EGR1 transcription factor has distinct roles in early and late macrophage maturation, limiting macrophage activation and inflammation.
PHILADELPHIA – (January 13, 2021) – Scientists at the Westar Institute have discovered that Early Growth Response 1 (EGR1), a protein that turns on and off specific genes during the growth of blood cells, prevents the expression of pro-inflammatory genes in macrophages. As part of their job to protect the body from pathogens, macrophages play a major role in initiating, maintaining, and treating inflammation. The discovery broadens the understanding of how macrophages are triggered and disrupted in the inflammatory process, which is critical in many natural and pathological conditions. These results were published online in the journal Science advances.
“By deepening the understanding of the role of EGR1, we shed light on the basic process of macrophage maturation, which is required for many aspects of the immune response including inflammation,” said Alessandro Jardini, Ph.D., assistant professor of gene. The Expression and Organization Program at the Westar Institute and lead author of the study. “Our data indicate that EGR1 acts as a major regulator of inflammation in the macrophage.”
Macrophages are specialized immune cells that destroy foreign substances, cellular debris and cancer cells. Their multi-step maturation of progenitor cells in the bone marrow requires the concerted action of important transcription factors that regulate the expression of specific genes. EGR1 is one such factor, but its function has remained elusive.
In response to tissue damage and infection, immune system white blood cells called monocytes can leave the bloodstream and infiltrate tissues, where they undergo a detailed developmental program and mature into macrophages. Macrophages have the ability to “eat” pathogens, enhance inflammation and elicit pathogen-specific immune responses.
The molecular mechanisms underlying this maturation process are not well defined. The same set of transcription factors involved in the early development of monocytes was thought to be involved in converting monocytes into macrophages.
Gardini and colleagues used a model for re-differentiation of monocytes into macrophages in vitro and performed a systematic genetic analysis of EGR1’s role in this process. They found that EGR1 binds to different DNA regulation regions in delayed differentiation macrophages unlike progenitor cells that differentiate into monocytes.
The laboratory previously uncovered a mechanism whereby EGR1 regulates gene expression in monocytes and macrophages through interaction with enhancers. These are short regulatory DNA sequences that, when linked to specific transcription factors, increase the expression of linked genes.
In the new study, researchers found that EGR1 suppresses inflammation promoters in developing and mature macrophages, limiting their activation and immune response.
“Our results indicate that EGR1’s role in modulating inflammation may extend beyond blood cell growth and be relevant to controlling inflammation in health and disease conditions,” said Avery Zuko, Ph.D., postdoctoral researcher in the Jardini lab. And co-author of the study.
Co-authors: Marco Trezzino (co-first author), Sandra Dilliard, Vang Wang, Elisa Barberry, Filippo
Viglia and Dmitry Gabrielovich from Westar.
Work supported by: National Institutes of Health (NIH) awards 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 Westar facilities was provided through the Cancer Center Support Grant P30 CA010815.
Publication information: EGR1 is the gatekeeper for inflammation promoters in human macrophages, Science advances (2021). Online publishing.
The Westar Institute is a leading international biomedical research institute with special expertise in cancer research and vaccine development. Founded in 1892 as the first non-profit independent biomedical research institute in the United States, Westar has been awarded the prestigious cancer center title from the National Cancer Institute since 1972. The institute has been actively working to ensure that research progress moves from the laboratory to the clinic as quickly as possible. wistar.org.