Search Results (908)

Background/Objectives: Osteoarthritis (OA) is biologically heterogeneous, and the relationship between MRI-detected inflammation and circulating innate immune activity remains uncertain. This study aimed to determine whether serum soluble Toll-like receptor 4 (sTLR4) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) distinguish between the study-specific MRI-defined INF-OA and non-INF-OA categories, and whether these biomarkers are associated with OA disease burden. Methods: This prospective, single-center, cross-sectional study included 30 patients with knee OA and 30 asymptomatic healthy controls. Patients with active OA flare-up, defined by a Knee Osteoarthritis Flare-Ups Score (KOFUS) ≥ 7, were excluded before MRI assessment and category assignment. Patients with OA were assigned to study-specific MRI-defined categories using MRI Osteoarthritis Knee Score (MOAKS) features: INF-OA (n = 16) required effusion-synovitis and/or Hoffa-synovitis-related signal alteration graded ≥ 1, whereas non-INF-OA (n = 14) required grade 0 for both features. Biomarkers were measured by enzyme-linked immunosorbent assay. Primary within-OA biomarker comparisons were Holm-corrected, and adjusted models included age, sex, and body mass index (BMI). Results: Serum sTLR4 and sTREM-1 did not differ between INF-OA and non-INF-OA after Holm correction (adjusted p = 0.710 for both). In age-, sex-, and BMI-adjusted models, the INF-OA versus non-INF-OA geometric mean ratios were 1.15 (95% CI 0.92–1.44; p = 0.219) for sTLR4 and 1.09 (95% CI 0.89–1.35; p = 0.398) for sTREM-1. Given the modest within-OA subgroup sizes, smaller or moderate between-category differences cannot be excluded. After covariate adjustment, the overall OA cohort had higher geometric mean concentrations than controls for sTLR4 (ratio 1.85, 95% confidence interval 1.56–2.20; p < 0.001) and sTREM-1 (ratio 1.67, 95% confidence interval 1.43–1.97; p < 0.001). None of the systemic inflammatory measurements significantly distinguished INF-OA from non-INF-OA after correction for multiple comparisons. Within the OA cohort, each 1 ng/mL increase in sTLR4 was associated with a 4.99-point higher Western Ontario and McMaster Universities Osteoarthritis Index total score after adjustment for age and body mass index (95% confidence interval 2.28–7.70; p < 0.001). Conclusions: Circulating sTLR4 and sTREM-1 concentrations were higher in patients with OA than in asymptomatic healthy controls but did not distinguish the study-specific INF-OA and non-INF-OA categories in this sample. These findings should not be interpreted as evidence of biological equivalence between the MRI-defined categories. sTLR4 warrants further evaluation as a circulating correlate of current OA burden in larger longitudinal and multimodal studies. Full article

A high-fat diet (HFD) promotes lipid metabolic disorders, chronic low-grade inflammation and skeletal muscle dysfunction. Kukoamine B (KB), a Lycium-derived polyamine alkaloid with reported anti-inflammatory and antioxidant activities, may protect against HFD-associated muscle impairment. C57BL/6J mice were fed an HFD and orally administered KB for 12 weeks. Muscle function was evaluated using inverted grid, forelimb grip strength and treadmill exhaustion tests. Histological, transcriptomic, ELISA, immunofluorescence and Western blot analyses were used to assess muscle injury and inflammatory signalling. KB reduced intramuscular lipid deposition, collagen accumulation and myofibre damage, improved muscle strength and exercise endurance, and partially restored AKT/mTOR-associated protein metabolic signalling. Transcriptomic analysis showed that KB downregulated HFD-activated inflammatory responses, chemokine signalling, lipopolysaccharide responses and Toll-like receptor-related pathways. KB also reduced plasma and skeletal muscle LPS levels, inhibited TLR4/MyD88/NF-κB signalling, and decreased TNF-α and IL-1β expression. TAK-242 mimicked the anti-inflammatory and muscle function-improving effects of KB, whereas their combination produced no statistically detectable additional effect under the conditions tested. These findings suggest that KB attenuates HFD-induced skeletal muscle dysfunction, potentially involving reduced LPS burden and suppression of TLR4/NF-κB-mediated metabolic inflammation. Full article

The skin of Rana amurensis serves as an important defense barrier against microbial challenges, yet the molecular basis of its cutaneous immune defense and antimicrobial peptide (AMP) repertoire remains incompletely understood. Here, we established a skin transcriptomic profile of R. amurensis following Aeromonas hydrophila infection and integrated transcriptomic and bioinformatic approaches to characterize transcriptional responses and identify candidate AMPs. A total of 1669 differentially expressed genes (DEGs) were identified between the uninfected and infected groups, including 1091 up-regulated and 578 down-regulated genes. Infection with A. hydrophila induced marked transcriptional changes in innate immune-related genes and pathways, including differential expression of genes associated with the Toll-like receptor (TLR) signaling pathway. Transcriptome-based screening identified 151 candidate AMP sequences. Based on sequence characteristics, evolutionary conservation, and physicochemical properties (length ≤50 amino acids and net charge ranging from +2 to +9), six candidates were selected and three randomly selected candidates were chemically synthesized and exhibited antimicrobial activity against bacterial pathogens, inducing less than 10% hemolysis and maintaining L929 cell viability above 79% at 64 μg/mL. These findings indicate that A. hydrophila infection induces coordinated transcriptional responses involving innate immune-related pathways and diverse candidate AMPs in R. amurensis. This study supports the utility of transcriptome-guided discovery for identifying candidate AMPs in amphibians and provides insights into the molecular basis of skin defense in R. amurensis. Full article

Feline intestinal inflammation is a common gastrointestinal disorder in cats and is associated with immune dysregulation, epithelial barrier injury, microbial imbalance, and persistent inflammatory signaling. This entirely in silico study investigated predicted molecular associations between vine tea (Ampelopsis grossedentata) constituents and feline intestinal inflammation using network pharmacology, molecular docking, and molecular dynamics simulation. No feline cells, tissues, animals, or clinical samples were used. Candidate compounds were screened and evaluated with SwissADME as a computational prioritization step, and potential targets were predicted using multiple databases. Human-centric database-derived genes associated with the broad intestinal-inflammation phenotype were subjected to feline ortholog mapping/verification and intersected with predicted vine tea targets. Protein–protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed, followed by construction of a compound-target-pathway-disease network. Ten representative compounds were cross-docked against six core targets, producing 60 docking combinations, and the lowest-energy complex was subjected to a 100 ns molecular dynamics simulation. Seventeen candidate compounds, 966 predicted vine tea targets, and 102 candidate shared targets were retained in the archived workflow. IL6, TNF, IL1B, STAT3, CASP3, and TLR4 were prioritized as core targets. Enrichment analysis linked the shared-target set to inflammatory responses, innate immunity, cytokine activity, Th17 cell differentiation, and the IL-17, Toll-like receptor, NOD-like receptor, NF-kappa B, TNF, JAK-STAT, and PI3K-Akt signaling pathways. Molecular docking predicted favorable interactions between several compounds and the core targets, particularly IL6, and the IL6-cianidanol complex showed the lowest docking energy and relative stability during simulation. Overall, the analyses prioritize candidate compounds, targets, and pathways for subsequent feline-specific validation; they do not demonstrate therapeutic efficacy, target regulation, or biologically relevant exposure in cats. Full article

Sepsis-associated acute kidney injury (AKI) is a severe inflammatory complication with limited therapeutic options. This study investigated the protective effects of Taiwan Chingguan Yihau (NRICM101), a herbal formulation, against lipopolysaccharide (LPS)-induced AKI. Male C57BL/6 mice were injected with LPS to induce AKI in vivo, followed by therapeutic administration of NRICM101. NRK-52E renal epithelial cells were stimulated with LPS to induce inflammatory responses and oxidative stress in vitro. Key bioactive compounds were identified via HPLC and analyzed using molecular docking. NRICM101 significantly alleviated renal dysfunction, as indicated by blood urea nitrogen (BUN) and serum creatinine (Scr) levels, and reduced histopathological damage in mice. It effectively suppressed the production of pro-inflammatory cytokines, attenuated intracellular and mitochondrial ROS, and preserved mitochondrial membrane potential. Mechanistically, NRICM101 markedly downregulated the expression of phosphorylated p65 (p-p65), NOD-like receptor protein 3 (NLRP3), and cleaved caspase-1, indicating modulation of nuclear factor kappa-B (NF-κB)/NLRP3 inflammasome signaling associated with renal pyroptosis. Molecular docking predicted potential interactions of NRICM101-derived bioactive constituents with the toll-like receptor 4 (TLR4)/MD-2 complex. Collectively, our findings suggest that NRICM101 ameliorates LPS-induced acute renal injury through anti-inflammatory and antioxidant effects associated with modulation of NF-κB/NLRP3-related signaling. Full article

The progression of tuberculosis (TB) from a latent infection to an active disease involves intricate modifications in host immune, inflammatory, oxidative, and metabolic pathways. Ferroptosis represents a distinct form of regulated cell death that requires iron and is associated with excessive lipid peroxidation and has been associated with tissue damage in TB; however, its connection with host transcriptional changes during active TB is not fully understood. This study sought to identify and externally validate immune–inflammatory hub genes among differentially expressed genes (DEGs) in active TB that overlap with a ferroptosis-associated gene set derived from FerrDb, employing an integrated transcriptomic and systems-biology methodology. Differential expression analysis of GSE37250 revealed 1015 DEGs in active TB compared to latent TB, comprising 585 upregulated and 430 downregulated genes, and 93 DEGs in active TB compared to healthy controls, including 65 upregulated and 28 downregulated genes. Intersection analysis identified 94 DEGs common to the active TB versus latent TB comparison and the ferroptosis-associated gene set, and eight DEGs common to the active tuberculosis versus healthy-control comparison and the same gene set, with no genes shared across all three sets. Functional enrichment of the 94 intersection genes underscored immune response, defense response, stress response, Toll-like receptor signaling, NOD-like receptor signaling, IL-17 signaling, TNF signaling, glutathione metabolism, neutrophil degranulation, cytokine signaling, and antimicrobial metal sequestration. Protein–protein interaction analysis followed by cytoHubba prioritization identified 10 hub genes: IL1B, TLR4, CXCL10, MMP9, CYBB, MPO, CD36, LCN2, S100A8, and LTF. Subsequent to outcome-independent probe selection, external validation in GSE28623 demonstrated significant positive differential expression of LCN2, S100A8, and LTF, while GSE62525 showed significant positive differential expression of IL1B, TLR4, MMP9, MPO, LCN2, and LTF. LCN2 and LTF were significantly upregulated in both validation datasets, indicating the strongest cross-dataset reproducibility. These results identify an immune–inflammatory transcriptional network intersecting with ferroptosis-associated genes in active TB. Notably, the transcriptomic findings do not confirm ferroptotic cell death but suggest candidate genes and biological processes for future experimental exploration. Full article

The aim of this study was to summarize current evidence on dust-related diseases of the bronchopulmonary system, medicinal plants, herbal formulations, and their underlying mechanisms of action. A literature review was conducted based on publications indexed in ScienceDirect, Google Scholar, SciFinder, Scopus, and Medline (PubMed), focusing on the mechanisms underlying dust-related diseases of the bronchopulmonary system, pneumoconiosis, and the potential of phytotherapeutic approaches to modulate these processes. The following keywords were used: bronchopulmonary system, pneumoconiosis, dust-related lung diseases, medicinal plants, herbal preparations, pulmonary rehabilitation, and lymphatic sanitation. The pathogenesis of pneumoconiosis involves the deposition of inhaled dust particles in the lung tissue, followed by chronic inflammation, oxidative stress, and progressive fibrosis. In experimental models, flavonoids, alkaloids, terpenoids, glycosides, tannins, and other phytochemical groups have demonstrated therapeutic potential in bronchopulmonary diseases. Among the compounds investigated, emodin, celastrol, kaempferol, sodium tanshinone IIA sulfonate, astragaloside IV, and dioscin have shown promising effects by modulating key signaling pathways and reducing inflammatory responses. Experimental evidence indicates that these phytochemicals can target major pathways involved in inflammation and fibrogenesis, thereby exerting antioxidant, anti-inflammatory, and antifibrotic effects. The lymphatic system also contributes to the pathogenesis of pneumoconiosis by transporting inhaled dust particles to regional lymph nodes, where their accumulation may promote lymph node sclerosis. Therefore, lymphatic sanitation may represent an important therapeutic mechanism of action of herbal formulations in pneumoconiosis. Our proposed lymphotropic herbal formulation enhances physiological lymphatic drainage and may positively influence the motility and functional activity of the tracheobronchial lymph nodes. The therapeutic potential of medicinal plants and herbal formulations in pneumoconiosis is supported by experimental findings for Tripterygium wilfordii (celastrol, through suppression of the EDNRB/Kng1–(endothelin receptor type B/kininogen1), Delphinium, Camellia, and Berberis species (kaempferol, through inhibition of TLR4 (Toll-like receptor 4 signaling), Astragalus membranaceus (astragaloside IV, through antifibrotic activity mediated by inhibition of the TGF-β1 (transforming growth factor beta 1)/Smad3 (SMAD family member 3) pathway), and Reynoutria japonica Houtt., Rheum, and Aloe species (emodin, through inhibition of Smad3 and NF-κB (nuclear factor kappa B) phosphorylation and reduction of TGF-β1, α-SMA (alpha-smooth muscle actin), collagen I, TNF-α (tumor necrosis factor alpha), and IL-1β (interleukin-1 beta) levels in lung tissue). For these and several other medicinal plants and their flavonoids, antifibrotic activity has been demonstrated through inhibition of the Akt/NF-κB (protein kinase B/nuclear factor kappa B) signaling pathway. A promising direction for future research is to evaluate the combined use of herbal formulations with established antifibrotic agents to determine whether synergistic therapeutic effects can be achieved. Full article

A novel sulfated α-glucan (VpG), with an ultra-high molecular weight of approximately 2250 kDa and a sulfation degree of 18.6%, was previously isolated from Volutharpa ampullacea perryi and shown to alleviate dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. However, the underlying mechanisms remain unclear. In the present study, we further characterized the structural features of VpG using scanning electron microscopy (SEM), atomic force microscopy (AFM) and UV-Vis spectroscopy, and evaluated its immunomodulatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. SEM revealed a dense, porous surface with co-existing filamentous and flake-like structures, while AFM imaging showed that VpG adopted an irregular branched chain-like conformation. In functional assays, VpG significantly inhibited the production of pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and toll-like receptor 4 (TLR4) in a dose-dependent manner. Flow cytometric analysis revealed that VpG downregulated LPS-induced expression of the M1 surface marker CD80, while Western blotting showed that VpG suppressed the phosphorylation of p38, ERK1/2, and JNK1/2/3, indicating blockade of the MAPK signaling pathway. In addition, VpG exhibited potent radical scavenging activity against hydroxyl and superoxide anion radicals, which is associated with its anti-inflammatory activity. Collectively, these findings indicate that VpG exerts its anti-inflammatory effects through the inhibition of M1 macrophage polarization and suppression of MAPK activation, with its antioxidant capacity potentially contributing to the overall effect. This study provides a mechanistic basis for understanding the anti-inflammatory action of VpG and supports its potential as a therapeutic candidate for ulcerative colitis. Full article

Tripartite motif-containing protein 21 (TRIM21/Ro52) is a pivotal E3 ubiquitin ligase and cytoplasmic fragment crystallizable receptor (FcR). It plays a crucial role in viral infections, autoimmune disorders, and cancers by regulating multiple cell signaling axes, including the NF-κB, RIG-I-like receptor (RLR), cGAS-STING, and Toll-like receptor (TLR) pathways. Type I interferon (IFN-I), a pleiotropic cytokine, is produced via these immune signaling pathways, which are often triggered by viral components. TRIM21 both activates IFN-I signaling and mediates its negative feedback through post-translational modification of key immune signaling proteins, thereby maintaining immune homeostasis. In recent years, TRIM21 has been found to dually regulate autophagy and IFN-I in the context of virus–host interplay. Herein, we systematically summarize the functional roles of TRIM21 in virus-triggered intracellular immunity, aiming to provide insights for researchers and inspire further investigation in this area. Full article

Interleukin-1 receptor-associated kinase 4 (IRAK4) is one of the IRAK family proteins and plays an important role in the regulation of innate and inflammatory responses. In particular, IRAK4 acts as a key regulator of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and has attracted attention as a therapeutic target for immune and inflammatory diseases. In this study, an integrated computational approach combining machine learning, molecular docking, and molecular dynamics simulations was applied to identify putative IRAK4 inhibitor candidates. Bioactivity data of IRAK4 were obtained from the ChEMBL and PubChem databases and evaluated for multiple binary classification models. The optimized XGBoost model based on ECFP4 and PubChem fingerprints achieved an ROC-AUC of 0.996 and an average precision (AP) of 0.991 on the independent test set. After that, 20 candidate compounds with high predictive probability score were finally selected through subsequent screening of the DrugBank database. Among them, DB12168 (MK-0557), DB15040 (TP-271), and DB18152 (Zilurgisertib) exhibited favorable binding free energies and stable complex formation with IRAK4 through molecular dynamics simulations and MM-PBSA calculations. Overall, these results demonstrate that approaches incorporating machine learning and structure-based computational analysis can be useful for discovering and prioritizing potential IRAK4 inhibitor candidates. Full article

This study investigated the pathological processes by which two Salmonella strains induce orchitis and impair spermatogenesis in mice, with emphasis on inflammation and blood–testis barrier (BTB) integrity. Thirty male Kunming mice were randomly assigned to the human-derived Salmonella enterica serovar Enteritidis H71 group, the sheep-derived Salmonella enterica serovar Agona W42 group, or the phosphate-buffered saline control group (n = 10 per group). An acute orchitis model was established by intrascrotal injection. Histopathological examination revealed marked testicular and epididymal lesions, disruption of the spermatogenic epithelium, and reduced sperm abundance in infected mice. Transcriptomic analysis identified 4546 differentially expressed genes shared by the two infected groups and showed enrichment of the Toll-like receptor (TLR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways. Real-time quantitative PCR further showed increased expression of interleukin 6 (Il6), interleukin 1 beta (Il1b), and tumor necrosis factor (Tnf), accompanied by reduced expression of tight junction protein 1 (Tjp1), occludin (Ocln), and synaptonemal complex protein 3 (Sycp3) in infected mice (p < 0.05), except for Tjp1 in the W42 group. These findings indicate that Salmonella-induced inflammatory activation is associated with BTB disruption and impaired spermatogenesis, providing a basis for further investigation of bacterial orchitis and zoonotic reproductive risks. Full article

Bacterial infection triggered excessive inflammatory responses, yet the mechanisms linking inflammatory activation to immunometabolic adaptation remained incompletely understood. The mitochondrial translocator protein (TSPO) has been implicated in inflammatory activation and cellular metabolism. This study aimed to investigate the role of TSPO in inflammation mediated by Toll-like receptor 4 (TLR4). Herein, we integrated transcriptomic data from the human peripheral blood dataset GSE72829, and single-cell transcriptomic profiles from the CELLxGENE platform with cellular mechanistic experiments in BV2 microglia and RAW264.7 macrophages. Transcriptomic analyses revealed that TSPO expression was markedly upregulated in patients with bacterial infection (n = 52) and exhibited diagnostic potential to distinguish bacterial infection from healthy controls (HCs, n = 16) and viral infection (n = 92). TSPO-correlated genes were enriched in Toll-like receptor (TLR) signaling, inflammatory response, and immunometabolic pathways. Mechanistically, TSPO interacted with TLR4 and selectively modulated TLR4-driven inflammatory activation. TSPO deficiency augmented lipopolysaccharide (LPS) induced tumor necrosis factor‑α (TNF-α) and interleukin‑6 (IL-6) secretion, accompanied by disrupted Ca²⁺ homeostasis, impaired cholesterol balance, and compensatory metabolic remodeling characterized by elevated L-lactate and sustained Adenosine triphosphate (ATP) levels. Collectively, these findings identified TSPO as an immunometabolic regulator bridging TLR4 signaling and metabolic adaptation during inflammatory activation. Besides, TSPO represented a promising biomarker and therapeutic target to limit exaggerated inflammatory responses. Full article

Background and Objectives: Oxidized LDL (oxLDL) and Toll-like receptor (TLR) signaling are implicated in inflammatory bone loss and periodontitis, but their cooperative effects on osteoclastogenesis remain unclear. We investigated whether TLR2/4 stimulation regulates the transcription of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a receptor for oxLDL, and whether oxLDL enhances TLR-mediated osteoclastogenic responses in the absence of exogenous RANKL. Materials and Methods: Mouse bone marrow cells (BMCs) were differentiated into bone marrow macrophages (BMMs) with M-CSF and stimulated with TLR ligands (Pam3CSK4 for TLR2 and Lipid A for TLR4) and/or oxLDL, with or without exogenous RANKL. Raw264.7 cells were stimulated with TLR ligands or Porphyromonas gingivalis lipopolysaccharide (LPS). LOX-1 transcriptional activity and osteoclastogenic responses were evaluated using luciferase assays, quantitative RT-PCR, and tartrate-resistant acid phosphatase (TRAP) staining. Results: In Raw264.7 cells, stimulation with Pam3CSK4, Lipid A, or LPS significantly increased LOX-1 promoter activity. In BMCs, Pam3CSK4 significantly increased LOX-1 and MyD88 mRNA expression on day 1, whereas expression decreased by day 3; these changes were suppressed by a TLR2 inhibitor. Lipid A significantly increased LOX-1 and MyD88 mRNA expression on day 3, and the increase in LOX-1 expression was inhibited by a TLR4 inhibitor. Functionally, Pam3CSK4 or Lipid A alone increased mononuclear TRAP-positive cells but did not induce multinucleated TRAP-positive cells. In contrast, co-stimulation of oxLDL with either Pam3CSK4 or Lipid A promoted multinucleated TRAP-positive cell formation even in the absence of exogenous RANKL. Conclusions: TLR2/4 stimulation transiently enhanced LOX-1 transcription and expression in association with increased MyD88 expression. TLR ligands cooperated with oxLDL to promote multinucleated TRAP-positive cell formation in the absence of exogenous RANKL, suggesting that inflammatory and metabolic signals may act synergistically during osteoclastogenesis. These findings improve our understanding of how dyslipidemia-associated factors may contribute to inflammatory bone-resorptive diseases, including periodontitis. Full article

The structural and immunomodulatory properties of arabinogalactan proteins (AGPs) from edible medicinal plants remain largely unexplored. Here, A homogenous AG-II-like arabinogalactan protein (CTSP-W2, 9862 Da) was isolated from Cynanchum thesioides via hot-water extraction, ethanol precipitation, and column chromatography. Its structure was thoroughly characterized by high-performance gel permeation chromatography (HPGPC), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), Congo-red, scanning electron microscopy (SEM), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), methylation analysis. The mechanism of immune activity was examined using specific inhibitors, Western blotting, and molecular docking. It comprises galactose, arabinose, glucose, galacturonic acid, xylose, and 18 amino acids (asparagine-rich), with a backbone of →3,6)-Galp-(1→ and →6)-Galp-(1→. CTSP-W2 significantly enhanced macrophage proliferation, phagocytosis, and secretion of Nitric oxide (NO), Tumor necrosis factor-alpha (TNF-α), and Interleukin-6 (IL-6). Inhibitor assays showed that Toll-like receptor 4 (TLR4, TAK-242) and Toll-like receptor 9 (TLR9, E6446) antagonists markedly reduced CTSP-W2-induced TNF-α, IL-6, and NO in a dose-dependent manner, whereas Toll-like receptor 2 (TLR2) inhibition (C29) unexpectedly upregulated these mediators. Western blot revealed that CTSP-W2 upregulated TLR4 and TLR9 protein expression and increased phosphorylation of Inhibitor of nuclear factor kappa-B alpha (IκBα), nuclear factor kappa B (NF-κB p65), and p38, indicating activation of the TLR4/9–NF-κB–p38 mitogen-activated protein kinase (MAPK) signaling axis. Furthermore, Molecular docking analysis further indicated that CTSP-W2 forms extremely strong hydrogen-bonding and hydrophobic interactions with TLR4 through its galactose chains. This study elucidates the immunoregulatory mechanism of CTSP-W2 and establishes a molecular basis for arabinogalactan proteins as potential natural immunomodulators. Full article

The innate system’s recognition of non-self and danger signals is mediated by a limited number of germline-encoded pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) are single, non-catalytic, membrane-spanning PRRs present in invertebrates and vertebrates. They act by specifically recognizing PAMPs of a variety of microbes and activate signalling cascades to induce innate immunity. A large number of TLRs has been identified in various teleosts and basal vertebrates. The varied evolutionary lineages of aquatic and warm-blooded higher animals result in some unique characteristics in their TLRs. In innate immunity and pathogen recognition, the majority of them share conserved signalling pathways. Comparing the immunology of teleosts, chondrichthyans, agnathans, and warm-blooded vertebrates requires a functional analysis of novel TLRs in teleosts and basal vertebrates. Furthermore, TLRs play important roles in adaptive immunity in addition to innate immunity. This review describes the discovery of TLRs and their role in fish immunity along their signalling pathway and ligand specificity. Full article