETS2 pathway in macrophage-mediated inflammation, providing new insights into the molecular mechanisms driving TAK. By pinpointing specific genetic elements that regulate ETS2 expression and macrophage function, new therapeutic targets, which modulate ETS2 activity, or its regulatory network may be identified. These drugs potentially mitigate inflammation and may slow disease progression in TAK patients. Furthermore, the identified SNPs within the enhancer regions could also serve as biomarkers for assessing disease risk and tailoring personalized treatment strategies.

References
[1] A disease-associated gene desert directs macrophage inflammation through ETS2. Stankey CT. et al. Nature. 2024 Jun;630(8016):447-456. doi: 10.1038/s41586-024-07501-1. Epub 2024 Jun 5.
Composed by
Dr. med. Andrea Gloor
Resident Doctor and Vice President VASAS