News – P.HILADELPHIA – (January 13, 2021) – Scientists at the Wistar Institute have found that Early Growth Response 1 (EGR1), a protein that turns on and off specific genes during blood cell development, inhibits the expression of pro genes -inflammatory in macrophages. As part of their work to protect the body against pathogens, macrophages play a key role in initiating, maintaining and relieving inflammation. The discovery broadens the understanding of how macrophages are secreted and excreted in the inflammatory process, which is crucial in many normal and pathological conditions. These results were published online in the journal Advances in science.
“By deepening understanding of the role of EGR1, we shed light on the underlying process of macrophage maturation, which is essential for many aspects of the immune response including inflammation,” he said. Alessandro Gardini, Ph.D., assistant professor in the Wistar Institute’s Gene Expression & Control Program and lead author of the study. “Our data suggest that EGR1 acts as a key regulator of inflammation in macrophages. ”
Macrophages are special immune cells that destroy foreign matter, cell debris and cancer cells. The multistage maturation of progenitor cells in the bone marrow requires a coordinated action of critical transcription factors that regulate the expression of specific genes. EGR1 is one of these factors but has not been able to fulfill its role.
In response to damage and tight infection, white blood cells of the immune system called monocytes can leave the bloodstream and weave in, where they pass through a complex and mature development program into macrophages. Macrophages have the ability to “eat” pathogens, stimulate inflammation and elicit specific pathogen-specific immune responses.
The molecular mechanisms underlying this maturation process are not well defined. The same set of transcription factors acting in early monocyte development was thought to be involved in the conversion of monocytes to macrophages.
Gardini and colleagues used a model to replicate the differentiation of monocytes to macrophages in vitro and performed a systematic genomic analysis of the role of EGR1 in this process. They found that EGR1 binds to different DNA regulatory regions in late-differentiated macrophages compared to progenitor cells differentiating into monocytes.
Previously the laboratory found a way in which EGR1 regulates gene expression in monocytes and macrophages by interacting with therapists. These are short regulatory DNA sequences that, when linked to specific transcription factors, contribute to the expression of the associated genes.
In the new study, researchers found that EGR1 reverses inflammatory therapies in the development and growth of macrophages, suppressing their activity and immune response.
“Our findings suggest that the role of EGR1 in altering inflammation may extend beyond the development of blood cells and be relevant to the control of inflammation in health and disease settings,” said Avery Zucco, Ph.D. D., a postdoctoral researcher in the Gardini laboratory. and co-author of the study.
Co-authors: Marco Trizzino (co-author), Sandra Deliard, Fang Wang, Elisa Barbieri, FilippoVeglia, and Dmitry Gabrilovich of Wistar.
Work supported by: National Institutes of Health (NIH) grants R01 HL141326 and T32 CA009171; grants from the American Cancer Society (RSG-18-157-01-DMC) and The G. Harold and Leila Y. Mathers Foundation. Support for Wistar Institute facilities was provided by the P30 CA010815 Cancer Center Support Grant.
Publication information: EGR1 is a gateway of inflammatory agents in human macrophages, Science Advances (2021). Online publication.
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