Deciphering IFN signaling in gastric cancer: A single-cell and bulk transcriptomic integration reveals CXCR4 as a key immunomodulator and prognostic determinant.

Aging is a myeloid-biased process, i.e., the differentiation of myeloid cells increases, while the lymphoid lineage declines. Cellular senescence increases the secretion of inflammatory mediators which skew hematopoiesis toward myeloid cell generation. Myeloid cell nuclear differentiation antigen (MNDA) is a type-1 interferon (IFN)-inducible factor which is mainly expressed in the cells of the granulocyte-monocyte lineage, especially it is enriched in M2 macrophages and myeloid-derived suppressor cells (MDSC). MNDA regulates gene expression in the cooperation with the IRF7, Sp1, and YY1 transcription factors. MNDA also inhibits the function of two antiapoptotic proteins, i.e., MCL1 and BCL2, thus promoting apoptotic clearance of myeloid cells during the resolution of inflammation. Moreover, MNDA can prevent excessive inflammation by inducing the polarization of M2 macrophages and enhancing the recruitment of MDSCs into inflamed tissues. Immunosuppressive cells not only inhibit inflammation but they can also promote senescence of immune and non-immune cells as well as triggering fibrosis and other age-related alterations. We propose a scenario where the accumulation of senescent cells with aging promotes a leakage of double-stranded DNA (dsDNA) from impaired mitochondria and nuclei thus activating cytoplasmic dsDNA sensors. Activation of cGAS-STING signaling generates the production of type-1 IFNs and thus MNDA may potentially enhance the myeloid-biased aging process and aggravate many age-related diseases.

Protective efficacy of GMAI-02, a cDNA-derived inactivated hepatitis A vaccine, against HM175/mp7 challenge in interferon-receptor-deficient mice.

The host PYHIN (pyrin and HIN domain family) protein IFN-γ-inducible protein 16 (IFI16) was first discovered as a nuclear sensor of double-stranded DNA (dsDNA). Since then its roles in innate immunity have expanded to include restriction of infection of both DNA and RNA viruses. Mechanistically, IFI16 restricts DNA viruses through four principal mechanisms: (i) direct repression of viral gene expression by binding viral genomes and promoting epigenetic-mediated silencing; (ii) sequestration of host transcription factor Sp1; (iii) induction of interferons (IFNs) after sensing viral genomes in the nucleus and cytosol; and (iv) assembly of apoptosis-associated speck-like protein containing a CARD (ASC)-dependent inflammasomes that activates caspase-1 leading to maturation of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) and pyroptosis. These mechanisms have been reported across dsDNA virus families, including Herpesviridae, Papillomaviridae, Hepadnaviridae, Parvoviridae, Polyomaviridae, and Poxviridae. For RNA viruses, IFI16 can: (i) directly bind viral genomes or sequester Sp1; (ii) amplify antiviral signalling by promoting RIG-I transcription or activation or cooperating with cyclic GMP-AMP synthase (cGAS)- stimulator of IFN genes (STING), and (iii) in some settings activate inflammasomes and pyroptosis. These mechanisms were reported for RNA virus families including, Togaviridae, Flaviviridae, Picornaviridae, Caliciviridae, Arteriviridae, Orthomyxoviridae, Paramyxoviridae and Retroviridae. Consistent with these antiviral roles, many viruses have evolved both destructive (IFI16 degradation) and non-destructive mechanisms to evade IFI16. This review summarizes the current understanding of how IFI16 mediates broad antiviral restriction and how diverse viruses subvert this role to facilitate their replication.

Retinoic acid-inducible gene I (RIG-I)-like receptors, including RIG-I and MDA5, are key cytoplasmic pattern-recognition receptors that detect viral RNA in the cytoplasm and trigger the production of interferon (IFN). Among them, MDA5, rather than RIG-I, is considered the primary sensor during picornavirus infection due to the unique features of picornaviral RNA. However, previous studies have indicated that RIG-I also possesses antiviral activity against several picornaviruses, suggesting its potential importance during viral replication. Here, we found that 3A proteins from various picornaviruses, including Senecavirus A (SVA), Enterovirus 71 (EV71), Encephalomyocarditis virus (EMCV), foot-and-mouth disease virus (FMDV), and Coxsackievirus A16 (CA16), directly target RIG-I to suppress RIG-I-like receptor-mediated IFN-β production. Mechanistically, these picornaviral 3A proteins partially share the following similar strategies to dysregulate RIG-I activation: (i) all interact with RIG-I, (ii) EMCV and FMDV 3A reduce RIG-I expression, and (iii) SVA, EV71, EMCV, and FMDV 3A impair the interaction between RIG-I and MAVS by diminishing K63-linked ubiquitination of RIG-I. These findings broaden our understanding of how picornaviruses employ nonstructural proteins to evade innate immune responses during early infection.IMPORTANCEPicornaviruses cause a broad spectrum of human and animal diseases; however, the mechanisms by which they counteract host antiviral defenses remain incompletely understood. Owing to the distinct structural features of picornaviral RNA, MDA5 is widely regarded as the primary sensor mediating antiviral responses during picornavirus infection. However, accumulating evidence suggests that RIG-I also contributes to antiviral defense. Picornaviruses have evolved various means to suppress RIG-I and MDA5 activity, thereby facilitating evasion of the innate immune response and underscoring the importance of RIG-I during picornavirus infection. This study identifies RIG-I as a conserved target of the nonstructural protein 3A from multiple picornaviruses, including Senecavirus A, Enterovirus 71, Encephalomyocarditis virus, foot-and-mouth disease virus, and Coxsackievirus A16, and uncovers both shared and virus-specific strategies that dysregulate RIG-I-mediated interferon production. Collectively, these findings expand our understanding of the antagonistic mechanisms of how picornaviruses manipulate the host innate immune system.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by chronic inflammation and dysregulated interferon (IFN) signaling. Many patients remain refractory to existing treatments, underscoring the need for novel therapeutic approaches achievable through drug repurposing. Fluvoxamine, an antidepressant with anti-inflammatory and immunomodulatory properties, has not been systematically studied in SLE. Differentially expressed genes (|Z| ≥ 2) were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Gene Set Enrichment Analysis (GSEA) was applied to assess pathway-level modulation of six hallmark SLE-related signatures. Fluvoxamine induced cell line-specific transcriptomic changes. Jurkat and THP-1 cells showed strong enrichment of TNF-α/NF-κB signaling and regulation of apoptosis-related genes, while HEK293 and A549 cells displayed modulation of cytokine and fibrotic pathways, including NOS3 upregulation. U2OS cells exhibited prominent apoptotic signatures. Although hallmark interferon-α/γ responses were modestly altered at the pathway level, canonical interferon-stimulated genes (e.g. IFI44L, ISG15, MX1) were not significantly downregulated in immune-derived lines. Overall, TNF-α/NF-κB activation and apoptosis emerged as the most consistently affected pathways across models. This integrative transcriptomic study supports fluvoxamine as a candidate immunomodulator with potential relevance for SLE, particularly through modulation of NF-κB and apoptotic pathways. These findings provide a mechanistic rationale for further investigation of sigma-1 receptor-targeting agents in autoimmune diseases.

Interferon (IFN) alpha (IFNα) and lambda3 (IFNλ3) constitute first line responses of immunity against SARS-CoV-2 infection by increasing interferon-stimulated genes (ISGs). Prolonged IFN production may exacerbate inflammation, contributing to endotheliitis and vascular dysfunction in COVID-19. We investigated whether spike protein S1 (SP1) of SARS-CoV-2 via IFN influences inflammation in human vascular and lymphatic endothelial cells (EC) and whether these processes contribute to vascular dysfunction in the context of hypertension. We focused on ISG15, a crucial immune protein that is also implicated in hypertension-associated vascular injury. Exposure of microvascular ECs to SP1 of SARS-CoV-2 induced expression of ISGs: ISG15, MX1 and IFIT1. These effects were potentiated by IFNs and reduced by ADAM17 and STAT1 inhibition and genetic inhibition of IFN alpha and beta receptor subunit 1 (IFNAR1). In microvascular ECs IFNλ3 and IFNα increased expression of ISGs, TMPRSS2, ADAM17, production of pro-inflammatory mediators (TNFα, IL-6, PAI-1) and reduced phosphorylation of eNOS (Ser1177). In pulmonary, lymphatic and aortic ECs, IFNα, but not IFNλ3, increased expression of ISGs and IL-6. To explore the relevance in intact vessels, effects of IFNs were studied in isolated microvessels from wildtype (WT), hypertensive and ISG15-/- mice. IFNα, IFNλ3 and SP1 reduced endothelium-dependent relaxation in WT vessels, whereas IFNα increased contraction in vessels from hypertensive mice. Vascular dysfunction induced by IFNα, IFNλ3 or spike protein was abrogated in vessels from ISG15-/- mice. SP1 and IFNs synergically increase EC expression of ISGs through ADAM17. IFNλ3 and IFNα promote endothelial inflammation and vascular dysfunction through ISG15. These processes may play a role in the endotheliopathy and vascular damage associated with SP1 and might contribute to cardiovascular sequelae, including hypertension, of SARS-CoV-2 infection.

Stronger type I interferon responses in females compared to males, starting from intrauterine life, underpin the sex differences observed in HIV-1 cure/remission outcomes in children and adults. In adults these innate immune sex differences favour females achieving HIV-1 cure/remission over males. Recent studies of the adult viral reservoir reflect the ability of innate immune responses in females, including natural killer (NK) cell activity, to remove cells harbouring intact proviral DNA more effectively than males. In children, the situation is more complex. Initially, in the first years of life, males have a higher propensity to achieve HIV-1 cure/remission, at this stage benefiting from the effects of having weaker interferon (IFN)-I responses, including low baseline HIV-1 DNA loads and being recipients of an IFN-I sensitive transmitted founder virus. By mid-childhood, the picture is mixed, with the impact of stronger innate immunity in females combined with the development of more effective HIV-specific CD8+ T-cell response via immune ontogeny tending to favour females beyond the age of 5-10 years. In children, therefore, the double-edged sword effects of IFN-I in the setting of vertical transmission and immune ontogeny results in distinct, dynamic sex advantages through childhood.

In August 2024, mpox was declared a public health emergency. However, little is known about how the proteins of the mpox virus (MPXV) interact with host innate immunity. This study identified that the D8L protein of MPXV inhibited the interferon (IFN)-mediated antiviral innate immune response and suppressed the mRNA transcription and protein expression of several IFN-stimulated genes, including Cig5, MX2, ISG56, IFITM1, OAS1, and ISG15. Mechanistically, D8L prevented antiviral immune responses by interacting with signal transducer and activator of transcription 1 (STAT1). Furthermore, D8L interacted with the SH2 structural domain of the STAT1 protein but not with other regions. The point-mutant plasmids capable of binding STAT1 were D8L-9-11, D8L-13, and D8L-18. In addition, D8L attenuated IFN responses by inhibiting the phosphorylation and nuclear translocation of STAT1. These findings provide valuable information for the development of novel antiviral therapies.

ObjectiveB-cell activating factor (BAFF) is essential for B-cell survival and innate immune activation, and its dysregulation contributes to the pathogenesis of lupus nephritis (LN). This study investigated whether BAFF-pathway inhibition alters the balance between regulatory B cells (Bregs) and type 1 innate lymphoid cells (ILC1s) in paediatric LN.MethodsIn this prospective, open-label randomised study, 60 paediatric patients with biopsy-confirmed class III/IV LN were randomised to standard therapy (mycophenolate mofetil and corticosteroids; n=30) or standard therapy plus the belimumab (10 mg/kg intravenously every 4 weeks for 6 months; n=30). Ten healthy children and three patients with biopsy-confirmed minimal change disease served as controls. Flow cytometry quantified IL-10-producing Bregs and circulating ILC1s. Clinically indicated paired renal biopsies (n=3) underwent transcriptomic and immunofluorescence analyses.ResultsBelimumab was associated with greater increases in serum C3, reductions in antidouble-stranded DNA titres, decreased proteinuria, improved Systemic Lupus Erythematosus Disease Activity Index 2000 scores and reduced corticosteroid exposure. Belimumab expanded memory B cells and IL-10-producing CD19+CD5+ and CD19+CD24hi+CD38hi+ Bregs, with enhanced suppression of CD4+ T cell proliferation. Treatment reduced circulating and renal ILC1s, downregulated interferon (IFN)-stimulated genes and modulated inflammatory pathways. Serum cytokine profiling showed decreased IFN-γ, interleukin (IL)-17A, IL-10 and BAFF levels, alongside increased IL-35. Phosphorylation of the aryl hydrocarbon receptor and signal transducer and activator of transcription 3 (STAT3) in Bregs was partially restored.ConclusionsBAFF inhibition in paediatric LN is associated with rebalancing of innate and adaptive immunity through enhancement of Breg function and suppression of ILC1-driven inflammation.

Single-cell RNA-seq reveals a persistent interferon signature in immune cells from systemic lupus erythematosus patients with high versus low polygenic risk scores despite antimalarial treatment.

All viruses of the genus Mammarenavirus possess an exoribonuclease (ExoN) domain in their nucleoproteins (NP). Through this domain, the NP efficiently prevents the activation of the interferon (IFN) response, presumably by degrading double-stranded RNA (dsRNA) produced during the viral replication. While the importance of this ExoN activity regarding Mammarenavirus virulence is well established, little is known about the dsRNA molecules that are targeted by NP for degradation, and the contribution of cellular sensors activated by these molecules has yet to be described. Here, we addressed these questions using recombinant viruses with abrogated ExoN domains that are no longer able to control the IFN response. We infected RIG-I, MDA5, and MAVS deficient cells and demonstrated that ExoN mutants activate the interferon response through RIG-I, but not MDA5. We then purified RIG-I-associated RNA from infected cells and confirmed its immunostimulatory activity in transfected cells. We sequenced the RIG-I-associated RNA and identified different enriched sequences in the Mopeia virus (MOPV) or Lassa virus (LASV) RNA. RIG-I activating sequences corresponded to the extremities of the 5' ends and intergenic regions of the MOPV genome and to a glycoprotein precursor complex (GPC) sequence in the LASV genome. We produced corresponding synthetic RNA molecules and confirmed their RIG-I-dependent activation of the IFN response. These results underline the central role of the ExoN domain in MOPV and LASV NP for immune escape and identify new virus-derived RNA molecules with high immunostimulatory properties.IMPORTANCEArenaviruses prevent the activation of the interferon response due to the exonuclease activity of their nucleoprotein, suggesting that infection leads to the production of immunostimulatory RNA molecules. However, neither the exact nature of the immune RNA sensors nor the identity of the RNA activating these sensors is clearly identified. By taking advantage of recombinant MOPV and LASV deficient for their exonuclease activity and that are strong activators of the interferon response, we have identified RIG-I as the major sensor of arenaviruses in infected cells. We also identified the RNA molecules recognized by RIG-I upon infection, and we highlighted differences between MOPV and LASV viruses. Our results represent critical information regarding the factors of immunogenicity and pathogenicity of Old-World arenaviruses and can help us explain key differences between pathogenic and non-pathogenic arenaviruses.

Efficacy and mechanism of topical Chinese herbal formulation JieZe-1 on female lower genital tract co-infection with HSV-2 and Candida albicans via upregulating the cGAS/STING/IFN-I pathway.

5'-Triphosphate guanosine RNAs recruit GTP-binding proteins to suppress RIG-I/IFN type I signaling.

Psoriasis is a chronic skin disease characterized by keratinocyte hyperproliferation and inflammation, largely driven by the cytokines IL-22 and interferon (IFN)-γ. These cytokines activate the signal transducer and activator of transcription (STAT) 3 and STAT1 molecular pathways, leading to abnormal proliferation, impaired differentiation, and increased production of inflammatory mediators in keratinocytes. While the IL-22/STAT3 pathway primarily promotes de-differentiation in keratinocytes, IFN-γ/STAT1-3 signaling induces pronounced inflammation, despite exerting antiproliferative effects on these cells. Recent research has highlighted the role of serine/glycine metabolism in the pathogenesis of psoriasis, by supporting T cell and keratinocyte proliferation. Furthermore, pharmacological inhibition of serine catabolism through targeting serine hydroxymethyltranferase (SHMT)1/2 enzymes reduced the infiltration of inflammatory cells in the skin of the imiquimod-induced mouse model of psoriasis. This study investigates the role of serine catabolism in psoriasis, focusing on its influence on keratinocyte proliferation and inflammation. We examined how pharmacological inhibition of SHMT1/2, mediated by a folate-competitive cell-permeable inhibitor Serine Hydroxymethyltransferase INhibitor 1 (SHIN1), affects keratinocyte proliferation and inflammatory signaling pathways in response to psoriasis-associated cytokines IL-22 and IFN-γ, using both in vitro and ex vivo models of the disease. We found that SHIN1 reduced keratinocyte proliferation, particularly under IL-22 stimulation, and restored differentiation in ex vivo psoriasis skin explants by reversing the effects of IL-22. SHIN1 also inhibited IFN-γ-induced expression of pro-inflammatory genes (e.g., CXCL10, CXCL9, CCL5, CCL2, IL-6) and reduced STAT3 activation, with only modest effects on STAT1 and extracellular signal-regulated kinase 1/2 activation. In psoriasis explants, SHIN1 decreased the expression of Ki67, Keratin 16, and pro-inflammatory cytokines including IL-17A, IL-22, and IFN-γ. These findings support the therapeutic potential of SHIN1 as a metabolism-targeted agent for psoriasis and other cytokine-mediated skin disorders, providing a rationale for further exploration of novel treatment strategies.

Ablation of ASF1B mitigates the proliferation of A549 cells and enhances anti-PD-L1 therapy by regulating ferroptosis.

Juvenile dermatomyositis (JDM) is a chronic multisystem vasculopathy and inflammatory myopathy characterized by proximal muscle weakness, distinct rash, and risk of complications such as calcinosis cutis, skin ulceration, and mortality. Molecular insight from diagnostic muscle biopsy histology is limited, and the mechanistic pathoetiology of JDM remains poorly defined. We used single nuclei transcriptomics to assess muscle samples from patients with newly diagnosed treatment-naïve JDM. As a control, we assessed muscle samples from patients with congenital (nemaline) myopathy (CM), a non-inflammatory disorder. A total of 25,794 high quality nuclei were analyzed and clustered into various muscle-resident or infiltrating cellular populations. JDM tissue was characterized by an enriched interferon (IFN) response signature across endothelial, stromal, and immune cell compartments. Endothelial and perivascular populations showed increased inflammatory and angiogenic programs. Intercellular communication inference analysis identified dysregulated vascular endothelial growth factor (VEGF)-related signaling involving endothelial, stromal, and myonuclear populations as a possible mechanism for myonuclear-driven modulation of the muscle microvasculature. Spatial RNA in situ hybridization supported increased expression of selected IFN responsive and angiogenesis signaling genes in JDM tissue. Collectively, these data provide a cell type-resolved view of treatment-naïve JDM muscle and highlight vascular and IFN pathways for follow-up in larger cohorts.

Although toll like receptor (TLR) ligands are effective vaccine adjuvants, current synthetic TLR2 agonists suffer from low solubility, high cost, and detrimental effect towards protein antigen. Present study aimed to evaluate the immunostimulatory potential of five in-house PAM2CS lipopeptide-based TLR2 agonists (P1, P2, P6, P7 and P8) using peripheral blood mononuclear cells (PBMCs) from chicken (n = 4). Each agonist (10µg/mL) significantly upregulated the expression of interleukin (IL)-1 β and inducible nitric oxide synthase (iNOS) at 3h post-treatment with highest expression of IL-1β mRNA was observed with P1. There was a significant up-regulation of interferon (IFN)-β and IFN-γ by treatment with P1 at 3 and 12h intervals (p < 0.05). Further, IL-4 mRNA was significantly upregulated with P1 and P7 treatment at 12 and 24h post-treatment respectively. Our results demonstrate that among all five agonists, P1 was the most effective in enhancing immune response genes expression including both type I and type II interferons, and in eliciting a balanced Th1 and Th2 responses.

Comparative structural analysis of Nipah virus V proteins highlights V-MDA5 complex stability in pig and bat isolates.

Aging-related frailty is associated with immune dysregulation, including chronic inflammation and immunosenescence. Human allogeneic mesenchymal stem cells (hMSCs) have been proposed as immunomodulatory therapies; however, the responsive immune domains remain unclear. This systematic review and meta-analysis explored immune and inflammatory biomarkers reported in randomized controlled trials (RCTs) of hMSC therapy for aging-related frailty. Major databases were searched through April 2026 for RCTs enrolling adults aged ≥60 years with clinically diagnosed frailty. Outcomes encompassed innate inflammation, adaptive immune activation and composition, immunosenescence-related measures, and alloimmune responses. Biomarkers reported by at least two trials were pooled using a random-effects model. Three RCTs (n = 196) met the eligibility criteria. hMSC therapy was associated with a significant reduction in tumor necrosis factor-α (TNF-α) at 6 months (mean difference [MD] −0.61, 95% CI −1.08 to −0.14), while interleukin (IL)-6, IL-8, interferon (IFN)-γ, and the CD4/CD8 ratio showed no consistent effects. Limited alloimmune data indicated no clinically meaningful immune sensitization. Overall, hMSC therapy may preferentially attenuate innate TNF-α–driven inflammation, while other immune effects remain exploratory.