Search Results (2,632)

Maternal immune tolerance and controlled inflammatory responses are essential for fetal development and successful pregnancy. Regulatory T cells (Tregs) and B cells with regulatory properties (Bregs) maintain this balance by limiting excessive immune activation through the secretion of anti-inflammatory and tolerogenic cytokines, such as IL-10, TGF-β, and IL-35. Moreover, alterations in the costimulatory potential of antigen-presenting cells (APCs), including B cells, modulate the activation and differentiation of T cells. Toll-like receptors (TLRs), particularly TLR9, influence B-cell antigen presentation and cytokine production, thereby affecting the balance between pro-inflammatory and tolerogenic responses at the maternal–fetal interface. TLR9 overexpression has been observed in several pregnancy-related disorders in both humans and murine models. In this study, we examine whether blocking TLR9 shortly after mating could improve pregnancy outcomes and modulate the regulatory and antigen-presenting functions of B cells, as well as their interactions with T cells. Using an abortion-prone murine model (CBA/J × DBA/2J), we show that intraperitoneal administration of a TLR9 antagonist (ODN 2088) shortly after mating increases embryo resorption in CBA/J females compared to controls without affecting implantation. Flow cytometry analysis further reveals that mice receiving the TLR9 antagonist are characterized by downregulation of CD80 and upregulation of CD86 on B cells, accompanied by reduced expression of CD40L and CD28 on T cells, as well as a lower percentage of Tregs and activated T cells. In conclusion, blocking TLR9 signaling shortly after mating does not improve pregnancy outcomes; conversely, it exacerbates pregnancy loss in the CBA/J × DBA/2J abortion-prone model, while altering the costimulatory phenotype of B and T cells and impairing Treg development during pregnancy. Full article

Sharp declines in temperature pose a significant risk for mass mortality events in the Chinese soft-shelled turtle (Pelodiscus sinensis). To assess the effects of acute cold stress on intestinal health, turtles were exposed to temperatures of 28 °C (control), 14 °C, and 7 °C for 1, 2, 4, 8, and 16 days. The results showed that acute cold stress at 14 °C and 7 °C induced time-dependent alterations in intestinal morphology and histopathology. The damage was more severe at 7 °C, characterized by inflammatory cell infiltration, lymphoid hyperplasia, and extensive detachment and necrosis across the villi, muscle layer, and submucosa. 16S rDNA sequencing revealed significant shifts in intestinal microbiota composition in the 7 °C group, dominated by Helicobacter and Citrobacter. Transcriptomic analysis identified differentially expressed genes (DEGs) that respond to acute cold stress and are involved in the Toll-like receptor signaling pathway (Tlr2, Tlr4, Tlr5, Tlr7, and Tlr8), the NOD-like receptor signaling pathway (Traf6, Traf2, Casr, Rnasel, Pstpip1, Plcb2, Atg5, and Mfn2), apoptosis (Tuba1c, Ctsz, Ctsb, Kras, Hras, Pik3ca, Bcl2l11, Gadd45a, Pmaip1, Ddit3, and Fos), and the p53 signaling pathway (Serpine1, Sesn2, Ccng2, Igf1, Mdm2, Gadd45a, Pmaip1, and Cdkn1a). Metabolomic profiling highlighted differentially expressed metabolites (DEMs) that cope with acute cold stress, such as organic acids (oxoglutaric acid, L-aspartic acid, fumaric acid, DL-malic acid, and citric acid) and amino acids (including L-lysine, L-homoserine, and allysine). The integrated analysis of DEGs and DEMs underscored three key pathways modulated by acute cold stress: linoleic acid metabolism, neuroactive ligand–receptor interaction, and the FoxO signaling pathway. This study provides a comprehensive evaluation of intestinal health in Chinese soft-shelled turtles under acute cold stress and elucidates the underlying mechanisms. Full article

Parkinson’s disease is a neurodegenerative disorder that affects the elderly population worldwide. Rotenone (ROT) is an environmental toxin that impairs mitochondrial dynamics by inhibiting respiratory chain complex I and thus inducing oxidative stress. Farnesol (FSL) is a dietary sesquiterpene with antioxidant and anti-inflammatory properties reported in various in vivo models. To evaluate the efficacy of FSL in the management of PD, Wistar rats were injected with ROT (2.5 mg/kg, i.p) and pretreated with FSL. Immunohistochemical staining measured tyrosine hydroxylase-positive cells in the substantia nigra and striatum. Western blotting was employed to determine protein expression of inflammatory, apoptotic, and autophagic markers. Our results indicate that FSL significantly protected against ROT-induced inflammation by suppressing microglial and astrocytic activation through the downregulation of Toll-Like receptor 4 (TLR4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inhibitor of kappa B (IkB), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX), matrix metalloproteinase-9 (MMP-9) expression. FSL has also demonstrated an antioxidant effect by enhancing the activity of superoxide dismutase and catalase while reducing the level of Malondialdehyde and nitric oxide. Moreover, it restored homeostasis in ROT-induced imbalance between pro- and anti-apoptotic proteins. Impaired autophagy observed in ROT-injected rats was corrected by FSL treatment, which upregulated phosphorylated mammalian target of rapamycin (p-mTOR) expression and downregulated P62, an autophagosome marker. The protective effect of FSL was further supported by preserving the brain-derived neurotrophic factor (BDNF) and tyrosine hydroxylase in the brain. These findings demonstrate the neuroprotective ability of FSL and its potential to be developed as a pharmaceutical or nutraceutical agent for the prevention and treatment of PD by mitigating neuropathological changes observed in dopaminergic neurodegeneration. Full article

Acute lung injury may occur after cardiac arrest (CA), with innate immunity likely playing an important role in lung inflammation after CA. This study aimed to survey serial changes in the toll-like receptor (TLR) 4 signaling pathway in post-resuscitation lung injury in CA rats. A randomized animal study was conducted in rats with CA followed by successful cardiopulmonary resuscitation (CPR). The expression of TLR4 pathway biomarkers was analyzed and compared to the sham controls at different time points after CA with CPR. Lung tissues were collected for histological analysis to assess structural damage. Bronchoalveolar lavage fluid (BALF) was analyzed to quantify inflammatory cytokines and to assess changes in regulatory B cells (Bregs) and regulatory T cells (Tregs). Histological examination revealed marked pulmonary hemorrhage and structural injury shortly after CA. CA with CPR increased myeloid differentiation factor 88 (MyD88) mRNA and protein expression compared to controls at 2 h after CA. Cytokine analysis of BALF showed elevated IFN-γ, interleukin (IL)-1α, IL-1β, IL-2, IL-6, and IL-10 at 2 h after CA. A reduction in Bregs was noted at 2 h, whereas Tregs transiently increased between 2 and 4 h but declined at 6 h after CA. The MyD88-dependent signaling pathway appears to be rapidly activated in rats with CA after CPR, which may contribute to the early pulmonary inflammation observed as soon as 2 h after CA. Full article

White Spot Syndrome Virus (WSSV) remains one of the most devastating pathogens in global shrimp aquaculture, causing massive economic losses annually. This study employed comparative transcriptomics to elucidate the molecular basis of the differential resistance to WSSV between the highly susceptible Pacific white shrimp (Litopenaeus vannamei) and the remarkably resistant oriental river prawn (Macrobrachium nipponense). Our analysis of gill, hepatopancreas, and muscle tissues at 24 h post-infection revealed fundamentally distinct defense strategies. The resistant M. nipponense employs a unique “proactive homeostatic reinforcement” strategy, characterized by significant enrichment of pathways central to cellular homeostasis, including signal transduction, cellular processes, and transport/catabolism. This approach, supported by coordinated up-regulation of heat shock proteins and structural genes, enables effective viral control without triggering excessive immune activation. In contrast, susceptible L. vannamei displays either widespread metabolic dysregulation leading to systemic collapse in moribund individuals or dependency on specific immune pathways (Toll-like receptor signaling and apoptosis) in survivors. Through comparative KEGG analysis, we identified heat shock protein 70 kDa (HSP70, K03283) as a key conserved gene and functionally validated its critical role in antiviral defense using RNA interference. Knockdown of HSP70 in M. nipponense significantly increased cumulative mortality and viral load, confirming its essential protective function. These findings provide novel insights into crustacean antiviral immunity and identify promising genetic targets for breeding WSSV-resistant shrimp strains, offering sustainable solutions for disease management in aquaculture. Full article

Ovarian cancer (OC), the third most common gynecologic malignancy, is characterized by high mortality largely driven by chemotherapy resistance, leading to recurrence and metastasis. Using transcriptomic data from GSE73935, we constructed a weighted gene co-expression network and identified eight hub genes (IGF1R, CDH2, PDGFRA, CDKN1A, SHC1, SPP1, CAV1 and FGF18) associated with cisplatin resistance, among which CDH2 emerged as the most clinically relevant candidate. CDH2 demonstrated moderate diagnostic potential (AUC = 0.792) and was markedly upregulated in cisplatin-resistant A2780/CP70 cells. Independent validation using clinical single-cell RNA-seq data (GSE211956) confirmed its selective enrichment in resistant tumor cell subpopulations. Gene set enrichment analysis linked elevated CDH2 expression to p53 signaling, DNA replication, nucleotide excision repair, and Toll-like receptor pathways, with qPCR supporting upregulation of key downstream genes in resistant cells. Immune deconvolution further indicated that high CDH2 expression correlated with increased infiltration of NK cells, Tregs, macrophages, and neutrophils, and immunohistochemistry verified CDH2 overexpression in cisplatin-resistant tissues. In addition, virtual screening and drug sensitivity profiling identified several FDA-approved agents with potential relevance to CDH2-associated drug response. These findings indicate that CDH2 may serve as a candidate marker associated with cisplatin response in OC, and its association with immune cell infiltration provides further insight into mechanisms potentially underlying chemoresistance. Full article

Background and Objectives: Toll-like receptors (TLRs) are pattern recognition receptors with an essential role in regulating both the innate and adaptive immune response. Given their pleiotropic effects in mounting an immune response, previous studies have proposed targeting these TLRs might render alternative strategies for cancer therapy. Synthetic immune response modifiers, such as imidazoquinolines, stimulate the immune cells by activating Toll-like receptors, particularly TLR7/8 receptors, consequently mounting an immune response. Agonists of this class activate, via TLR-mediated signaling, dendritic and B cells, as well as myeloid cells and T cells, thus exhibiting good prospects for cancer immunotherapy. In the present study, we sought to evaluate the effect of imiquimod and gardiquimod, two TLR 7 and 7/8 agonists, respectively, on tumor growth and phenotype of NK cells associated with melanoma. Materials and Methods: We generated a syngeneic model of melanoma in C57BL/6J mice by subcutaneously injecting murine melanoma cells and monitoring tumor growth. Starting on day 8 or 14, we applied TLR agonists either intratumorally or topically and followed the tumor dynamics and NK cell-associated pattern. Results: Our results suggest that both TLR agonists displayed an antitumor effect along with a phenotypically activated profile of NK cells. Both imiquimod and gardiquimod treatment inhibited tumor growth, with gardiquimod showing an increased potency compared to imiquimod. Conclusions: This implies that TLR agonists like imiquimod and gardiquimod could serve as neoadjuvant, adjuvant, or complementary immunotherapeutic agents in melanoma therapy. Full article

Background/Objectives: This study aimed to evaluate the serum activating transcription factor 4 (ATF4) and toll-like receptor 4 (TLR4) levels in patients with metabolic dysfunction–associated steatotic liver disease (MASLD), and to explain the mechanism in the inflammatory and fibrogenic signaling pathways that are thought to play a role in the development of MASLD through these parameters. Methods: Eighty-eight patients with MASLD and 88 age-sex matched healthy controls were included in this study. Serum ATF4 and TLR4 concentrations were measured using an ELISA method. Results: Both TLR4 (p = 0.010) and ATF4 (p < 0.001) levels were higher in the MASLD group. In this group, TLR4 showed a negative correlation with age. ROC analysis indicated that an ATF4 value of 1.305 or above identified MASLD with 93.2% sensitivity and 85.2% specificity (AUC = 0.968, p < 0.001). For TLR4, a cut-off of 343.5 yielded a sensitivity of 54.5% and a specificity of 70.5% (AUC = 0.613, p = 0.01), indicating limited discriminative ability. Conclusions: Patients with MASLD had higher serum TLR4 and ATF4 levels, consistent with their involvement in inflammatory and fibrotic pathways. ATF4 showed strong diagnostic performance and may serve as a useful non-invasive marker for early MASLD. When evaluated together with TLR4, it may provide complementary information regarding inflammatory pathway activation. Full article

Autoimmune flares are often accompanied by abrupt surges of circulating plasmablasts—short-lived, high-output antibody-secreting cells generated through extrafollicular B-cell activation in response to microbial cues. Three categories of microbial input appear to repeatedly trigger these “plasmablast storms”: latent herpesvirus reactivations (Epstein–Barr virus, cytomegalovirus, human herpesvirus-6, varicella–zoster virus), acute respiratory or gastrointestinal infections including SARS-CoV-2, and chronic oral or gut dysbiosis. Although biologically distinct, these stimuli converge on innate sensing pathways driven by pathogen-associated molecular patterns such as unmethylated CpG DNA, single-stranded RNA, lipopolysaccharide, and bacterial lipoglycans. Through Toll-like receptors and type I interferon signalling, microbial signatures accelerate class switching, amplify inflammatory cytokine milieus, and lower B-cell activation thresholds, enabling rapid plasmablast mobilisation. Dysbiosis further maintains B cells in a hyper-responsive state by disrupting mucosal homeostasis and altering microbial metabolite profiles, thereby reducing the stimulus required to trigger plasmablast bursts. Once generated, these waves of oligoclonal plasmablasts home to inflamed tissues, where chemokine and adhesion landscapes shape their retention during flares. Emerging evidence suggests that such episodic plasmablast expansions promote autoantibody diversification, somatic hypermutation, and epitope spreading, progressively eroding tolerance. This review synthesizes these insights into a unified model in which infections and dysbiosis promote microbe-licensed plasmablast storms that influence the tempo and severity of autoimmune disease. Full article

Salmonella typhimurium (S.T) infection of the central nervous system (CNS) induces severe inflammation, leading to elevated expression of inducible nitric oxide synthase (iNOS) in microglia. This process catalyzes excessive production of nitric oxide (NO), resulting in irreversible damage to neuronal mitochondria. Asiatic acid (AA) is a small molecule with neuroprotective potential; however, its ability to counteract nerve injury induced by S.T and the underlying mechanisms remain unclear. In this study, we established an S.T-infected mouse model (in vivo) and an S.T-stimulated microglial model using BV-2 cells (in vitro) and employed techniques including immunofluorescence (IF), Western blot, co-immunoprecipitation (Co-IP), and RNA extraction and quantitative reverse transcription PCR (RT-qPCR) to systematically evaluate the protective effects and mechanisms of AA. The results showed that pre-treatment with AA significantly reduced the expression of iNOS and the production of NO caused by S.T infection in mouse hippocampal tissue and BV-2 cells. Mechanistically, AA exerts its effects by inhibiting the upstream Toll-like receptor 2 (TLR2)/Notch and nuclear factor-κB (NF-κB) signaling axis. It interferes with the nuclear translocation of Notch and p65 proteins and their complex formation under S.T stimulation, thereby blocking downstream expression of iNOS and production of NO. This study reveals a novel mechanism by which AA alleviates infection-related neuroinflammation through targeting Notch-p65 interactions, providing a new theoretical basis for its clinical application. Full article

Chronic HBV infection remains a global health challenge, driving liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver injury is primarily mediated by host immune responses rather than direct viral cytotoxicity. Macrophages, including Kupffer cells, play dual roles in antiviral defense and disease progression. HBV skews macrophages toward an M2-like, immunosuppressive phenotype, promoting viral persistence and fibrogenesis via cytokines such as Interleukin (IL)-10 and Transforming growth factor-beta (TGF-β). Therapeutic strategies targeting macrophage polarization, including Toll-like receptor (TLR) agonists, immune checkpoint inhibitors, and nanoparticle-based systems, are under investigation. Addressing macrophage heterogeneity and the immunosuppressive hepatic microenvironment using advanced models is essential. Modulating macrophages offers a promising avenue to control HBV, restore immune balance, and mitigate liver injury. This review highlights the central role of macrophages in chronic HBV infection and explores emerging therapeutic strategies. Full article

Compound yeast culture (CYC) is known to enhance animal health, but its effects on hepatic immune function are unclear. This study systematically examined CYC’s regulatory effects on the liver of weaned lambs using transcriptomics and integrative bioinformatics. Ten lambs were randomly assigned to a control diet or a basal diet supplemented with 30 g/d per head of Saccharomyces cerevisiae and Kluyveromyces marxianus co-culture (CYC group) for 42 days. Histological analysis showed that CYC improved hepatocyte arrangement and sinusoidal integrity, suggesting enhanced hepatic tissue stability. Cytokine analysis revealed CYC significantly increased IL-6 and IL-1β while reducing IL-10, TGF-β1, TNF-α, and CXCL9, indicating a bidirectional modulation of the immune response. Additionally, CYC enhanced antioxidant defenses by increasing T-SOD, GSH-Px, and T-AOC activities and decreasing MDA content. Transcriptomic sequencing indicated that CYC reshaped hepatic gene expression. Upregulated genes were enriched in immune-regulatory and structural pathways, including PI3K-AKT signaling, ECM–receptor interactions, Toll-like receptor pathways, and cell adhesion molecules. Protein-level validation further confirmed activation of PI3K and AKTAKT phosphorylation with limited engagement of NF-κB signaling. Conversely, downregulated genes were mainly associated with oxidative stress and energy metabolism, such as ROS-related pathways and MAPK signaling. WGCNA identified key hub genes (PTPRC, CD86, and ITGAV), which correlate with pro-inflammatory factors and participate in immune recognition, T-cell activation, and cell adhesion. These data suggest that CYC promotes hepatic immune homeostasis by enhancing immune signaling, stabilizing tissue architecture, and modulating oxidative stress/metabolic processes. This study provides mechanistic insights into CYC’s regulation of liver immune function and supports its targeted application as a functional feed additive for ruminants. Full article

Deprivation of sleep (DS) is linked to increased risk of immune-mediated diseases. Toll-like receptors (TLR7, TLR9) and BANK1 are key B-cell signaling components that may contribute to their pathogenesis. Seventy-six adults underwent polysomnography (PSG) followed by DS. Venous blood was collected after PSG and DS. Mood was evaluated before and after each stage using Montgomery–Åsberg Depression Rating Scale. Participants were classified as Responders (REs) or Non-Responders (NRs) based on mood changes post-DS. Gene mRNA expression of TLR7, TLR9, and BANK1 in peripheral blood mononuclear cells was analyzed by qRT-PCR. DS reduced TLR7 expression in the entire study group and within NRs, REs, and male and female subgroups (all p < 0.001). During analysis of covariance, women exhibited higher TLR7 expression than men post-DS (p = 0.022), independent of age and body mass index (BMI). At baseline, women exhibited lower expression of TLR9 (p = 0.009, independent of age and BMI), which was abolished after DS (p = 0.570). BANK1 expression increased post-DS in the entire study group and in NRs (p = 0.021), but not REs (p = 0.329). DS modulates B-cell-related immune signaling, with reduced TLR7 and increased BANK1 expression in a sex- and mood-dependent manner. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disease in which barrier impairment, immune dysregulation, and gut–skin dysbiosis intersect, prompting growing interest in probiotics as microbiota-modulating adjuncts. We conducted a narrative review of peer-reviewed articles indexed in PubMed, Scopus, and Google Scholar, restricted to publications from 1 January 2018 to 31 October 2025 (searches last run in December 2025). Eligible evidence included randomized controlled trials (RCTs), observational studies, and mechanistic or conceptual reviews addressing microbiome alterations and microbiota-modulating interventions in AD. Most pediatric RCTs using multistrain, Lactobacillus-dominant formulations (often combined with Bifidobacterium) reported modest improvements in AD severity and pruritus and in selected barrier- and inflammation-related biomarkers. However, direct cutaneous microbiome “restoration” outcomes were reported in a minority of studies, and most clinical evidence relies on clinical endpoints and gut–skin axis plausibility rather than longitudinal skin microbiome readouts. Single-strain regimens showed inconsistent effects, and evidence in adolescents and adults remained heterogeneous. Mechanistically, probiotics may enhance short-chain fatty acid (SCFA) signaling, dampen toll-like receptor 2/4 (TLR2/4)-nuclear factor kappa B (NF-κB) activation, and promote interleukin-10 (IL-10)- and transforming growth factor-β (TGF-β)-driven tolerance. Probiotics are a biologically plausible adjunct targeting the gut–skin axis in AD and are generally well tolerated; however, heterogeneity across trials, limited follow-up, inconsistent adverse-event reporting, and scarce skin microbiome endpoints preclude firm clinical recommendations. Full article

Toll-like receptor 7 (TLR7) and Stimulator of Interferon Genes (STING) ligands possess a series of immunomodulatory effects such as anti-infection, anti-tumor, and autoimmune-disease-alleviating effects. In this study, porcine TLR7 (pTLR7) and porcine STING (pSTING) were selected as targets, and molecular docking and virtual screening methods were used for screening of dual-target livestock immunomodulators. Finally, two compounds were screened with molecular docking scores higher than the positive control compounds. They have good binding ability with pTLR7 and pSTING proteins, as well as satisfactory predictive safety and pharmacokinetic properties. Molecular dynamics (MD) simulation results also indicated that the above ligands can form stable complexes with two target proteins. The average binding free energies of compound 2 with pTLR7 and pSTING were −28.65 kcal/mol and −30.12 kcal/mol, respectively, and of compound 7 with pTLR7 and pSTING were −35.93 kcal/mol and −31.70 kcal/mol, respectively, which were comparable to that of positive control ligands. The similarity of target proteins between pigs, humans, and mice, as well as the interactions between ligands and TLR7 and STING in different species, were analyzed. And analysis of predicted structure–activity relationship (SAR) was conducted. Briefly, compound 2 and compound 7 were predicted to form stable complexes with pTLR7 and pSTING, with satisfactory predicted physicochemical properties and pharmacokinetic characteristics, and represented candidates for experimental validation. This study supplies a research basis for the development, design, and structural modification of immune enhancers for animals. Full article