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1.
PLoS Pathog ; 20(5): e1011820, 2024 May.
Article En | MEDLINE | ID: mdl-38718306

The production of IFN-γ is crucial for control of multiple enteric infections, but its impact on intestinal epithelial cells (IEC) is not well understood. Cryptosporidium parasites exclusively infect epithelial cells and the ability of interferons to activate the transcription factor STAT1 in IEC is required for parasite clearance. Here, the use of single cell RNA sequencing to profile IEC during infection revealed an increased proportion of mid-villus enterocytes during infection and induction of IFN-γ-dependent gene signatures that was comparable between uninfected and infected cells. These analyses were complemented by in vivo studies, which demonstrated that IEC expression of the IFN-γ receptor was required for parasite control. Unexpectedly, treatment of Ifng-/- mice with IFN-γ showed the IEC response to this cytokine correlates with a delayed reduction in parasite burden but did not affect parasite development. These data sets provide insight into the impact of IFN-γ on IEC and suggest a model in which IFN-γ signalling to uninfected enterocytes is important for control of Cryptosporidium.


Cryptosporidiosis , Interferon-gamma , Intestinal Mucosa , Mice, Knockout , Animals , Interferon-gamma/metabolism , Interferon-gamma/immunology , Cryptosporidiosis/immunology , Cryptosporidiosis/parasitology , Mice , Intestinal Mucosa/parasitology , Intestinal Mucosa/metabolism , Intestinal Mucosa/immunology , Cryptosporidium , Epithelial Cells/parasitology , Epithelial Cells/metabolism , Epithelial Cells/immunology , Enterocytes/parasitology , Enterocytes/metabolism , Enterocytes/immunology , Mice, Inbred C57BL , Interferon gamma Receptor , STAT1 Transcription Factor/metabolism , Receptors, Interferon/metabolism , Receptors, Interferon/genetics , Signal Transduction
2.
J Virol ; 98(5): e0049324, 2024 May 14.
Article En | MEDLINE | ID: mdl-38578092

CD4+ T cells play a key role in γ-herpesvirus infection control. However, the mechanisms involved are unclear. Murine herpesvirus type 4 (MuHV-4) allows relevant immune pathways to be dissected experimentally in mice. In the lungs, it colonizes myeloid cells, which can express MHC class II (MHCII), and type 1 alveolar epithelial cells (AEC1), which lack it. Nevertheless, CD4+ T cells can control AEC1 infection, and this control depends on MHCII expression in myeloid cells. Interferon-gamma (IFNγ) is a major component of CD4+ T cell-dependent MuHV-4 control. Here, we show that the action of IFNγ is also indirect, as CD4+ T cell-mediated control of AEC1 infection depended on IFNγ receptor (IFNγR1) expression in CD11c+ cells. Indirect control also depended on natural killer (NK) cells. Together, the data suggest that the activation of MHCII+ CD11c+ antigen-presenting cells is key to the CD4+ T cell/NK cell protection axis. By contrast, CD8+ T cell control of AEC1 infection appeared to operate independently. IMPORTANCE: CD4+ T cells are critical for the control of gamma-herpesvirus infection; they act indirectly, by recruiting natural killer (NK) cells to attack infected target cells. Here, we report that the CD4+ T cell/NK cell axis of gamma-herpesvirus control requires interferon-γ engagement of CD11c+ dendritic cells. This mechanism of CD4+ T cell control releases the need for the direct engagement of CD4+ T cells with virus-infected cells and may be a common strategy for host control of immune-evasive pathogens.


CD4-Positive T-Lymphocytes , Herpesviridae Infections , Interferon-gamma , Killer Cells, Natural , Receptors, Interferon , Rhadinovirus , Animals , CD4-Positive T-Lymphocytes/immunology , Interferon-gamma/immunology , Interferon-gamma/metabolism , Mice , Herpesviridae Infections/immunology , Herpesviridae Infections/virology , Killer Cells, Natural/immunology , Receptors, Interferon/genetics , Receptors, Interferon/metabolism , Rhadinovirus/immunology , Mice, Inbred C57BL , Interferon gamma Receptor , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/virology , CD8-Positive T-Lymphocytes/immunology , CD11c Antigen/metabolism , CD11c Antigen/immunology , Lung/immunology , Lung/virology
4.
Curr Opin Immunol ; 86: 102413, 2024 Feb.
Article En | MEDLINE | ID: mdl-38608537

Type I and type III interferons (IFNs) are major components in activating the innate immune response. Common to both are two distinct receptor chains (IFNAR1/IFNAR2 and IFNLR1/IL10R2), which form ternary complexes upon binding their respective ligands. This results in close proximity of the intracellularly associated kinases JAK1 and TYK2, which cross phosphorylate each other, the associated receptor chains, and signal transducer and activator of transcriptions, with the latter activating IFN-stimulated genes. While there are clear similarities in the biological responses toward type I and type III IFNs, differences have been found in their tropism, tuning of activity, and induction of the immune response. Here, we focus on how these differences are embedded in the structure/function relations of these two systems in light of the recent progress that provides in-depth information on the structural assembly of these receptors and their functional implications and how these differ between the mouse and human systems.


Interferon Type I , Interferons , Humans , Animals , Mice , Receptors, Interferon/metabolism , Receptor, Interferon alpha-beta/genetics , Signal Transduction/genetics , Immunity, Innate , Interferon Type I/metabolism
5.
Sci Signal ; 16(806): eadf5494, 2023 10 10.
Article En | MEDLINE | ID: mdl-37816090

Interferons (IFNs) play crucial roles in antiviral defenses. Despite using the same Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) signaling cascade, type I and III IFN receptors differ in the magnitude and dynamics of their signaling in terms of STAT phosphorylation, gene transcription, and antiviral responses. These differences are not due to ligand-binding affinity and receptor abundance. Here, we investigated the ability of the intracellular domains (ICDs) of IFN receptors to differentiate between type I and III IFN signaling. We engineered synthetic, heterodimeric type I and III IFN receptors that were stably expressed at similar amounts in human cells and responded to a common ligand. We found that our synthetic type I IFN receptors stimulated STAT phosphorylation and gene expression to greater extents than did the corresponding type III IFN receptors. Furthermore, we identified short "box motifs" within ICDs that bind to JAK1 that were sufficient to encode differences between the type I and III IFN receptors. Together, our results indicate that specific regions within the ICDs of IFN receptor subunits encode different downstream signaling strengths that enable type I and III IFN receptors to produce distinct signaling outcomes.


Interferon Type I , Receptors, Interferon , Humans , Receptors, Interferon/genetics , Receptors, Interferon/metabolism , Ligands , Interferons/metabolism , Signal Transduction , Interferon Type I/genetics , Interferon Type I/metabolism , Janus Kinases/metabolism , Phosphorylation , Antiviral Agents/pharmacology , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism
6.
Int J Mol Sci ; 24(19)2023 Sep 26.
Article En | MEDLINE | ID: mdl-37834019

Janus tyrosine kinase (JAK) variants are known drivers for hematological disorders. With the full-length structure of mouse JAK1 being recently resolved, new observations on the localization of variants within closed, open, and dimerized JAK structures are possible. Full-length homology models of human wild-type JAK family members were developed using the Glassman et al. reported mouse JAK1 containing the V658F structure as a template. Many mutational sites related to proliferative hematological disorders reside in the JH2 pseudokinase domains facing the region important in dimerization of JAKs in both closed and open states. More than half of all JAK gain of function (GoF) variants are changes in polarity, while only 1.2% are associated with a change in charge. Within a JAK1-JAK3 homodimer model, IFNLR1 (PDB ID7T6F) and the IL-2 common gamma chain subunit (IL2Rγc) were aligned with the respective dimer implementing SWISS-MODEL coupled with ChimeraX. JAK3 variants were observed to encircle the catalytic site of the kinase domain, while mutations in the pseudokinase domain align along the JAK-JAK dimerization axis. FERM domains of JAK1 and JAK3 are identified as a hot spot for hematologic malignancies. Herein, we propose new allosteric surfaces for targeting hyperactive JAK dimers.


Hematologic Neoplasms , Janus Kinases , Animals , Humans , Mice , Janus Kinases/genetics , Tyrosine/genetics , Janus Kinase 1/genetics , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/genetics , Mutation , Drug Development , Janus Kinase 2/genetics , Receptors, Interferon/genetics
7.
Front Immunol ; 14: 1253279, 2023.
Article En | MEDLINE | ID: mdl-37809086

Cutaneous lupus erythematosus (CLE), the main manifestation of systemic lupus erythematosus (SLE), is driven by type I interferons (IFNs) and often only partially responds to conventional therapies. Treatment of seven SLE patients with the monoclonal antibody anifrolumab induced fast and sustained remission of previously refractory CLE lesions, beginning within the first weeks of treatment. Decline in CLASI-A score was paralleled by a reduction in IFN score determined by mRNA expression of seven IFN-stimulated genes (ISGs) in blood. These data suggest that a subset of ISGs could be a valuable biomarker in CLE.


Interferon Type I , Lupus Erythematosus, Cutaneous , Lupus Erythematosus, Systemic , Humans , Receptors, Interferon , Lupus Erythematosus, Cutaneous/diagnosis , Lupus Erythematosus, Cutaneous/drug therapy , Antibodies, Monoclonal/therapeutic use , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/drug therapy
8.
J Interferon Cytokine Res ; 43(9): 427-434, 2023 09.
Article En | MEDLINE | ID: mdl-37725010

Biliary atresia (BA) is a life-threatening cholangiopathy occurring in infancy, the most common indication for pediatric liver transplantation. The etiology of BA remains unknown; however, a viral etiology has been proposed as multiple viruses have been detected in explants of infants afflicted with BA. In the murine model of BA, Rhesus rotavirus (RRV) infection of newborn BALB/c pups results in a cholangiopathy that mirrors human BA. Infected BALB/c pups experience 100% symptomatology and mortality, while C57BL/6 mice are asymptomatic. Interferon-λ (IFN-λ) is an epithelial cytokine that provides protection against viral infection. We demonstrated that IFN-λ is highly expressed in C57BL/6, leading to reduced RRV replication. RRV-infection of C57BL/6 IFN-λ receptor knockout (C57BL/6 IFN-λR KO) pups resulted in 90% developing obstructive symptoms and 45% mortality with a higher viral titer in bile ducts and profound periportal inflammation compared to C57BL/6. Histology revealed complete biliary obstruction in symptomatic C57BL/6 IFN-λR KO pups, while C57BL/6 ducts were patent. These findings suggest that IFN-λ is critical in preventing RRV replication. Deficiency in IFN-λ permits RRV infection, which triggers the inflammatory cascade causing biliary obstruction. Further IFN-λ study is warranted as it may play an important role in infant susceptibility to BA.


Biliary Atresia , Cholestasis , Receptors, Interferon , Animals , Mice , Biliary Atresia/genetics , Disease Models, Animal , Interferon Lambda/metabolism , Interferons , Mice, Inbred C57BL , Receptors, Interferon/genetics , Receptors, Interferon/metabolism
9.
J Biol Chem ; 299(8): 104990, 2023 08.
Article En | MEDLINE | ID: mdl-37392850

Cycloartenyl ferulate (CF) is abundant in brown rice with multiple biologic functions. It has been reported to possess antitumor activity; however, the related mechanism of action of CF has not been clarified. Herein, we unexpectedly uncover the immunological regulation effects of CF and its molecular mechanism. We discovered that CF directly enhanced the killing capacity of natural killer (NK) cells for various cancer cells in vitro. In vivo, CF also improved cancer surveillance in mouse models of lymphoma clearance and metastatic melanoma dependent on NK cells. In addition, CF promoted anticancer efficacy of the anti-PD1 antibody with improvement of tumor immune microenvironment. Mechanistically, we first unveiled that CF acted on the canonical JAK1/2-STAT1 signaling pathway to enhance the immunity of the NK cells by selectively binding to interferon γ receptor 1. Collectively, our results indicate that CF is a promising immunoregulation agent worthy of attention in clinical application in the future. Due to broad biological significance of interferon γ, our findings also provide a capability to understand the diverse functions of CF.


Coumaric Acids , Killer Cells, Natural , Neoplasms , Receptors, Interferon , Animals , Mice , Interferon-gamma/immunology , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Neoplasms/immunology , Tumor Microenvironment , Coumaric Acids/pharmacology , Receptors, Interferon/immunology , Interferon gamma Receptor
10.
J Interferon Cytokine Res ; 43(9): 403-413, 2023 09.
Article En | MEDLINE | ID: mdl-37499093

Type III interferons (IFN-lambdas, IFN-λs) are important antiviral cytokines that can also modulate immune responses by acting through a heterodimeric receptor composed of the specific and limited expressed IFN-λR1 chain and the ubiquitous IL-10R2 chain, which is shared with IL-10 family cytokines. Conflicting data have been reported regarding which cells express the IFN-λR1 subunit and directly respond to IFN-λs. This is, in part, owing to transcript levels of the IFN-λR1 gene, IFNLR1, not always correlating with cell surface protein levels. In this study, we tested a panel of novel monoclonal antibodies (mAbs) that specifically recognize human IFN-λR1. Initially, antigen specificity was confirmed by enzyme-linked immunosorbent assay (ELISA), from which a subset of antibodies was selected for additional flow cytometry and neutralization assays. We further characterized two antibodies based on their strong ELISA binding activity (HLR1 and HLR14) and found only HLR14 could reliably detect cell surface IFN-λR1 protein on a variety of cell lines by flow cytometry. HLR14 could also detect IFN-λR1 protein on certain primary human blood cells, including plasmacytoid dendritic cells and B cells from peripheral blood. Availability of the HLR14 mAb will enable the quantification of IFN-λR1 protein levels on cells and better characterization of the cell specificity of the IFN-λ response.


Interferons , Receptors, Interferon , Humans , Receptors, Interferon/genetics , Interferon Lambda , Membrane Proteins , Antibodies, Monoclonal , Cytokines
11.
Cell Rep ; 42(7): 112806, 2023 07 25.
Article En | MEDLINE | ID: mdl-37440406

This study identifies interleukin-6 (IL-6)-independent phosphorylation of STAT3 Y705 at the early stage of infection with several viruses, including influenza A virus (IAV). Such activation of STAT3 is dependent on the retinoic acid-induced gene I/mitochondrial antiviral-signaling protein/spleen tyrosine kinase (RIG-I/MAVS/Syk) axis and critical for antiviral immunity. We generate STAT3Y705F/+ knockin mice that display a remarkably suppressed antiviral response to IAV infection, as evidenced by impaired expression of several antiviral genes, severe lung tissue injury, and poor survival compared with wild-type animals. Mechanistically, STAT3 Y705 phosphorylation restrains IAV pathogenesis by repressing excessive production of interferons (IFNs). Blocking phosphorylation significantly augments the expression of type I and III IFNs, potentiating the virulence of IAV in mice. Importantly, knockout of IFNAR1 or IFNLR1 in STAT3Y705F/+ mice protects the animals from lung injury and reduces viral load. The results indicate that activation of STAT3 by Y705 phosphorylation is vital for establishment of effective antiviral immunity by suppressing excessive IFN signaling induced by viral infection.


Influenza A virus , Orthomyxoviridae Infections , STAT3 Transcription Factor , Animals , Mice , Antiviral Agents , Immunity, Innate , Interferons , Receptors, Interferon , Signal Transduction , Orthomyxoviridae Infections/immunology , STAT3 Transcription Factor/immunology
12.
J Interferon Cytokine Res ; 43(7): 287-298, 2023 07.
Article En | MEDLINE | ID: mdl-37428556

Diet-induced obesity triggers elevation of circulating pro-inflammatory cytokines and acute-phase proteins, including interferons (IFNs). IFNs strongly contribute to low-grade inflammation associated with obesity-related complications, such as nonalcoholic fat liver disease and diabetes. In this study, AG129 mice model (double-knockout strain for IFN α/ß/γ receptors) was fed with a high-fat high-sucrose (HFHS) diet (Western diet) for 20 weeks aiming to understand the impact of IFN receptor ablation on diet-induced obesity, insulin resistance, and nonalcoholic fat liver disease. Mice were responsive to the diet, becoming obese after 20 weeks of HFHS diet which was accompanied by 2-fold increase of white adipose tissues. Moreover, animals developed glucose and insulin intolerance, as well as dysregulation of insulin signaling mediators such as Insulin Receptor Substrate 1 (IRS1), protein kinase B (AKT), and S6 ribosomal protein. Liver increased interstitial cells, and lipid accumulation was also found, presenting augmented fibrotic markers (transforming growth factor beta 1 [Tgfb1], Keratin 18 [Krt18], Vimentin [Vim]), yet lower expression on IFN receptor downstream proteins (Toll-like receptor [TLR] 4, nuclear factor kappa-light-chain-enhancer of activated B cells [NFκB], and cAMP response element-binding protein [CREB]). Thus, IFN receptor ablation promoted effects on NFκB and CREB pathways, with no positive effects on systemic homeostasis in diet-induced obese mice. Therefore, we conclude that IFN receptor signaling is not essential for promoting the complications of diet-induced obesity and thus cannot be correlated with metabolic diseases in a noninfectious condition.


Insulin Resistance , Non-alcoholic Fatty Liver Disease , Mice , Animals , Insulin Resistance/physiology , Diet, Western , Obesity/complications , Liver/metabolism , Insulin/metabolism , Non-alcoholic Fatty Liver Disease/complications , Diet, High-Fat/adverse effects , Receptors, Interferon/metabolism , Mice, Inbred C57BL
13.
Cytokine ; 169: 156274, 2023 09.
Article En | MEDLINE | ID: mdl-37327531

Interferon-gamma (IFN-γ) is a pro-inflammatory cytokine playing essential role in immunity against tuberculosis (TB). IFN-γ performs function by binding to its receptor complex, consisting of two polypeptide chains viz. IFN-γ receptor 1 (IFN-γR1) and IFN-γ receptor 2 (IFN-γR2). Structural and functional deficiencies in IFN-γR1 can make individual vulnerable to even weak mycobacterial infections. Studies from different populations of the world have reported the association of single nucleotide polymorphisms (SNPs) present in IFNGR1 gene with TB, however, there are no such studies from India. Thus, the present study was designed to analyse the association of rs2234711 (C/T), rs7749390 (C/T) and rs1327475 (C/T) SNPs of IFNGR1 with TB in the population of North India. For the present study, 263 TB patients (at zero day of anti-tuberculosis therapy) and 256 healthy controls (HCs) were recruited. The genotyping of selected SNPs was done by high-resolution melting (HRM) curve analysis. The mRNA and surface expression data of IFNGR1 was extracted from our previous study and was grouped according to the genotypes of studied SNPs. The genotype 'TT' and 'T' allele of SNP rs2234711 (C/T) were found to be associated with TB in studied population ['T' vs 'C': OR (CI) = 1.79 (1.39-2.29); p-value < 0.0001]. The haplotypes 'C-C-C' of rs2234711-rs7749390-rs1327475 confers protection, while haplotype 'T-C-C' is a risk factor for TB in studied population. It was also found that 'TT' genotype of rs2234711 in HCs is associated with lower surface expression of IFNGR1 (p-value = 0.0078). In conclusion, 'TT' genotype is associated with lower surface expression of IFNGR1 and is increasing the susceptibility to TB in North Indian population.


Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Receptors, Interferon , Tuberculosis, Pulmonary , Humans , Case-Control Studies , Genotype , Interferon-gamma/genetics , Polymorphism, Single Nucleotide/genetics , Receptors, Interferon/genetics , Tuberculosis, Pulmonary/genetics , Interferon gamma Receptor
14.
Nat Genet ; 55(6): 1034-1047, 2023 06.
Article En | MEDLINE | ID: mdl-37277650

Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.


Down Syndrome , Heart Defects, Congenital , Animals , Mice , Down Syndrome/genetics , Receptors, Interferon/genetics , Interferons , Phenotype , Disease Models, Animal
15.
BMC Pediatr ; 23(1): 278, 2023 06 05.
Article En | MEDLINE | ID: mdl-37277724

BACKGROUND: Interferon-gamma receptor deficiency is a heterogeneous spectrum of disease which involves mutations in IFNGR1, IFNGR2 genes, and the downstream signaling proteins such as STAT1. These mutations are associated with immunodeficiency 27 A and 27B, making the patient prone to mycobacterial infections. Patients with this condition are also at increased risk for affliction with viral and bacterial infections, such as with the Herpesviridae family, Listeria, and Salmonella. Moreover, SH2B3 mutation is associated with autoimmune and lymphoproliferative conditions. CASE PRESENTATION: the patient was a 19-month-old infant girl who presented with a two-week history of fever. She had near-normal flowcytometry with high IgM and IgE. She had pneumonic infiltration in her chest and right hilar and para-aortic lymphadenopathy. PCR of whole blood for Aspergillus fumigatus came back positive. In her Whole Exome Sequencing she had IFNGR1 and SH2B3 mutations. CONCLUSION: systemic fungal infections such as Aspergillosis can occur in patients with interferon-gamma receptor one deficiency. This type of immunodeficiency should be considered in treating patients with systemic Aspergillosis.


Aspergillosis , Immunologic Deficiency Syndromes , Infant , Female , Humans , Interferon-gamma/genetics , Aspergillosis/diagnosis , Aspergillosis/genetics , Receptors, Interferon/genetics , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/genetics , Interferon gamma Receptor
16.
In Vitro Cell Dev Biol Anim ; 59(5): 366-380, 2023 May.
Article En | MEDLINE | ID: mdl-37353697

Astrocytes play essential roles in the central nervous system (CNS), such as the regulation of glutamate metabolism, antioxidant defenses, and inflammatory/immune responses. Moreover, hypothalamic astrocytes seem to be crucial in the modulation of inflammatory processes, including those related to type I interferon signaling. In this regard, the polyphenol resveratrol has emerged as an important glioprotective molecule to regulate astrocyte functions. Therefore, this study aimed to investigate the immunomodulatory and protective effects of resveratrol in hypothalamic astrocyte cultures obtained from mouse depleted of type I interferon receptors (INF-α/ß-/-), a condition that can impair immune and inflammatory functions. Resveratrol upregulated glutamate transporter and glutamine synthetase gene expression, as well as modulated the release of wide range of cytokines and genes involved in the control of inflammatory response, besides the expression of adenosine receptors, which display immunomodulatory functions. Resveratrol also increased genes associated with redox balance, mitochondrial processes, and trophic factors signaling. The putative genes associated with glioprotective effects of resveratrol, including nuclear factor erythroid derived 2 like 2 (Nrf2), heme oxygenase 1 (HO-1), sirtuin 1 (SIRT1), and phosphoinositide 3-kinase (PI3K)/Akt, were further upregulated by resveratrol. Thus, our data show that resveratrol was able to modulate key genes associated with glial functionality and inflammatory response in astrocyte cultures derived from IFNα/ßR-/- mice. These data are in agreement with previous results, reinforcing its glioprotective effects even in hypothalamic astrocytes with altered inflammatory and immune signaling. Finally, this polyphenol can prepare astrocytes to better respond to injuries, including those associated with neuroimmunology defects.


Astrocytes , Receptors, Interferon , Rats , Animals , Mice , Resveratrol/pharmacology , Resveratrol/metabolism , Astrocytes/metabolism , Receptors, Interferon/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Rats, Wistar , Cells, Cultured
17.
Cell Mol Life Sci ; 80(6): 154, 2023 May 19.
Article En | MEDLINE | ID: mdl-37204469

Inflammation can impair intestinal barrier, while increased epithelial permeability can lead to inflammation. In this study, we found that the expression of Tspan8, a tetraspanin expressed specifically in epithelial cells, is downregulated in mouse model of ulcerative disease (UC) but correlated with those of cell-cell junction components, such as claudins and E-cadherin, suggesting that Tspan8 supports intestinal epithelial barrier. Tspan8 removal increases intestinal epithelial permeability and upregulates IFN-γ-Stat1 signaling. We also demonstrated that Tspan8 coalesces with lipid rafts and facilitates IFNγ-R1 localization at or near lipid rafts. As IFN-γ induces its receptor undergoing clathrin- or lipid raft-dependent endocytosis and IFN-γR endocytosis plays an important role in Jak-Stat1 signaling, our analysis on IFN-γR endocytosis revealed that Tspan8 silencing impairs lipid raft-mediated but promotes clathrin-mediated endocytosis of IFN-γR1, leading to increased Stat1 signaling. These changes in IFN-γR1 endocytosis upon Tspan8 silencing correlates with fewer lipid raft component GM1 at the cell surface and more clathrin heavy chain in the cells. Our findings indicate that Tspan8 determines the IFN-γR1 endocytosis route, to restrain Stat1 signaling, stabilize intestine epithelium, and subsequently prevent intestine from inflammation. Our finding also implies that Tspan8 is needed for proper endocytosis through lipid rafts.


Intestinal Mucosa , Receptors, Interferon , Tetraspanins , Animals , Mice , Clathrin/metabolism , Endocytosis/physiology , Inflammation/metabolism , Interferons/metabolism , Intestinal Mucosa/metabolism , Receptors, Interferon/metabolism , Tetraspanins/genetics , Tetraspanins/metabolism
19.
J Med Chem ; 66(8): 5584-5610, 2023 04 27.
Article En | MEDLINE | ID: mdl-37027512

Stimulator of interferon gene (STING) is a critical adaptor protein that has a pivotal role in triggering inherent immune responses to infection. STING-linked interferon production has been involved in anti-inflammation, anti-infection, and antitumor immunity. Herein, a series of amidobenzimidazole analogues as STING agonists were profiled for potency and drug-like properties. By structure-based modification and optimization based on mono-aminobenzimidazole (ABZI), analogues with nanomolar STING agonistic activities were obtained. Among them, compounds D59 and D61 significantly increased the transcription of IFN-ß and proinflammatory cytokine CXCL10, as well as dramatically induced the phosphorylation of STING downstream proteins in THP1 cells. Furthermore, compound D61 exhibited favorable pharmacokinetic properties and metabolic stabilities. In a CT-26 syngeneic mice-bearing tumor model, D61 effectively inhibited tumor growth with good tolerance when administered via intratumoral, intravenous, intraperitoneal, and oral routes. This research on orally bioavailable amidobenzimidazole analogues expands the diversity of chemical structures of agonists for STING-mediated immunotherapy.


Neoplasms , Receptors, Interferon , Animals , Mice , Phosphorylation , Interferons
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