Summary: New research has identified the gene Egr-1 as a critical regulator of immune balance, offering hope for autoimmune disease therapies. In a mouse model of multiple sclerosis, loss of Egr-1 led to reduced regulatory T cell activity and heightened inflammation.
The study showed Egr-1 directly boosts the expression of Foxp3, a protein essential for Treg cells, via the TGF-ฮฒ signaling pathway. Researchers also demonstrated that a natural compound, calycosin, can activate Egr-1, restoring Treg function and alleviating disease symptoms.
Key Facts:
- Egr-1 Role: Egr-1 enhances Foxp3 expression, strengthening regulatory T cells and reducing autoimmune inflammation.
- Disease Link: Mice lacking Egr-1 showed more severe symptoms and fewer Treg cells in a model of multiple sclerosis.
- Therapeutic Potential: The natural compound calycosin activated Egr-1, improving immune balance and disease outcomes.
Source: Research
Autoimmune diseases, such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and rheumatoid arthritis (RA), affect millions of people worldwide.
These conditions arise when the bodyโs immune system fails to distinguish between โselfโ and โforeignโ cells, and mistakenly attacks its own healthy cells, resulting in persistent inflammation and tissue damage.
Central to these autoimmune responses are CD4+ย T cells, a class of immune cells that can either promote or suppress the condition.
Regulatory T cells (Treg) are a special subtype of CD4+ย T cells that act as the immune systemโs peacekeepers. Tregย cells, marked by protein Foxp3, help in suppressing harmful immune responses.
However, when the function of Tregย cells is compromised, as seen in cases of MS and IBD, the immune response is dominated by the Th1 and Th17 cells (other CD4+T cell subtypes), which promote inflammation, further worsening the disease symptoms.
Therefore, boosting the development and activity of Tregย cells is emerging as a promising therapeutic approach, but the mechanisms underlying its effective regulation remain unclear.
In pursuit of a deeper understanding of these mechanisms, a team of Chinese scientists led by Dr. Xiaojun Wu and Dr. Fei Huang from the Shanghai Key Laboratory of Compound Chinese Medicines, SHUTCM, China, and Dr. Weidong Pan from the Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China, explored the role of Early Growth Response Gene 1 (Egr-1) in promoting the activity of Tregย cells.
The study was conducted in a well-established animal model of MS, called experimental autoimmune encephalomyelitis (EAE), to confirm the mechanisms.
The findings of this study were published in Volume 8 ofย Researchย on April 15, 2025.
Elaborating more, Dr. Wu, the lead author of this study, says โWe started by screening the genes that appeared different between mice with mild and severe EAE.โ Further, he adds, โAmong the top identified genes in CD4+ย T cells,ย Egr-1ย stood out as significantly downregulated in severe disease.โ
After identifyingย Egr-1ย as a regulatory gene, the team assessed its role by using genetically engineered mice lackingย Egr-1ย in CD4+ย T cells. These mice were induced with EAE and tracked for disease progression.
The researchers also analyzed the immune cell compositions in the spleen, lymph nodes, and central nervous system of these mice.
โThe mice lackingย Egr-1ย showed worse disease, fewer Tregย cells, and more inflammatory TH17 and TH1 cellsโ explains Dr. Huang.
The researchers also conducted additionalย in vitroย experiments. By analyzing isolated human CD4+ย T cells from MS patients and healthy donors, they confirmed that bothย Egr-1ย andย Foxp3ย levels were reduced in patient samples. Further, to determine whetherย Egr-1ย directly regulatesย Foxp3, the researchers used chromatin immunoprecipitation, which revealed thatย Egr-1ย binds to theย Foxp3ย promoter.
Additionally, using luciferase reporter assays, they also confirmed thatย Egr-1ย binding increasesย Foxp3ย gene activity. They then traced the pathway to TGF-ฮฒ (Transforming Growth Factor Beta) signaling via the Raf/Mek/Erk cascade, which activatesย Egr-1.
โWe identified a unique mechanism ofย Egr-1,โย explains Dr. Pan, โFirst, TGF-ฮฒ activates the Raf/Mek/Erk cascade, which activatesย Egr-1.ย Egr-1ย then directly binds to theย Foxp3ย promoter to enhance its expression, bypassing the classical Smad3-dependent pathway.โ
Whatโs more, the researchers also investigated the effect of a natural compound, Calycosin, which acts as an Egr-1 agonist. Treatment with calycosin restored Treg cell functions and improve clinical outcomes in mice with EAE, but only in those with functional Egr-1.
Overall, the study underscores the essential role ofย Egr-1ย in Tregย cell development and function, identifying it as a central molecular switch in immune regulation.
By elucidating its mechanism and validating the effect of a naturalย Egr-1ย agonist, the study suggests that targetingย Egr-1ย may offer a promising treatment strategy, potentially transforming therapeutic approaches to autoimmune diseases.
About this genetics and multiple sclerosis research news
Author: Tian Tian
Source: Research
Contact: Tian Tian – Research
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Early Growth Response Gene 1 Benefits Autoimmune Disease by Promoting Regulatory T Cell Differentiation as a Regulator of Foxp3” by Weidong Pan et al. Research
Abstract
Early Growth Response Gene 1 Benefits Autoimmune Disease by Promoting Regulatory T Cell Differentiation as a Regulator of Foxp3
Foxp3+ย regulatory T (Treg) cells, as one of the subtypes of CD4+ย T cells, are the crucial gatekeeper in the pathogenesis of self-antigen reactive diseases.
In this context, we demonstrated that the selective ablation of early growth response gene 1 (Egr-1) in CD4+ย T cells exacerbated experimental autoimmune encephalomyelitis (EAE) in murine models.
The absence of Egr-1 in CD4+ย T cells, obtained from EAE mice and naรฏve CD4+ย T cells, impeded the differentiation and influence of Treg. Importantly, in CD4+ย T cells of multiple sclerosis patients, both Egr-1 and Foxp3 were found to decrease.
Further studies showed that distinct from the classical Smad3 route, TGF-ฮฒ could activate Egr-1 through the RafโErk signaling route to promote Foxp3 genetic modulation, thereby promoting Tregย cell differentiation and reducing EAE inflammation.
A novel natural Egr-1 agonist, calycosin, was found to attenuate EAE progression by regulating the differentiation of Treg.
Together, the above results indicate the value of Egr-1, as a novel Foxp3 transactivator, for the differentiation of Tregย cells in the development of self-antigen reactive diseases.
