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Interferons (IFNs) are a group of cytokines with a well-established antiviral function. They can be induced by viral infection, are secreted and bind to specific receptors on the same or neighbouring cells to activate the expression of hundreds of IFN stimulated genes (ISGs) with antiviral function. Type I IFN has been known for more than half a century. However, more recently, type III IFN (IFNλ, IL-28/29) was shown to play a similar role and to be particularly important at epithelial surfaces. Here we show that airway epithelia, the primary target of influenza A virus, produce both IFN I and III upon infection, and that induction of both depends on the RIG-I/MAVS pathway. While IRF3 is generally regarded as the transcription factor required for initiation of IFN transcription and the so-called \"priming loop\", we find that IRF3 deficiency has little impact on IFN expression. In contrast, lack of IRF7 reduced IFN production significantly, and only IRF3(-/-)IRF7(-/-) double deficiency completely abolished it. The transcriptional response to influenza infection was largely dependent on IFNs, as it was reduced to a few upregulated genes in epithelia lacking receptors for both type I and III IFN (IFNAR1(-/-)IL-28Rα(-/-)). Wild-type epithelia and epithelia deficient in either the type I IFN receptor or the type III IFN receptor exhibit similar transcriptional profiles in response to virus, indicating that none of the induced genes depends selectively on only one IFN system. In chimeric mice, the lack of both IFN I and III signalling in the stromal compartment alone significantly increased the susceptibility to influenza infection. In conclusion, virus infection of airway epithelia induces, via a RIG-I/MAVS/IRF7 dependent pathway, both type I and III IFNs which drive two completely overlapping and redundant amplification loops to upregulate ISGs and protect from influenza infection.

Innate antiviral immunity deteriorates with aging but how this occurs is not entirely clear. Here we identified SIRT1-mediated DNA-binding domain (DBD) deacetylation as a critical step for IRF3/7 activation that is inhibited during aging. Viral-stimulated IRF3 underwent liquid–liquid phase separation (LLPS) with interferon (IFN)-stimulated response element DNA and compartmentalized IRF7 in the nucleus, thereby stimulating type I IFN (IFN-I) expression. SIRT1 deficiency resulted in IRF3/IRF7 hyperacetylation in the DBD, which inhibited LLPS and innate immunity, resulting in increased viral load and mortality in mice. By developing a genetic code expansion orthogonal system, we demonstrated the presence of an acetyl moiety at specific IRF3/IRF7 DBD site/s abolish IRF3/IRF7 LLPS and IFN-I induction. SIRT1 agonists rescued SIRT1 activity in aged mice, restored IFN signaling and thus antagonized viral replication. These findings not only identify a mechanism by which SIRT1 regulates IFN production by affecting IRF3/IRF7 LLPS, but also provide information on the drivers of innate immunosenescence.The deacetylase SIRT1 regulates IRF3/IRF7-mediated antiviral interferon signaling. Here the authors show that SIRT1 deactylates the DNA-binding domain resulting in liquid–liquid phase separation of IRF3/IRF7 and that this signaling is inhibited in aging, an effect that can be reversed with a SIRT1 agonist to restore antiviral response.

The authors identify Irf7 and associated interferon signaling as an important factor suppressing bone metastasis of breast cancers. Irf7 is lost in experimental metastasis and human bone metastastic tissue, and this fosters an immunosuppressive environment that facilitates metastasis. Manipulating this innate immune signaling pathway emerging from tumor cells by interferon administration had beneficial effects in mouse models by reducing bone metastasis and increasing survival time. Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8 + T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis–free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis.

There is significant variability in antidepressant treatment outcome, with ∼30–40% of patients with major depressive disorder (MDD) not presenting with adequate response even following several trials. To identify potential biomarkers of response, we investigated peripheral gene expression patterns of response to antidepressant treatment in MDD. We did this using Affymetrix HG-U133 Plus2 microarrays in blood samples, from untreated individuals with MDD ( N =63) ascertained at a community outpatient clinic, pre and post 8-week treatment with citalopram, and used a regression model to assess the impact of gene expression differences on antidepressant response. We carried out technical validation of significant probesets by quantitative reverse transcriptase PCR and conducted central nervous system follow-up of the most significant result in post-mortem brain samples from 15 subjects who died during a current MDD episode and 11 sudden-death controls. A total of 32 probesets were differentially expressed according to response to citalopram treatment following false discovery rate correction. Interferon regulatory factor 7 ( IRF7 ) was the most significant differentially expressed gene and its expression was upregulated by citalopram treatment in individuals who responded to treatment. We found these results to be concordant with our observation of decreased expression of IRF7 in the prefrontal cortex of MDDs with negative toxicological evidence for antidepressant treatment at the time of death. These findings point to IRF7 as a gene of interest in studies investigating genomic factors associated with antidepressant response.

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.

The roles of individual microRNAs in the CD8 + T cell response remain mostly unexplored. Katsikis and colleagues show that miR-155 regulates type I interferon responsiveness and CD8 + T cell responses to pathogens in vivo . We found upregulation of expression of the microRNA miR-155 in primary effector and effector memory CD8 + T cells, but low miR-155 expression in naive and central memory cells. Antiviral CD8 + T cell responses and viral clearance were impaired in miR-155-deficient mice, and this defect was intrinsic to CD8 + T cells, as miR-155-deficient CD8 + T cells mounted greatly diminished primary and memory responses. Conversely, miR-155 overexpression augmented antiviral CD8 + T cell responses in vivo . Gene-expression profiling showed that miR-155-deficient CD8 + T cells had enhanced type I interferon signaling and were more susceptible to interferon's antiproliferative effect. Inhibition of the type I interferon–associated transcription factors STAT1 or IRF7 resulted in enhanced responses of miR-155-deficient CD8 + T cells in vivo . We have thus identified a previously unknown role for miR-155 in regulating responsiveness to interferon and CD8 + T cell responses to pathogens in vivo .

Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder associated with voiding symptoms and pain in the pelvic or perineal area. Macrophages, particularly the pro-inflammatory M1 subtype, are crucial initiating of CP/CPPS. Interferon regulatory factor 7 (Irf7) has been implicated in promoting M1 polarization, contributing to the onset and progression of autoimmunity. However, the role of Irf7 in the etiology and progression of CP/CPPS remains unclear. Method We established the experimental autoimmune prostatitis (EAP) mouse model by subcutaneous injection of prostate antigen combined with complete Freund’s adjuvant. Six weeks after the first immunization, we analyzed the prostates, spleen, and blood to assess the degree of prostate inflammation, Irf7 expression levels, glycolysis, and M1 polarization to evaluate whether Irf7 could exacerbate the development of EAP by enhancing Hif-1α transcription, thereby increasing glycolysis and M1 polarization. Further investigations included sh-Irf7 intervention, Dimethyloxalylglycine (a Hif-1α agonist), and in vitro M1 polarization experiments. We also employed ChIP assays, dual-luciferase reporter assays, and q-PCR to explore if Irf7 could directly interact with the Hif-1α promoter in macrophages. Results In the EAP mouse and cell models, elevated Irf7 expression was observed in inflamed tissues and cells. Reducing Irf7 expression decreased M1 cell glycolysis by inhibiting the nuclear translocation of Hif-1α, thus mitigating M1 cell polarization. Additionally, Irf7 was identified as a transcription factor that regulates Hif-1α transcription by interacting with its promoter in macrophages, confirmed through ChIP and dual-luciferase assays. Co-culturing macrophage cells with 3T3 fibroblasts with reduced Irf7 levels resulted in decreased fibrosis, and a significant reduction in prostate tissue fibrosis was noted in mice with Irf7 knockdown. Conclusion Our findings indicate that Irf7 can contribute to the development and progression of CP/CPPS by promoting glycolysis, which can enhance both M1 polarization as well as interstitial fibrosis in the prostate. This process was found to be mediated by the upregulation of Hif-1α transcription, presenting new potential therapeutic targets for managing CP/CPPS.

Interferon regulatory factors (IRFs) are innate immune transcription factors responsible for inducing the expression of type I interferons (IFN-I), which combat pathogen invasions via initiating the downstream Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway. Among them, IRF7 plays a central role by forming heterodimers with IRF3 to initiate IFN-I production and is therefore frequently targeted by viruses to evade immune detection. Contrary to this common paradigm, we show that IRF7 is activated and upregulated by the retrovirus human T-cell leukemia virus type 1 (HTLV-1), via its oncoprotein HBZ. Moreover, IRF7 is highly expressed in HTLV-1 induced CD4 T-cell malignancy named adult T-cell leukemia/lymphoma (ATLL), and promotes the proliferation of infected cells both in vitro and in vivo. Intriguingly, HBZ is able to interfere with the interaction of IRF7 and IRF3, suppressing IFN-I pathway activation. On the other hand, IRF7 was found to upregulate and activate STAT5B, a transcription factor of the JAK-STAT pathway frequently mutated in hematological malignancies. Together, these findings reveal a mechanism by which HTLV-1 hijacks a critical innate immune effector to sustain persistent infection and drive oncogenesis without activating antiviral IFN-I pathway. In this work, authors show that HTLV-1 subverts the typical antiviral role of the innate immune effector protein IRF7; instead of triggering an IFN-I response, the virus uses IRF7 to promote the growth of infected cells by establishing an oncogenic IRF7-STAT5B axis via HBZ protein.

Combining the kinase inhibitor sorafenib with allogeneic stem cell transplantation boosts immune responses against a subtype of acute myelogenous leukemia, suggesting potential clinical benefit. Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD + leukemia cells. This synergized with the allogeneic CD8 + T cell response, leading to long-term survival in six mouse models of FLT3-ITD + AML. Sorafenib-related IL-15 production caused an increase in CD8 + CD107a + IFN-γ + T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro . Human FLT3-ITD + AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 + T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7–IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and systemic lupus erythematosus (SLE), glomerulonephritis is a severe kidney complication driven by immune cells, including T cells. However, the mechanisms underlying T cell activation in these contexts remain elusive. Here we report that in patients with AAV and SLE, type I interferon (IFN-I) induces T cell differentiation into interferon-stimulated genes-expressing T (ISG-T) cells, which are characterized by an elevated IFN-I signature, an immature phenotype, and cytotoxicity in inflamed tissue. Mechanistically, IFN-I stimulates the expression of interferon regulatory factor 7 (IRF7) in T cells, which in turn induces granzyme B production. In mice, blocking IFN-I signaling reduces IRF7 and granzyme B expression in T cells, thus ameliorating glomerulonephritis. In parallel, spatial transcriptomic analyses of kidney biopsies from patients with AAV or SLE reveal an elevated ISG signature and the presence of ISG-T cells in close proximity to plasmacytoid dendritic cells, the primary producers of IFN-I. Our results from both patients and animal models thus suggest that IFN-I production in inflamed tissue may drive ISG-T cell differentiation to expand the pool of cytotoxic T cells in autoimmune diseases. Glomerulonephritis is a frequent complication of autoimmune diseases, and involves aberrant activation of immune cells, but the underlying insights remain unclear. Here the authors use both patient data and a mouse glomerulonephritis model to show that increased type I interferon may expand a subset of pro-inflammatory T cells for subsequent kidney pathology.