Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice.

Metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH), is a growing concern worldwide, with liver fibrosis being a critical determinant of its prognosis. Monocyte-derived macrophages have been implicated in MASH-associated liver fibrosis, yet their precise roles and the underlying differentiation mechanisms remain elusive. In this study, we unveil a key orchestrator of this process: long chain saturated fatty acid-Egr2 pathway. Our findings identify the transcription factor Egr2 as the driving force behind monocyte differentiation into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Notably, Egr2-deficiency reroutes monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift has a profound impact, suppressing the transition from benign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long-chain saturated fatty acids that accumulate in MASH liver emerge as potent inducers of Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Furthermore, oral oleic acid administration effectively reduces hLAMs in MASH mice. In conclusion, our work not only elucidates the intricate interplay between saturated fatty acids, Egr2, and monocyte-derived macrophages but also highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management.

Deletion of TECRL promotes skeletal muscle repair by up-regulating EGR2.

Myogenic regeneration relies on the proliferation and differentiation of satellite cells. TECRL (trans-2,3-enoyl-CoA reductase like) is an endoplasmic reticulum protein only expressed in cardiac and skeletal muscle. However, its role in myogenesis remains unknown. We show that TECRL expression is increased in response to injury. Satellite cell-specific deletion of TECRL enhances muscle repair by increasing the expression of EGR2 through the activation of the ERK1/2 signaling pathway, which in turn promotes the expression of PAX7. We further show that TECRL deletion led to the upregulation of the histone acetyltransferase general control nonderepressible 5, which enhances the transcription of EGR2 through acetylation. Importantly, we showed that AAV9-mediated TECRL silencing improved muscle repair in mice. These findings shed light on myogenic regeneration and muscle repair.

Antitumor progenitor exhausted CD8+ T cells are sustained by TCR engagement.

The durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8+ T cells (Tpex). Tpex serve as a resource for replenishing effector T cells and preserve their quantity through self-renewal. However, it is unknown how T cell receptor (TCR) engagement affects the self-renewal capacity of Tpex in settings of continued antigen exposure. Here we use a Lewis lung carcinoma model that elicits either optimal or attenuated TCR signaling in CD8+ T cells to show that formation of Tpex in tumor-draining lymph nodes and their intratumoral persistence is dependent on optimal TCR engagement. Notably, attenuated TCR stimulation accelerates the terminal differentiation of optimally primed Tpex. This TCR-reinforced Tpex development and self-renewal is coupled to proximal positioning to dendritic cells and epigenetic imprinting involving increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, this study highlights the critical function of TCR engagement in sustaining Tpex during tumor progression.

Dysfunctional natural killer cells can be reprogrammed to regain anti-tumor activity.

Natural killer (NK) cells are critical to the innate immune system, as they recognize antigens without prior sensitization, and contribute to the control and clearance of viral infections and cancer. However, a significant proportion of NK cells in mice and humans do not express classical inhibitory receptors during their education process and are rendered naturally "anergic", i.e., exhibiting reduced effector functions. The molecular events leading to NK cell anergy as well as their relation to those underlying NK cell exhaustion that arises from overstimulation in chronic conditions, remain unknown. Here, we characterize the "anergic" phenotype and demonstrate functional, transcriptional, and phenotypic similarities to the "exhausted" state in tumor-infiltrating NK cells. Furthermore, we identify zinc finger transcription factor Egr2 and diacylglycerol kinase DGKα as common negative regulators controlling NK cell dysfunction. Finally, experiments in a 3D organotypic spheroid culture model and an in vivo tumor model suggest that a nanoparticle-based delivery platform can reprogram these dysfunctional natural killer cell populations in their native microenvironment. This approach may become clinically relevant for the development of novel anti-tumor immunotherapeutic strategies.

MicroRNA-150-5P regulates Th1/Th2 cytokines expression levels by targeting EGR2 in allergic rhinitis.

BACKGROUND: MiR-150-5p is one of the miRNAs in the expression profile of miRNAs, and in many previous studies, it has been shown that miR-150-5p may play an important role in peripheral blood dendritic cells (DCs) of allergic rhinitis (AR) patients. We sought to investigate the role and mechanism of miR-150-5p in regulating DC function by modulating EGR2 and influencing T cell derivation to promote AR development. METHODS: The expression of miR-150-5p and EGR2 in AR patients was examined by real-time quantitative polymerase chain reaction (qRT-PCR), the expression of IL-4 cytokines in the supernatant of AR patients was tested by enzyme-linked immunosorbent assay (ELISA), and the expression of eosinophils in the supernatant of AR patients was measured by HE staining. The expression of EGR2 was detected by immunohistochemistry and fluorescent m-immunohistochemistry. RESULTS: MiR-150-5p expression was up-regulated and EGR2 expression was down-regulated in peripheral blood DCs from AR patients. miR-150-5p upregulated DCs, which promoted T-cell differentiation. miR-150-5p further regulated EGR2, which suppressed DCs and caused alteration of T-cell differentiation, in turn triggering the occurrence of AR. CONCLUSION: MiR-150-5p and its target gene EGR2 are involved in the development of AR, and DCs foster T-cell differentiation in peripheral blood of AR patients.

Egr2 Deletion in Autoimmune-Prone C57BL6/lpr Mice Suppresses the Expression of Methylation-Sensitive Dlk1-Dio3 Cluster MicroRNAs.

We previously demonstrated that the upregulation of microRNAs (miRNAs) at the genomic imprinted Dlk1-Dio3 locus in murine lupus is correlated with global DNA hypomethylation. We now report that the Dlk1-Dio3 genomic region in CD4+ T cells of MRL/lpr mice is hypomethylated, linking it to increased Dlk1-Dio3 miRNA expression. We evaluated the gene expression of methylating enzymes, DNA methyltransferases (DNMTs), and demethylating ten-eleven translocation proteins (TETs) to elucidate the molecular basis of DNA hypomethylation in lupus CD4+ T cells. There was a significantly elevated expression of Dnmt1 and Dnmt3b, as well as Tet1 and Tet2, in CD4+ T cells of three different lupus-prone mouse strains compared to controls. These findings suggest that the hypomethylation of murine lupus CD4+ T cells is likely attributed to a TET-mediated active demethylation pathway. Moreover, we found that deletion of early growth response 2 (Egr2), a transcription factor gene in B6/lpr mice markedly reduced maternally expressed miRNA genes but not paternally expressed protein-coding genes at the Dlk1-Dio3 locus in CD4+ T cells. EGR2 has been shown to induce DNA demethylation by recruiting TETs. Surprisingly, we found that deleting Egr2 in B6/lpr mice induced more hypomethylated differentially methylated regions at either the whole-genome level or the Dlk1-Dio3 locus in CD4+ T cells. Although the role of methylation in EGR2-mediated regulation of Dlk1-Dio3 miRNAs is not readily apparent, these are the first data to show that in lupus, Egr2 regulates Dlk1-Dio3 miRNAs, which target major signaling pathways in autoimmunity. These data provide a new perspective on the role of upregulated EGR2 in lupus pathogenesis.

EGR2 gene-linked hereditary neuropathies present with a bimodal age distribution at symptoms onset.

BACKGROUND: Mutations in the Early-Growth Response 2 (EGR2) gene cause various hereditary neuropathies, including demyelinating Charcot-Marie-Tooth (CMT) disease type 1D (CMT1D), congenital hypomyelinating neuropathy type 1 (CHN1), Déjerine-Sottas syndrome (DSS), and axonal CMT (CMT2). METHODS: In this study, we identified 14 patients with heterozygous EGR2 mutations diagnosed between 2000 and 2022. RESULTS: Mean age was 44 years (15-70), 10 patients were female (71%), and mean disease duration was 28 years (1-56). Disease onset was before age 15 years in nine cases (64%), after age 35 years in four cases (28%), and one patient aged 26 years was asymptomatic (7%). All symptomatic patients had pes cavus and distal lower limbs weakness (100%). Distal lower limbs sensory symptoms were observed in 86% of cases, hand atrophy in 71%, and scoliosis in 21%. Nerve conduction studies showed a predominantly demyelinating sensorimotor neuropathy in all cases (100%), and five patients needed walking assistance after a mean disease duration of 50 years (47-56) (36%). Three patients were misdiagnosed as inflammatory neuropathy and treated with immunosuppressive drugs for years before diagnosis was corrected. Two patients presented with an additional neurologic disorder, including Steinert's myotonic dystrophy and spinocerebellar ataxia (14%). Eight EGR2 gene mutations were found, including four previously undescribed. INTERPRETATION: Our findings demonstrate EGR2 gene-related hereditary neuropathies are rare and slowly progressive demyelinating neuropathies with two major clinical presentations, including a childhood-onset variant and an adult-onset variant which may mimic inflammatory neuropathy. Our study also expands the genotypic spectrum of EGR2 gene mutations.

Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell-Intrinsic Dysfunction.

Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematologic cancers, but resistance is common and efficacy is limited in solid tumors. We found that CAR T cells autonomously propagate epigenetically programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knockout not only blocks this type I interferon-mediated inhibitory program but also independently expands early memory CAR T cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T cells against chronic antigen-induced exhaustion can be overridden by interferon-ß exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I interferon signaling. Finally, a refined EGR2 gene signature is a biomarker for type I interferon-associated CAR T cell failure and shorter patient survival. These findings connect prolonged CAR T cell activation with deleterious immunoinflammatory signaling and point to an EGR2-type I interferon axis as a therapeutically amenable biological system. SIGNIFICANCE: To improve CAR T cell therapy outcomes, modulating molecular determinants of CAR T cell-intrinsic resistance is crucial. Editing the gene encoding the EGR2 transcriptional regulator renders CAR T cells impervious to type I interferon pathway-induced dysfunction and improves memory differentiation, thereby addressing major barriers to progress for this emerging class of cancer immunotherapies. This article is highlighted in the In This Issue feature, p. 1501.

Temozolomide protects against the progression of glioblastoma via SOX4 downregulation by inhibiting the LINC00470-mediated transcription factor EGR2.

OBJECTIVE: Temozolomide is extensively applied in chemotherapy for glioblastoma with unclear exact action mechanisms. This article seeks to address the potential molecular mechanisms in temozolomide therapy for glioblastoma involving LINC00470. METHODS: Bioinformatics analysis was conducted to predict the potential mechanism of LINC00470 in glioblastoma, which was validated by dual-luciferase reporter, RIP, ChIP, and RNA pull-down assays. LINC00470 expression and the predicted downstream transcription factor early growth response 2 (EGR2) were detected in the collected brain tissues from glioblastoma patients. Following temozolomide treatment and/or gain- and loss-of-function approaches in glioblastoma cells, cell viability, invasion, migration, cycle distribution, angiogenesis, autophagy, and apoptosis were measured. In addition, the expression of mesenchymal surface marker proteins was assessed by western blot. Tumor xenograft in nude mice was conducted for in vivo validation. RESULTS: Mechanistic analysis and bioinformatics analysis revealed that LINC00470 transcriptionally activated SRY-related high-mobility-group box 4 (SOX4) through the transcription factor EGR2. LINC00470 and EGR2 were highly expressed in brain tissues of glioblastoma patients. LINC00470 and EGR2 mRNA expression gradually decreased with increasing concentrations of temozolomide in glioblastoma cells, and SOX4 expression was reduced in cells by temozolomide and LINC00470 knockdown. Temozolomide treatment induced cell cycle arrest, diminished cell viability, migration, invasion, and angiogenesis, and increased apoptosis and autophagy in glioblastoma, which was counteracted by overexpressing LINC00470 or SOX4 but was further promoted by LINC00470 knockdown. Temozolomide restrained glioblastoma growth and angiogenesis in vivo, while LINC00470 or SOX4 overexpression nullified but LINC00470 knockdown further facilitated these trends. CONCLUSION: Conclusively, temozolomide repressed glioblastoma progression by repressing the LINC00470/EGR2/SOX4 axis.

COUP-TFII plays a role in cAMP-induced Schwann cell differentiation and in vitro myelination by up-regulating Krox20.

Schwann cells (SCs) are known to produce myelin for saltatory nerve conduction in the peripheral nervous system (PNS). Schwann cell differentiation and myelination processes are controlled by several transcription factors including Sox10, Oct6/Pou3f1, and Krox20/Egr2. Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan receptor that plays a role in the development and differentiation. However, the role of COUP-TFII in the transcriptional regulatory network of SC differentiation has not been fully identified yet. Thus, the objective of this study was to investigate the role and molecular hierarchy of COUP-TFII during cAMP-induced SC differentiation. Our results showed that dibutyryl-cAMP (db-cAMP) increased expression levels of COUP-TFII along with the expressions of Oct6, Krox20, and myelin-related genes known to be related to SC differentiation. Our mechanistic studies showed that COUP-TFII acted downstream of Hsp90/ErbB2/Gab1/ERK-AKT pathway during db-cAMP-induced SC differentiation. In addition, we found that COUP-TFII induced Krox20 expression by directly binding to Krox20-MSE8 as revealed by chromatin immunoprecipitation assay and promoter activity assay. In line with this, the expression of COUP-TFII was increased before up-regulation of Oct6, Krox20, and myelin-related genes in the sciatic nerves during early postnatal myelination period. Finally, COUP-TFII knockdown by COUP-TFII siRNA or via AAV-COUP-TFII shRNA in SCs inhibited db-cAMP-induced SC differentiation and in vitro myelination of sensory axons, respectively. Taken together, these findings indicate that COUP-TFII might be involved in postnatal myelination through induction of Krox20 in SCs. Our results present a new insight into the transcriptional regulatory mechanism in SC differentiation and myelination.

Early growth response 2 in the mPFC regulates mouse social and cooperative behaviors.

Adolescent social neglect impairs social performance, but the underlying molecular mechanisms remain unclear. Here we report that isolation rearing of juvenile mice caused cooperation defects that were rescued by immediate social reintroduction. We also identified the transcription factor early growth response 2 (Egr2) in the medial prefrontal cortex (mPFC) as a major target of social isolation and resocialization. Isolation rearing increased corticosteroid production, which reduced the expression of Egr2 in the mPFC, including in oligodendrocytes. Overexpressing Egr2 ubiquitously in the mPFC, but not specifically in neurons nor in oligodendroglia, protected mice from the isolation rearing-induced cooperation defect. In addition to synapse integrity, Egr2 also regulated the development of oligodendroglia, specifically the transition from undifferentiated oligodendrocyte precursor cells to premyelinating oligodendrocytes. In conclusion, this study reveals the importance of mPFC Egr2 in the cooperative behavior that is modulated by social experience, and its unexpected role in oligodendrocyte development.

BMSC-Derived Exosomal Egr2 Ameliorates Ischemic Stroke by Directly Upregulating SIRT6 to Suppress Notch Signaling.

Exosomes generated by BMSCs contribute to functional recovery in ischemic stroke. However, the regulatory mechanism is largely unknown. Exosomes were isolated from BMSCs. Tube formation, MTT, TUNEL, and flow cytometry assays were applied to examine cell angiogenesis, viability, and apoptosis. Protein and DNA interaction was evaluated by ChIP and luciferase assays. LDH release into the culture medium was examined. Infarction area was evaluated by TTC staining. Immunofluorescence staining was applied to examine CD31 expression. A mouse model of MCAO/R was established. BMSC-derived exosomes attenuated neuronal cell damage and facilitated angiogenesis of brain endothelial cells in response to OGD/R, but these effects were abolished by the knockdown of Egr2. Egr2 directly bound to the promoter of SIRT6 to promote its expression. The incompetency of Egr2-silencing exosomes was reversed by overexpression of SIRT6. Furthermore, SIRT6 inhibited Notch signaling via suppressing Notch1. Overexpression of SIRT6 and inhibition of Notch signaling improved cell injury and angiogenesis in OGD/R-treated cells. BMSC-derived exosomal Egr2 ameliorated MCAO/R-induced brain damage via upregulating SIRT6 to suppress Notch signaling in mice. BMSC-derived exosomes ameliorate OGD/R-induced injury and MCAO/R-caused cerebral damage in mice by delivering Egr2 to promote SIRT6 expression and subsequently suppress Notch signaling. Our study provides a potential exosome-based therapy for ischemic stroke.

Egr2 and 3 maintain anti-tumour responses of exhausted tumour infiltrating CD8 + T cells.

Although T cells can develop into an exhausted state in the tumour microenvironment, tumour infiltrating T cells (TILs) are important to control tumour growth. By analysing single cell RNA-sequencing data from human tumours, we found that the transcription factors Early Growth Response 2 (EGR2) and 3 were highly induced in TILs, but not peripheral CD8 + T cells, in multiple patient cohorts. We found that deficiency of Egr2 and 3 in T cells resulted in enhanced tumour growth and fewer TILs in mouse models. Egr2 is highly expressed together with checkpoint molecules in a proportion of CD8 + TILs and Egr2high cells exhibit better survival and proliferation than Egr2-/-Egr3-/- and Egr2low TILs. Anti-PD-1 treatment increases Egr2 expression in CD8 + TILs and reduces tumour growth, while anti-PD-1 efficacy is abrogated in the absence of Egr2 and 3. Thus, Egr2 and 3 are important for maintaining anti-tumour responses of exhausted CD8 + TILs.

The Landscape of Early Growth Response Family Members 1-4 in Hepatocellular Carcinoma: Their Biological Roles and Diagnostic Utility.

The incidence of hepatocellular carcinoma (HCC), which is one of the most frequent types of cancer seen all over the world, is steadily growing from year to year. EGR genes are members of the early growth response (EGR) gene family. It has been shown that EGR genes play an increasingly essential role in the development of tumors and the progression of numerous malignancies. However, the possible diagnostic and prognostic roles of EGR genes in HCC have only been examined in a limited number of studies. Expression and methylation data on EGR family members were obtained from TCGA datasets. The prognostic values of EGR members were studied. Additionally, the correlations of EGR members with immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA). In this study, we found that the expression of EGR1, EGR2, EGR3, and EGR4 was distinctly decreased in HCC specimens compared with nontumor specimens. ROC assays confirmed that they have a strong ability in screening HCC specimens from nontumor specimens. According to the findings of Pearson's correlation, EGR1, EGR2, EGR3, and EGR4 were found to have a negative association with the methylation level. Survival study revealed that EGR1, EGR2, and EGR3 were associated with the clinical outcome of HCC patients. Immune cell enrichment analysis demonstrated that the expressions of all EGR members were positively related to the levels of most types of immune cells, such as macrophages, NK cells, B cells, T cells, eosinophils, and CD8 T cells. Overall, the current work demonstrated the expression mode and prognostic value of EGR members in HCC in a comprehensive manner, offering insights for further research of the EGR family as possible clinical biomarkers in HCC.

BCR-Associated Protein 31 Regulates Macrophages Polarization and Wound Healing Function via Early Growth Response 2/C/EBPß and IL-4Rα/C/EBPß Pathways.

The BCR-associated protein 31 (BAP31), a transmembrane protein in the endoplasmic reticulum, participates in the regulation of immune cells, such as microglia and T cells, and has potential functions in macrophages that remain to be unexplored. In this study, we designed and bred macrophage-specific BAP31 knockdown mice to detect the polarization and functions of macrophages. The results revealed that M2 macrophage-associated genes were suppressed in mouse bone marrow-derived macrophages of Lyz2 Cre-BAP31flox/flox mice. Multiple macrophage-associated transcription factors were demonstrated to be able to be regulated by BAP31. Among these factors, C/EBPß was the most significantly decreased and was regulated by early growth response 2. BAP31 could also affect C/EBPß via modulating IL-4Rα ubiquitination and proteasome degradation in IL-4-stimulated macrophages. Furthermore, we found that BAP31 affects macrophages functions, including angiogenesis and skin fibrosis, during the wound healing process through IL-4Rα, as confirmed by infection with adeno-associated virus-short hairpin (sh)-IL-4Rα in Lyz2 Cre-BAP31flox/flox mice. Our findings indicate a novel mechanism of BAP31 in regulating macrophages and provide potential solutions for the prevention and treatment of chronic wounds.

EGR2 is a hub-gene in myocardial infarction and aggravates inflammation and apoptosis in hypoxia-induced cardiomyocytes.

BACKGROUND: Myocardial infarction (MI) is characterized by coronary artery occlusion, ischemia and hypoxia of myocardial cells, leading to irreversible myocardial damage. Therefore, it is urgent to explore the potential mechanism of myocardial injury during the MI process to develop effective therapies for myocardial cell rescue. METHODS: We downloaded the GSE71906 dataset from GEO DataSets, and the R software was used to identify the differentially expressed genes (DEGs) in mouse heart tissues of MI and sham controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed to understand the significantly activated signaling pathways in MI. Protein-protein interaction (PPI) network was constructed to highlight the hub genes in DEGs. The Western Blot, qRT-PCR and TUNEL staining were used to explore the function of hub gene in hypoxia-induced cardiomyocytes in vitro. RESULTS: A total of 235 DEGs were identified in GSE71906 dataset. Functional enrichment analysis revealed that the upregulated genes were primarily associated with the inflammatory response and apoptosis. 20 hub genes were identified in PPI network, and the early growth response 2 (EGR2) was highlighted. In vitro. We confirmed the EGR2 was upregulated induced by hypoxia and revealed the upregulated EGR2 aggravates pro-inflammation and pro-apoptotic genes expression. In addition, EGR2 knockout mitigates hypoxia-induced inflammation and apoptosis in cardiomyocytes. CONCLUSION: The present study identified the EGR2 was a hub gene in myocardial damage during MI process, the excessive EGR2 aggravates hypoxia-induced myocardial damage by accelerating inflammation and apoptosis in vitro. Therefore, targeting EGR2 offers a potential pharmacological strategy for myocardial cell rescue in MI.

EGR2 Deletion Suppresses Anti-DsDNA Autoantibody and IL-17 Production in Autoimmune-Prone B6/lpr Mice: A Differential Immune Regulatory Role of EGR2 in B6/lpr Versus Normal B6 Mice.

Previous studies have reported that deletion of the transcription factor, early growth response protein 2 (EGR2), in normal C57BL/6 (B6) resulted in the development of lupus-like autoimmune disease. However, increased EGR2 expression has been noted in human and murine lupus, which challenges the notion of the autoimmune suppressive role of EGR2 in B6 mice. In this study, we derived both conditional EGR2-/-B6/lpr and EGR2-/-B6 mice to elucidate the immune and autoimmune regulatory roles of EGR2 in autoinflammation (B6/lpr) versus physiologically normal (B6) conditions. We found that conditional EGR2 deletion increased spleen weight, enhanced T cell activation and IFNγ production, and promoted germinal center B cells and LAG3+ regulatory T cells development in both B6/lpr and B6 mice. Nevertheless, EGR2 deletion also showed strikingly differential effects in these two strains on T lymphocyte subsets profile, Foxp3+ Tregs and plasma cell differentiation, anti-dsDNA autoantibodies and immunoglobulins production, and on the induction of IL-17 in in vitro activated splenocytes. Specifically, EGR2 deletion in B6/lpr mice significantly decreased serum levels of anti-dsDNA autoantibodies, total IgG, IgM, IgG1, and IgG2a with reduced plasma cells differentiation. Furthermore, EGR2 deletion in B6/lpr mice had no obvious effect on IgG immunocomplex deposition, medium caliber vessel, and glomeruli inflammation but increased complement C3 immunocomplex deposition and large caliber vessel inflammation in the kidneys. Importantly, we demonstrated that EGR2 deletion in B6/lpr mice significantly reduced pathogenic CD4-CD8-CD3+B220+ double negative T cells, which correlated with the reduced anti-dsDNA autoantibodies in serum and decreased IL-17 production in splenocytes of EGR2-/-B6/lpr mice. Together, our data strongly suggest that the role of EGR2 is complex. The immunoregulatory role of EGR2 varies at normal or autoinflammation conditions and should not be generalized in differential experimental settings.

EGR2-related mixed demyelinating and axonal Charcot-Marie-Tooth disease: An electrodiagnostic, nerve imaging, and histological study.

BACKGROUND AND AIMS: The early growth response 2 gene (EGR2) mutations are associated with a group of hereditary neuropathy, including axonal neuropathy and hypomyelinating neuropathy or Charcot-Marie-Tooth disease (CMT) type 1D. We aim to perform an electrodiagnostic, nerve imaging, and histological study of EGR2-associated neuropathy. MATERIALS AND METHODS: We performed a retrospective analysis of two patients with EGR2-related neurology at our hospital. The neuropathy was confirmed by the nerve conduction study. Nerve imaging and sural biopsies were performed in two patients. RESULTS: Two unrelated boys exhibited early-onset length-dependent neuropathy. Next generation sequencing identified EGR2 gene with previously described E412K mutation in the third zine finger domain in patient 1 and a previously undescribed variant D355N mutation in the first zinc finger domain in patient 2. The magnetic resonance imaging of the lumbosacral plexus showed no abnormalities in patient 1 and thickened lumbosacral plexuses in patient 2. Electrophysiology and nerve biopsies showed a prominent axonal neuropathy, accompanied with demyelinating involvement. CONCLUSION: Therefore, it seemed that the EGR2 mutations could cause not only the known demyelinating type and axonal type but also mixed-type CMT. Our findings expanded the phenotypic heterogeneities of EGR2-associated neuropathy.