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[This corrects the article DOI: 10.3389/fimmu.2025.1671848.].

Background Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by chronic inflammation and multi-organ damage. A central factor in SLE pathogenesis is the excessive production of type I interferon (IFN-I), which drives immune dysregulation. Monocytes, key components of the immune system, significantly contribute to IFN-I production. However, their specific roles in SLE remain incompletely understood. Methods This study utilized bioinformatics and statistical analyses, including robust rank aggregation (RRA), DESeq2, and limma, to analyze transcriptome data from peripheral blood mononuclear cells (PBMCs) and monocytes of SLE patients and healthy controls. Single-cell RNA sequencing (scRNA-seq) data were processed using the Seurat R package to identify and characterize monocyte subsets with a strong IFN-driven gene signature. Flow cytometry was employed to validate key findings, using markers such as CD14, SIGLEC1, and IRF7 to confirm monocyte subset composition. Results Our research has found that monocytes in SLE undergo IFN-driven transcriptional reprogramming, with the upregulation of key interferon signature genes (ISGs), forming the SLE-Related Monocyte Signature (SLERRAsignature). Moreover, the composition of mononuclear phagocyte subsets in SLE patients changes, with an increase trend in the proportion of the CD14Mono8 subset in the flare group. The differentially expressed genes (DEGs) in 13 mononuclear phagocyte subsets of SLE are mainly ISGs, and the expression of ISGs is higher in severe patients. We identified SIGLEC1 + IRF7 + monocytes among these subsets and for the first time discovered this group of cells in the peripheral blood of healthy individuals. In SLE, the enrichment score of the gene set representing SIGLEC1 + IRF7 + monocytes is positively correlated with the severity of SLE. Finally, flow cytometry confirmed that the frequency of CD14 + SIGLEC1 + IRF7 + monocytes in PBMCs was higher in SLE compared with healthy controls. Conclusions Our study found that the expansion of IFN-I-producing monocyte subsets, particularly the CD14 + SIGLEC1 + IRF7 + subset, plays a crucial role in SLE pathogenesis. This subset may serve as a potential biomarker and therapeutic target for managing SLE.

Interferon regulatory factor (IRF) 7 was originally identified as master transcriptional factor that produced IFN-I and regulated innate immune response, subsequent studies have revealed that IRF7 performs a multifaceted and versatile functions in multiple biological processes. In this review, we provide a comprehensive overview on the current knowledge of the role of IRF7 in immunity and autoimmunity. We focus on the latest regulatory mechanisms of IRF7 in IFN-I, including signaling pathways, transcription, translation, and post-translational levels, the dimerization and nuclear translocation, and the role of IRF7 in IFN-III and COVID-19. In addition to antiviral immunity, we also discuss the role and mechanism of IRF7 in autoimmunity, and the further research will expand our understanding of IRF7.

Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factors (IRFs) family, is located downstream of the pattern recognition receptors (PRRs)-mediated signaling pathway and is essential for the production of type I interferon (IFN-I). Activation of IRF7 inhibits various viral and bacterial infections and suppresses the growth and metastasis of some cancers, but it may also affect the tumor microenvironment and promote the development of other cancers. Here, we summarize recent advances in the role of IRF7 as a multifunctional transcription factor in inflammation, cancer and infection by regulating IFN-I production or IFN-I-independent signaling pathways.

Hepatocellular carcinoma (HCC) is a major global health challenge. Chemotherapy can cause HCC cells to become senescent. Senescent HCC cells play an important role in inhibiting or promoting cancer by producing extracellular vesicles with a senescence-associated secretory phenotype (EV-SASP). miRNA can be strongly upregulated in EV-SASP during the aging process and can substantially alter the phenotypic characteristics of cells. MiRNA microarray analysis revealed that miRNA-146a-5p was highly expressed in oxaliplatin- and H O -induced senescent Huh7 cells, and RT‒PCR confirmed its significant upregulation in exosomes. The transcriptome sequencing results of Huh7 cells overexpressing miRNA-146a-5p suggested that miRNA-146a-5p could regulate HCC cell glycolysis. Subsequently, a dual luciferase assay was used to verify whether miRNA-146a-5p can interact with IRF7 to promote aging. The key functions of miRNA-146a-5p and IRF7 in aerobic glycolysis in liver cancer cells were determined through experiments analyzing glucose uptake, lactate production, the oxygen consumption rate (OCR) and the proton efflux rate (PER). Subsequently, the regulatory effect of IRF7 on the key glycolytic gene PFKL was confirmed through luciferase reporter assays. The western blot experiment results showed that miR-146a-5p can activate CHK2 and p53 phosphorylated proteins by targeting IRF7, and upregulate p21 protein. Overexpression of miRNA-146a-5p effectively inhibited the aerobic glycolytic function of HCC cells. Moreover, silencing IRF7 effectively inhibited aerobic glycolysis. MiR-146a-5p. MiR-146a-5p can activate the phosphorylation of CHK2 phosphorylation protein and its downstream protein p53 by targeting IRF7, and the activated p53 upregulates the expression of p21. Our study revealed that exosomal miRNA-146a-5p produced by aging HCC cells, can inhibit HCC cell proliferation through inhibiting aerobic glycolysis and promote HCC cell aging by activating CHK2/p53/p21 signaling way by targeting IRF7.

Objective To investigate the mechanism of action of Srg3 in acute lung injury caused by sepsis. Methods First, a sepsis-induced acute lung injury rat model was established using cecal ligation and puncture (CLP). RNA sequencing (RNA-seq) was used to screen for highly expressed genes in sepsis-induced acute lung injury (ALI), and the results showed that Srg3 was significantly upregulated. Then, SWI3-related gene 3 ( Srg3 ) was knocked down using AAV9 vector in vivo, and changes in ALI symptoms in rats were analyzed. In vitro experiments were conducted by establishing a cell model using lipopolysaccharide (LPS)-induced BEAS-2B cells and coculturing them with phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells to analyze macrophage polarization. Next, downstream signaling pathways regulated by Srg3 and transcription factors involved in regulating Srg3 expression were analyzed using the KEGG database. Finally, gain-of-loss functional validation experiments were performed to analyze the role of downstream signaling pathways regulated by Srg3 and transcription factors involved in regulating Srg3 expression in sepsis-induced acute lung injury. Results Srg3 was significantly upregulated in sepsis-induced acute lung injury, and knocking down Srg3 significantly improved the symptoms of ALI in rats. Furthermore, in vitro experiments showed that knocking down Srg3 significantly weakened the inhibitory effect of LPS on the viability of BEAS-2B cells and promoted alternative activation phenotype (M2) macrophage polarization. Subsequent experiments showed that Srg3 can regulate the activation of the NF-κB signaling pathway and promote ferroptosis. Specific activation of the NF-κB signaling pathway or ferroptosis significantly weakened the effect of Srg3 knockdown. It was then found that Srg3 can be transcriptionally activated by interferon regulatory factor 7 (Irf7), and specific inhibition of Irf7 significantly improved the symptoms of ALI. Conclusions Irf7 transcriptionally activates the expression of Srg3 , which can promote ferroptosis and activate classical activation phenotype (M1) macrophage polarization by regulating the NF-κB signaling pathway, thereby exacerbating the symptoms of septic lung injury. Highlights Srg3 is highly expressed in sepsis-induced acute lung injury. Knockdown of Srg3 suppresses lung injury symptoms in septic rats. Srg3 regulates NF-κB signaling pathway and ferroptosis. Irf7 transcriptionally regulates Srg3 and activates its transcriptional activity in sepsis-induced acute lung injury. The overexpression of Irf7 weakens the beneficial effect of Srg3 knockdown on improving sepsis-induced acute lung injury.

Background Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS–STING in SAP-induced lung injury (LI) remains unknown. Methods Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS −/− and sting −/− mice . Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro. Results SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS / STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA–cGAS–STING axis and the NLRP3–pyroptosis axis. Conclusions Negative regulation of any molecule in the mtDNA–cGAS–STING–IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.

Background The BIN1 locus contains the second-most significant genetic risk factor for late-onset Alzheimer’s disease. BIN1 undergoes alternate splicing to generate tissue- and cell-type-specific BIN1 isoforms, which regulate membrane dynamics in a range of crucial cellular processes. Whilst the expression of BIN1 in the brain has been characterized in neurons and oligodendrocytes in detail, information regarding microglial BIN1 expression is mainly limited to large-scale transcriptomic and proteomic data. Notably, BIN1 protein expression and its functional roles in microglia, a cell type most relevant to Alzheimer’s disease, have not been examined in depth. Methods Microglial BIN1 expression was analyzed by immunostaining mouse and human brain, as well as by immunoblot and RT-PCR assays of isolated microglia or human iPSC-derived microglial cells. Bin1 expression was ablated by siRNA knockdown in primary microglial cultures in vitro and Cre-lox mediated conditional deletion in adult mouse brain microglia in vivo. Regulation of neuroinflammatory microglial signatures by BIN1 in vitro and in vivo was characterized using NanoString gene panels and flow cytometry methods. The transcriptome data was explored by in silico pathway analysis and validated by complementary molecular approaches. Results Here, we characterized microglial BIN1 expression in vitro and in vivo and ascertained microglia expressed BIN1 isoforms. By silencing Bin1 expression in primary microglial cultures, we demonstrate that BIN1 regulates the activation of proinflammatory and disease-associated responses in microglia as measured by gene expression and cytokine production. Our transcriptomic profiling revealed key homeostatic and lipopolysaccharide (LPS)-induced inflammatory response pathways, as well as transcription factors PU.1 and IRF1 that are regulated by BIN1. Microglia-specific Bin1 conditional knockout in vivo revealed novel roles of BIN1 in regulating the expression of disease-associated genes while counteracting CX3CR1 signaling. The consensus from in vitro and in vivo findings showed that loss of Bin1 impaired the ability of microglia to mount type 1 interferon responses to proinflammatory challenge, particularly the upregulation of a critical type 1 immune response gene, Ifitm3 . Conclusions Our convergent findings provide novel insights into microglial BIN1 function and demonstrate an essential role of microglial BIN1 in regulating brain inflammatory response and microglial phenotypic changes. Moreover, for the first time, our study shows a regulatory relationship between Bin1 and Ifitm3 , two Alzheimer’s disease-related genes in microglia. The requirement for BIN1 to regulate Ifitm3 upregulation during inflammation has important implications for inflammatory responses during the pathogenesis and progression of many neurodegenerative diseases. Graphical Abstract

Objectives Rheumatoid arthritis (RA) involves synovial inflammation driven by pathogenic macrophages, whose polarization is regulated by transcription factors (TFs). Interferon regulatory factor 7 (IRF7) is an innate immune regulator, but its role in RA macrophage-mediated inflammation and cartilage destruction remains unclear. This study aimed to define IRF7-dependent regulatory pathways in RA macrophages and evaluate their therapeutic potential. Methods Single-cell RNA sequencing (scRNA-seq) data and SCENIC analysis were used to identify TF-enriched macrophage subpopulations in the RA synovium. Chromatin immunoprecipitation sequencing data (ChIP-seq) were used to map IRF7 binding sites, and bulk RNA-seq data were used to analyse M1 polarization responses. Functional validation included IRF7 knockdown in human monocytes and intra-articular siRNA in a collagen-induced arthritis (CIA) mouse model to assess inflammatory genes, macrophage polarization, and joint pathology. Results A CD48 high S100A12 + proinflammatory macrophage subset was expanded in RA and enriched for IRF7 activity and downstream genes (PTGS2, CXCL10, NF-κB1, and IL-1β). IRF7 directly regulates these genes, and its knockdown reduces M1 polarization and inflammatory gene expression in vitro. In CIA mice, local IRF7 silencing attenuated joint inflammation, synovial hyperplasia, and bone erosion, which correlated with decreased proinflammatory macrophages and increased regulatory T cells. Conclusions IRF7 appears to promote pathogenic macrophage polarization and inflammatory signaling in RA, and its dysregulation has been associated with disease pathogenesis. Focal IRF7 perturbation can dampen pro-inflammatory networks, suggesting a potentially selective approach for tempering synovial inflammation while limiting systemic immunosuppression. Key messages IRF7 is enriched in a CD48 high S100A12 + proinflammatory macrophage subset in the RA synovium and directly regulates inflammatory genes (PTGS2, CXCL10, NF-κB1, and IL-1β). Knockdown of IRF7 reduces M1 macrophage polarization and inflammatory gene expression in vitro. Local IRF7 silencing in a collagen-induced arthritis mouse model attenuates joint inflammation, synovial hyperplasia, and bone erosion while increasing regulatory T cells. Local targeting of IRF7 offers a precise therapeutic strategy to mitigate RA synovial inflammation without systemic immunosuppression.

Interferon regulatory factor 7 (IRF7) was originally identified in the context of Epstein–Barr virus (EBV) infection, and has since emerged as the crucial regulator of type I interferons (IFNs) against pathogenic infections, which activate IRF7 by triggering signaling cascades from pathogen recognition receptors (PRRs) that recognize pathogenic nucleic acids. Moreover, IRF7 is a multifunctional transcription factor, underscored by the fact that it is associated with EBV latency, in which IRF7 is induced as well as activated by the EBV principal oncoprotein latent membrane protein-1 (LMP1). Aberrant production of type I IFNs is associated with many types of diseases such as cancers and autoimmune disorders. Thus, tight regulation of IRF7 expression and activity is imperative in dictating appropriate type I IFN production for normal IFN-mediated physiological functions. Posttranslational modifications have important roles in regulation of IRF7 activity, exemplified by phosphorylation, which is indicative of its activation. Furthermore, mounting evidence has shed light on the importance of regulatory ubiquitination in activation of IRF7. Albeit these exciting findings have been made in the past decade since its discovery, many questions related to IRF7 remain to be addressed.