Interferon Receptor Research Articles

CD8+ T Cells Mediate Lethal Lung Pathology in the Absence of PD-L1 and Type I Interferon Signalling following LCMV Infection.

CD8+ T cells are critical to the adaptive immune response against viral pathogens. However, overwhelming antigen exposure can result in their exhaustion, characterised by reduced effector function, failure to clear virus, and the upregulation of inhibitory receptors, including programmed cell death 1 (PD-1). However, exhausted T cell responses can be "re-invigorated" by inhibiting PD-1 or the primary ligand of PD-1: PD-L1. Further, the absence of the type I interferon receptor IFNAR1 also results in T cell exhaustion and virus persistence in lymphocytic choriomeningitis virus Armstrong (LCMV-Arm)-infected mice. In this study, utilizing single- and double-knockout mice, we aimed to determine whether ablation of PD-1 could restore T cell functionality in the absence of IFNAR1 signalling in LCMV-Arm-infected mice. Surprisingly, this did not re-invigorate the T cell response and instead, it converted chronic LCMV-Arm infection into a lethal disease characterized by severe lung inflammation with an infiltration of neutrophils and T cells. Depletion of CD8+ T cells, but not neutrophils, rescued mice from lethal disease, demonstrating that IFNAR1 is required to prevent T cell exhaustion and virus persistence in LCMV-Arm infection, and in the absence of IFNAR1, PD-L1 is required for survival. This reveals an important interplay between IFNAR1 and PD-L1 with implications for therapeutics targeting these pathways.

Mouse Type-I Interferon-Mannosylated Albumin Fusion Protein for the Treatment of Chronic Hepatitis.

Although a lot of effort has been put into creating drugs and combination therapies against chronic hepatitis, no effective treatment has been established. Type-I interferon is a promising therapeutic for chronic hepatitis due to its excellent anti-inflammatory effects through interferon receptors on hepatic macrophages. To develop a type-I IFN equipped with the ability to target hepatic macrophages through the macrophage mannose receptor, the present study designed a mouse type-I interferon-mannosylated albumin fusion protein using site-specific mutagenesis and albumin fusion technology. This fusion protein exhibited the induction of anti-inflammatory molecules, such as IL-10, IL-1Ra, and PD-1, in RAW264.7 cells, or hepatoprotective effects on carbon tetrachloride-induced chronic hepatitis mice. As expected, such biological and hepatoprotective actions were significantly superior to those of human fusion proteins. Furthermore, the repeated administration of mouse fusion protein to carbon tetrachloride-induced chronic hepatitis mice clearly suppressed the area of liver fibrosis and hepatic hydroxyproline contents, not only with a reduction in the levels of inflammatory cytokine (TNF-α) and fibrosis-related genes (TGF-β, Fibronectin, Snail, and Collagen 1α2), but also with a shift in the hepatic macrophage phenotype from inflammatory to anti-inflammatory. Therefore, type-I interferon-mannosylated albumin fusion protein has the potential as a new therapeutic agent for chronic hepatitis.

Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis.

Human metapneumovirus (HMPV) is an important cause of acute lower respiratory infection in children and adults worldwide. There are four genetic subgroups of HMPV and both neutralizing antibodies and T cells contribute to protection. However, little is known about mechanisms of pathogenesis and most published work is based on a few extensively passaged, laboratory-adapted strains of HMPV. In this study, we isolated and characterized a panel of low passage HMPV clinical isolates representing all four genetic subgroups. The clinical isolates exhibited lower levels of in vitro replication compared to a lab-adapted strain. We compared disease phenotypes using a well-established mouse model. Several virulent isolates caused severe weight loss, lung pathology, airway dysfunction, and fatal disease in mice, which was confirmed in three inbred mouse strains. Disease severity did not correlate with lung viral titer, as virulent strains exhibited restricted replication in the lower airway. Virulent HMPV isolates were associated with markedly increased proinflammatory cytokine production and neutrophil influx; however, depletion of neutrophils or genetic ablation of inflammasome components did not reverse disease. Virulent clinical isolates induced markedly increased type I and type III interferon (IFN) secretion in vitro and in vivo. STAT1/2-deficient mice lacking both type I and type III IFN signaling showed reduced disease severity and increased lung viral replication. Inhibition of type I IFN signaling using a blocking antibody or genetic ablation of the type I IFN receptor reduced pathology with minimal effect on viral replication. Conversely, blockade of type III IFN signaling with a neutralizing antibody or genetic ablation of the IFN-lambda receptor had no effect on pathogenesis but restored viral replication. Collectively, these results demonstrate distinct roles for type I and type III IFN in HMPV pathogenesis and immunity.

Altered peripheral blood leukocyte subpopulations, function, and gene expression in children with Down syndrome: implications for respiratory tract infection

ObjectivesWe tested the hypothesis that aberrant expression of Hsa21-encoded interferon genes in peripheral blood immune cells would correlate to immune cell dysfunction in children with Down syndrome (DS). Study designWe performed flow cytometry to quantify peripheral blood leukocyte subtypes and measured their ability to migrate and phagocytose. In matched samples, we measured gene expression levels for constituents of interferon signaling pathways. We screened 49 children, of which 29 were individuals with DS. ResultsWe show that the percentages of two peripheral blood myeloid cell subtypes (alternatively-activated macrophages and low-density granulocytes) in children with DS differed significantly from typical children, children with DS circulate a very different pattern of cytokines vs. typical individuals, and higher expression levels of type III interferon receptor Interleukin-10Rb in individuals with DS correlated with reduced migratory and phagocytic capacity of macrophages. ConclusionsIncreased susceptibility to severe and chronic infection in children with DS may result from inappropriate numbers and subtypes of immune cells that are phenotypically and functionally altered due to trisomy 21 associated interferonopathy.

The impact of polymorphic variants of interferon receptor genes on COVID-19 severity and antibiotic resistance

Single nucleotide substitutions in gene sequence associated with conformational changes in protein receptor or in expression of interferon receptors may explain variations in human susceptibility to infection and severity of COVID-19 along with other well-known risk factors. The study aimed to investigate associations between polymorphic variants of interferon receptor genes, COVID-19 severity and prevalence of antibiotic resistance genes in the gut microbiota. Materials and methods. The study was conducted using a random sample of Arkhangelsk population aged 42 to 76 years (n = 305). The research involved gathering COVID-19 data from the Federal Register, conducting blood tests for SARS-CoV-2 antibodies and polymorphic interferon receptor gene variants, and identifying antibiotic resistance genes in stool samples. Results. During the first 12–15 months of the COVID-19 pandemic, 17.4% of the study participants had symptomatic COVID-19, while 32.8% were asymptomatic. By the Autumn of 2022, symptomatic COVID-19 cases rose up to 36.4%, while asymptomatic cases increased to 61.3%. We reveal an association between the CC genotype of the IFNAR1 gene rs2257167 variant, the presence of the T allele of IFNAR2 gene rs2229207 variant, the CCTT haplotype and symptomatic COVID-19. The GCTC haplotype was associated with pneumonia and COVID-19 severity. In November 2022, macrolide resistance genes were observed in 98.4% of cases, whereas those to beta-lactams and glycopeptides — in 26.9% and 13.8% cases, respectively. Resistance to three classes of antibiotics was observed in 4.9% and was more frequently detected in individuals with the ССТТ haplotype. Genes encoding beta-lactamases were more often found in individuals with the GCTC haplotype, those who had COVID-19 with pneumonia and those who received hospital treatment. Glycopeptide resistance genes were associated with the CC genotype of the rs2257167 variant of IFNAR1 gene. Conclusion. We identified genetic determinants of susceptibility, symptomatic infection and COVID-19 severity. The associations between polymorphic variants of interferon receptor genes and COVID-19 severity can be used to identify people with a genetic predisposition to severe infection and to determine priority groups for vaccination, including the prevention of antibiotic resistance in complicated course of viral infections.

Deficiency of circadian clock gene Bmal1 exacerbates noncanonical inflammasome-mediated pyroptosis and lethality via Rev-erbα-C/EBPβ-SAA1 axis

Circadian arrhythmia has been linked to increased susceptibility to multiple inflammatory diseases, such as sepsis. However, it remains unclear how disruption of the circadian clock modulates molecular aspects of innate immune responses, including inflammasome signaling. Here, we examined the potential role of the circadian clock in inflammasome-mediated responses through myeloid-specific deletion of BMAL1, a master circadian clock regulator. Intriguingly, Bmal1 deficiency significantly enhanced pyroptosis of macrophages and lethality of mice under noncanonical inflammasome-activating conditions but did not alter canonical inflammasome responses. Transcriptome analysis of enriched peritoneal myeloid cells revealed that Bmal1 deficiency led to a marked reduction in Rev-erbα expression at steady state and a significant increase in serum amyloid A1 (SAA1) expression upon poly(I:C) stimulation. Notably, we found that the circadian regulator Rev-erbα is critical for poly(I:C)- or interferon (IFN)-β-induced SAA1 production, resulting in the circadian oscillation pattern of SAA1 expression in myeloid cells. Furthermore, exogenously applied SAA1 markedly increased noncanonical inflammasome-mediated pyroptosis of macrophages and lethality of mice. Intriguingly, our results revealed that type 1 IFN receptor signaling is needed for poly(I:C)- or IFN-β-induced SAA1 production. Downstream of the type 1 IFN receptor, Rev-erbα inhibited the IFN-β-induced association of C/EBPβ with the promoter region of Saa1, leading to the reduced transcription of Saa1 in macrophages. Bmal1-deficient macrophages exhibited enhanced binding of C/EBPβ to Saa1. Consistently, the blockade of Rev-erbα by SR8278 significantly increased poly(I:C)-stimulated SAA1 transcription and noncanonical inflammasome-mediated lethality in mice. Collectively, our data demonstrate a potent suppressive effect of the circadian clock BMAL1 on the noncanonical inflammasome response via the Rev-erbα-C/EBPβ-SAA1 axis.

The population context is a driver of the heterogeneous response of epithelial cells to interferons

Isogenic cells respond in a heterogeneous manner to interferon. Using a micropatterning approach combined with high-content imaging and spatial analyses, we characterized how the population context (position of a cell with respect to neighboring cells) of epithelial cells affects their response to interferons. We identified that cells at the edge of cellular colonies are more responsive than cells embedded within colonies. We determined that this spatial heterogeneity in interferon response resulted from the polarized basolateral interferon receptor distribution, making cells located in the center of cellular colonies less responsive to ectopic interferon stimulation. This was conserved across cell lines and primary cells originating from epithelial tissues. Importantly, cells embedded within cellular colonies were not protected from viral infection by apical interferon treatment, demonstrating that the population context-driven heterogeneous response to interferon influences the outcome of viral infection. Our data highlights that the behavior of isolated cells does not directly translate to their behavior in a population, placing the population context as one important factor influencing heterogeneity during interferon response in epithelial cells.

Interferon-α receptor antisense oligonucleotides reduce neuroinflammation and neuropathology in a mouse model of cerebral interferonopathy.

Chronic and elevated levels of the antiviral cytokine IFN-α in the brain are neurotoxic. This is best observed in patients with genetic cerebral interferonopathies such as Aicardi-Goutières syndrome. Cerebral interferonopathies typically manifest in early childhood and lead to debilitating disease and premature death. There is no cure for these diseases with existing treatments largely aimed at managing symptoms. Thus, an effective therapeutic strategy is urgently needed. Here, we investigated the effect of antisense oligonucleotides targeting the murine IFN-α receptor (Ifnar1 ASOs) in a transgenic mouse model of cerebral interferonopathy. Intracerebroventricular injection of Ifnar1 ASOs into transgenic mice with brain-targeted chronic IFN-α production resulted in a blunted cerebral interferon signature, reduced neuroinflammation, restoration of blood-brain barrier integrity, absence of tissue destruction, and lessened neuronal damage. Remarkably, Ifnar1 ASO treatment was also effective when given after the onset of neuropathological changes, as it reversed such disease-related features. We conclude that ASOs targeting the IFN-α receptor halt and reverse progression of IFN-α-mediated neuroinflammation and neurotoxicity, opening what we believe to be a new and promising approach for the treatment of patients with cerebral interferonopathies.

A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation.

The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded nuclear receptors and other transcriptional repressors by deacetylation of histone substrates. Recent studies provide evidence that NCoR/HDAC3 complexes can also exert coactivator functions in brown adipocytes by deacetylating and activating PPARγ coactivator 1α (PGC1α) and that signaling via receptor activator of nuclear factor kappa-B (RANK) promotes the formation of a stable NCoR/HDAC3/PGC1β complex that coactivates nuclear factor kappa-B (NFκB)- and activator protein 1 (AP-1)-dependent genes required for osteoclast differentiation. Here, we demonstrate that activation of Toll-like receptor (TLR) 4, but not TLR3, the interleukin 4 (IL4) receptor nor the Type I interferon receptor, also promotes assembly of an NCoR/HDAC3/PGC1β coactivator complex. Receptor-specific utilization of TNF receptor-associated factor 6 (TRAF6) and downstream activation of extracellular signal-regulated kinase 1 (ERK1) and TANK-binding kinase 1 (TBK1) accounts for the common ability of RANK and TLR4 to drive assembly of an NCoR/HDAC3/PGC1β complex in macrophages. ERK1, the p65 component of NFκB, and the p300 histone acetyltransferase (HAT) are also components of the induced complex and are associated with local histone acetylation and transcriptional activation of TLR4-dependent enhancers and promoters. These observations identify a TLR4/TRAF6-dependent signaling pathway that converts NCoR from a corepressor of nuclear receptors to a coactivator of NFκB and AP-1 that may be relevant to functions of NCoR in other developmental and homeostatic processes.

IFNAR(-/-) Mice Constitute a Suitable Animal Model for Epizootic Hemorrhagic Disease Virus Study and Vaccine Evaluation.

Epizootic hemorrhagic disease (EHD), caused by Epizootic hemorrhagic disease virus (EHDV), is an emerging and severe livestock disease. Recent incursion and distribution of EHDV in Europe have outlined the emerging character of EHD. Despite its worldwide impact, numerous knowledge gaps exist. A range of inconveniences restricts utilization of natural hosts of EHDV. Here, we show that adult mice deficient in type I IFN receptor (IFNAR(-/-)) are highly susceptible to EHDV-6 and EHDV-8 infection when the virus is administered subcutaneously. Disease was characterized by ruffled hair, reluctance to move, dehydration and conjunctivitis, with viraemia detected from day 5 post-infection. A deeper characterization of EHDV-8 infection showed viral replication in the lung, liver, spleen, kidney, testis and ovaries. Importantly, increased expression levels of pro-inflammatory cytokines IL-1β, IL-6 and CXCL2 were observed in spleen after EHDV-8 infection. Furthermore, IFNAR(-/-) adult mice immunized with a EHDV-8 inactivated vaccine elicited neutralizing antibodies specific of EHDV-8 and full protection against challenge with a lethal dose of this virus. This study also explores the possibilities of this animal model for study of BTV and EHDV coinfection. In summary, the IFNAR(-/-) mouse model faithfully recapitulates EHD and can be applied for vaccine testing, which can facilitate progress in addressing the animal health challenge posed by this virus.

Remission Possible: New Era of SLE Treatment with Biologics Involvement

Treat-to-target (T2T) is a therapeutic approach used in several rheumatologic disorders such as rheumatoid arthritis, gout, axial spondylarthritis, and other inflammatory diseases such as inflammatory bowel disease. Developing a T2T strategy for systemic lupus erythematosus (SLE) has been difficult due to the complexity of the disease. The 2019 EULAR recommendations for the management of SLE, reestablished in the 2023 EULAR guideline, specified that the primary treatment goal should be remission or the lowest possible disease activity. In SLE, remission is associated with reduced organ damage, fewer flares, reduced hospitalisation, reduced mortality, and improved health-related quality of life. Previously remission in SLE was seen as an unattainable goal; however, the treatment landscape for SLE has evolved, and recent advancements, particularly the use of biologics, have emerged as promising therapeutic options to improve patient outcomes. A new post-hoc analysis of the TULIP Phase III programme provides evidence across four years that remission is an achievable goal with anifrolumab, a type I interferon (IFN) receptor antagonist for adult patients with moderate to severe (SLE) who are receiving standard therapy. At Week 208, 30.3% (n=58/194) of patients treated with anifrolumab were in remission compared with 18.3% (n=12/65) of those in the standard therapy alone group. This was an increase from 19.7% (n=49/251) of patients treated with anifrolumab who achieved remission at the first LTE visit (Week 64) compared with 9.9% (n=10/104) of those in the standard therapy alone group. Treatment with anifrolumab was also associated with more frequent, prolonged, and sustained DORIS remission attainment compared with placebo during the 4-year TULIP+LTE period. Real-world case studies have also illustrated the effectiveness of biologics in controlling disease activity, enhancing quality of life, and establishing long-term safety profiles. In conclusion, biologic therapies have emerged as a valuable treatment option for achieving remission or lupus low disease activity state. Biologics has opened a new era revolutionizing the management of SLE, offering renewed hope for patients living with this challenging autoimmune disease.

Antiviral activity of bovine type III interferon against bovine viral diarrhea virus is greatly reduced in bovine turbinate cells due to limited expression of IFN lambda receptor 1 (IL-28Rα).

The antiviral activity of recombinant bovine interferon lambda 3 (bovIFN-λ3) against bovine viral diarrhea virus (BVDV) has been demonstrated in vitro in Madin-Darby bovine kidney cells (MDBK) and in vivo in cattle. However, anti-BVDV activity of bovIFN-λ3 has not been studied in bovine respiratory tract epithelial cells, supposedly a primary target of BVDV infection when entering the host by the oronasal route. Here we investigated the anti-BVDV activity of bovIFN-λ3 in bovine turbinate-derived primary epithelial cells (BTu) using BVDV infection and immunoperoxidase staining, TCID50, RT-qPCR, DNA and transcriptome sequencing, and transfection with plasmids containing the two subunits, IL-28Rα and IL-10Rβ that constitute the bovIFN-λ3 receptor. Our immunoperoxidase staining, RT-qPCR, and TCID50 results show that while BVDV was successfully cleared in MDBK cells treated with bovIFN-λ3 and bovIFN-α, only the latter, bovIFN-α, cleared BVDV in BTu cells. Preincubation of MDBK cells with bovIFN-λ3 before BVDV infection was needed to induce optimal antiviral state. Both cell types displayed intact type I and III IFN signaling pathways and expressed similar levels of IL-10Rβ subunit of the type III IFN receptor. Sequencing of PCR amplicon of the IL-28Rα subunit revealed intact transmembrane domain and lack of single nucleotide polymorphisms (SNPs) in BTu cells. However, RT-qPCR and transcriptomic analyses showed a lower expression of IL-28Rα transcripts in BTu cells as compared to MDBK cells. Interestingly, transfection of BTu cells with a plasmid encoding IL-28Rα subunit, but not IL-10Rβ subunit, established the bovIFN-λ3 sensitivity showing similar anti-BVDV activity to the response in MDBK cells. Our results demonstrate that the sensitivity of cells to bovIFN-λ3 depends not only on the quality but also of the quantity of the IL-28Rα subunit of the heterodimeric receptor. A reduction in IL-28Rα transcript expression was detected in BTu as compared to MDBK cells, despite the absence of spliced variants or SNPs. The establishment of bovIFN-λ3 induced anti-BVDV activity in BTu cells transfected with an IL-28Rα plasmid suggests that the level of expression of this receptor subunit is crucial for the specific antiviral activity of type III IFN in these cells.

A new subtype of type I IFN receptor, CRFB5b, plays an active role in host antiviral and antibacterial functions in Japanese eel (Anguilla japonica)

A new subtype of type I IFN receptor, CRFB5b, plays an active role in host antiviral and antibacterial functions in Japanese eel (Anguilla japonica)

Portrait of a patient with systemic lupus erythematosus for the prescription of the type I interferon inhibitor anifrolumab

In recent years the use of monoclonal antibodies that block activity of type I interferon (IFN) or its receptors has become the new approach in the pharmacotherapy of systemic lupus erythematosus (SLE).Objective: to characterize patients with SLE treated with the type I IFN receptor inhibitor anifrolumab (AFM, Saphnelo®).Material and methods. The prospective 12-month study included 21 patients with SLE who met the 2012 SLICC criteria. Standard laboratory and immunological markers for SLE were examined in all patients. The SLEDAI-2K index was used to determine the activity of SLE and the CLASI index was used to determine the severity of the mucocutaneous syndrome. Organ damage was assessed using the SLICC/ACR Damage Index (DI). The LupusQol and FACIT-Fatigue questionnaires were used to analyze health-related quality of life (HRQoL).Results and discussion. Female patients prevailed in the study, female/male ratio – 17 (81%)/4 (19%), median age – 31 [27; 46] years, disease duration – 9 [6.0; 11.0] years. The majority of patients (86%) had moderate or high disease activity according to the SLEDAI-2K index. Among the clinical manifestations of SLE, skin and mucous membranes lesions predominated (81%). Non-erosive polyarthritis of varying severity was observed in 66% of cases. Serositis showed 24% of patients (pleurisy, pericarditis), 43% had hematological abnormalities (hemolytic anemia, leukopenia, lymphopenia) and 14% - urinary syndrome (daily proteinuria up to 0.5 g/l and/or urinary sediment – leukocytes/erythrocytes/cylinders up to 5 in the field of view in the absence of urinary tract infection). All patients had immunological disorders. 14% of them were diagnosed with antiphospholipid syndrome (APS) and 43% with Sjögren's syndrome.All patients received hydroxychloroquine, 95% received glucocorticoids (GC) from 5 to 60 mg/day, 66% received immunosuppressants (cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate). 33% of patients had anamnesis of treatment with biologic disease modifying antirheumatic drugs (rituximab, belimumab, dual anti-B-cell therapy) and Janus kinase inhibitor baricitinib. All patients experienced a significant deterioration in HRQoL.Conclusion. The indications for prescribing AFM to 21 patients with SLE were: active SLE according to SLEDAI-2K and/or CLASI with predominant involvement of skin, its appendages and development of polyarthritis with immunological disorders, intolerance/ineffectiveness of previous standard therapy and inability to achieve low average daily doses of oral GCs. Other clinical manifestations in some patients were: serositis, mild hematological disorders (Coombs-positive anemia, leukopenia), urinary syndrome. AFM could be prescribed for a combination of SLE with secondary APS and Sjögren's syndrome as well as for a high DI SLICC.

Pathological and virological findings of type I interferon receptor knockout mice upon experimental infection with Heartland virus

Heartland virus (HRTV) causes generalized symptoms, severe shock, and multiple organ failure. We previously reported that interferon-α/β receptor knockout (IFNAR-/-) mice infected intraperitoneally with 1 × 107 tissue culture-infective dose (TCID50) of HRTV died, while those subcutaneously infected with the same dose of HRTV did not. The pathophysiology of IFNAR-/- mice infected with HRTV and the mechanism underlying the difference in disease severity, which depends on HRTV infection route, were analyzed in this study. The liver, spleen, mesenteric and axillary lymph nodes, and gastrointestinal tract of intraperitoneally (I.P.) infected mice had pathological changes; however, subcutaneously (S.C.) infected mice only had pathological changes in the axillary lymph node and gastrointestinal tract. HRTV RNA levels in the mesenteric lymph node, lung, liver, spleen, kidney, stomach, intestine, and blood were significantly higher in I.P. infected mice than those in S.C. infected mice. Chemokine ligand-1 (CXCL-1), tumor necrosis factor (TNF)-α, interleukin (IL)-12, interferon (IFN)-γ, and IL-10 levels in plasma of I.P. infected mice were higher than those of S.C. infected mice. These results indicated that high levels of viral RNA and the induction of inflammatory responses in HRTV-infected IFNAR-/- mice may be associated with disease severity.

TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin.

We aimed to investigate the effects of tumor necrosis factor (TNF)-α on the expression of interferon α/β receptor subunit 1 (IFNAR1) and cervical squamous cancer (CSCC) resistance to Cisplatin, as well as the underlying mechanisms. Kaplan-Meier analysis was used to plot the overall survival curves. SiHa cells were treated with 20 ng/ml TNF-α to determine cell proliferation in human CSCC cells and the expression of IFNAR1. The effects of TNF-α on the downstream signaling pathway, including casein kinase 1α (CK1α), were investigated using the caspase protease inhibitor FK009, the c-Jun kinase inhibitor SP600125, and the nuclear factor kappa-B inhibitor ammonium pyrrolidinedithiocarbamate (PDTC). TNF-α induced down-regulation of IFNAR1 in human CSCC cells and promoted proliferation of SiHa cells. SiHa cells were transfected with the catalytic inactive mutant CK1α K49A, and the ability of TNF-α to induce down-regulation of IFNAR1 expression was found to be significantly diminished in this context. FK009 and PDTC had no obvious effect on the expression of CK1α, however, SP600125 significantly reduced the expression of CK1α in the presence of TNF-α. SiHa cells treated with TNF-α showed reduced sensitivity to Cisplatin and exhibited higher cell viability, while the sensitivity of SiHa cells to Cisplatin was restored after treatment with CK1α inhibitor D4476. Additionally, we constructed a TNF-α overexpressing SiHa cell line and a transplanted tumor model. The results were similar to those of in vitro efficacy. We demonstrate that TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin.

Maternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling

Microbiota have an important function in shaping and priming neonatal immunity, although the cellular and molecular mechanisms underlying these effects remain obscure. Here we report that prenatal antibiotic exposure causes significant elevation of group 2 innate lymphoid cells (ILC2s) in neonatal lungs, in both cell numbers and functionality. Downregulation of type 1 interferon signaling in ILC2s due to diminished production of microbiota-derived butyrate represents the underlying mechanism. Mice lacking butyrate receptor GPR41 (Gpr41-/-) or type 1 interferon receptor IFNAR1 (Ifnar1-/-) recapitulate the phenotype of neonatal ILC2s upon maternal antibiotic exposure. Furthermore, prenatal antibiotic exposure induces epigenetic changes in ILC2s and has a long-lasting deteriorative effect on allergic airway inflammation in adult offspring. Prenatal supplementation of butyrate ameliorates airway inflammation in adult mice born to antibiotic-exposed dams. These observations demonstrate an essential role for the microbiota in the control of type 2 innate immunity at the neonatal stage, which suggests a therapeutic window for treating asthma in early life.

Roles and functions of IAV proteins in host immune evasion.

Influenza A viruses (IAVs) evade the immune system of the host by several regulatory mechanisms. Their genomes consist of eight single-stranded segments, including nonstructural proteins (NS), basic polymerase 1 (PB1), basic polymerase 2 (PB2), hemagglutinin (HA), acidic polymerase (PA), matrix (M), neuraminidase (NA), and nucleoprotein (NP). Some of these proteins are known to suppress host immune responses. In this review, we discuss the roles, functions and underlying strategies adopted by IAV proteins to escape the host immune system by targeting different proteins in the interferon (IFN) signaling pathway, such as tripartite motif containing 25 (TRIM25), inhibitor of nuclear factor κB kinase (IKK), mitochondrial antiviral signaling protein (MAVS), Janus kinase 1 (JAK1), type I interferon receptor (IFNAR1), interferon regulatory factor 3 (IRF3), IRF7, and nuclear factor-κB (NF-κB). To date, the IAV proteins NS1, NS2, PB1, PB1-F2, PB2, HA, and PA have been well studied in terms of their roles in evading the host immune system. However, the detailed mechanisms of NS3, PB1-N40, PA-N155, PA-N182, PA-X, M42, NA, and NP have not been well studied with respect to their roles in immune evasion. Moreover, we also highlight the future perspectives of research on IAV proteins.

Simvastatin Differentially Modulates Glial Functions in Cultured Cortical and Hypothalamic Astrocytes Derived from Interferon α/β Receptor Knockout mice.

Astrocytes have key regulatory roles in central nervous system (CNS), integrating metabolic, inflammatory and synaptic responses. In this regard, type I interferon (IFN) receptor signaling in astrocytes can regulate synaptic plasticity. Simvastatin is a cholesterol-lowering drug that has shown anti-inflammatory properties, but its effects on astrocytes, a main source of cholesterol for neurons, remain to be elucidated. Herein, we investigated the effects of simvastatin in inflammatory and functional parameters of primary cortical and hypothalamic astrocyte cultures obtained from IFNα/β receptor knockout (IFNα/βR-/-) mice. Overall, simvastatin decreased extracellular levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), which were related to a downregulation in gene expression in hypothalamic, but not in cortical astrocytes. Moreover, there was an increase in anti-inflammatory interleukin-10 (IL-10) in both structures. Effects of simvastatin in inflammatory signaling also involved a downregulation of cyclooxygenase 2 (COX-2) gene expression as well as an upregulation of nuclear factor κB subunit p65 (NFκB p65). The expression of cytoprotective genes sirtuin 1 (SIRT1) and nuclear factor erythroid derived 2 like 2 (Nrf2) was also increased by simvastatin. In addition, simvastatin increased glutamine synthetase (GS) activity and glutathione (GSH) levels only in cortical astrocytes. Our findings provide evidence that astrocytes from different regions are important cellular targets of simvastatin in the CNS, even in the absence of IFNα/βR, which was showed by the modulation of cytokine production and release, as well as the expression of cytoprotective genes and functional parameters.

Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression

Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response, e.g. through a direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones resistant to the antiproliferative effects of IFNs may contribute to immunoediting of tumours, leading to more aggressive disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that six weeks exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines, most prominently in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours. In both, long-term IFN selection and in dedifferentiated tumour cell lines, we found IFNAR2 expression to be substantially reduced, suggesting the receptor complex to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.