Search Results (2,056)

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

Upon RNA virus infection, viral RNA is sensed by the RIG-I-like receptors (RLRs), which signal through the adaptor protein VISA/MAVS to induce an innate antiviral response. How the VISA-mediated innate antiviral response is regulated and whether it can be targeted for drug development against diseases caused by RNA virus infection needs to be further investigated. Here we report that physalin F, a natural secosteroid isolated from Physalis angulata L., inhibits innate immune response to RNA virus. Mechanistically, physalin F binds to and promotes the activation of the mitochondrial m-AAA protease AFG3L2, which subsequently mediates the degradation of VISA. Knockdown of AFG3L2 promotes RLR-mediated innate antiviral signaling, whereas physalin F inhibits innate immune response to RNA virus both in cells and mice. Our study discovers physalin F as an inhibitor of VISA-mediated innate antiviral response as well as a candidate compound for the treatment of related diseases. More importantly, our findings suggest that AFG3L2 constitutively mediates degradation of VISA under physiological conditions, which represents a novel negative regulatory mechanism of RLR-mediated innate antiviral response. Full article

Vitamin D is involved in immune regulation through effects on innate and adaptive immune responses mediated by vitamin D receptor activation within immune cells. Experimental and translational studies support its role in promoting regulatory T-cell activity, modulating Th1/Th17 responses, and influencing autoantibody production. At the population level, low serum 25-hydroxyvitamin D concentrations are consistently associated with an increased risk of autoimmune diseases, including autoimmune thyroid disorders such as Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), suggesting a potential preventive association. In contrast, clinical evidence from interventional studies in patients with established disease is heterogeneous. Although vitamin D supplementation has been associated with reductions in thyroid autoantibody titers in some studies—particularly in patients with HT and baseline vitamin D deficiency—consistent effects on thyroid function, disease progression, or relapse prevention have not been demonstrated. Overall, current evidence supports vitamin D deficiency as a potentially modifiable risk marker rather than a confirmed disease-modifying therapeutic target in autoimmune thyroid diseases, highlighting the need for further studies focused on clinically meaningful outcomes. Full article

The Rhodomyrtus tomentosa (Aiton.) Hassk. berry is rich in structurally diverse polysaccharides with potential biological activity. However, its immunomodulatory properties remain understudied, limiting our current understanding of its functional significance. Two structurally distinct polysaccharides from Rhodomyrtus tomentosa (RTP-1 and RTP-2) were evaluated for immunostimulatory activity in RAW264.7 macrophages. Phagocytic function was assessed by neutral red assay, nitric oxide (NO) and reactive oxygen species were measured using the Griess assay and fluorescent probes, and cytokines (TNF-α, IL-6 and IL-1β) were quantified by enzyme-linked immunosorbent assay. Analysis of RNA-seq data using weighted gene co-expression network analysis revealed co-expression modules. The selected transcripts were independently validated by quantitative real-time PCR (RT-qPCR). The results showed that both polysaccharides enhanced phagocytosis, increased NO/ROS levels, and promoted cytokine secretion. Transcriptome results indicated that RTP-2 activated the MEturquoise co-expression module containing 222 hub genes, whereas RTP-1 was mainly associated with the MECyan module containing 49 hub genes. Module enrichment for RTP-2 revealed links with mitophagy–immune regulation, proteostasis/stress, and innate immune signaling. RT-qPCR further confirmed that in the RTP-2 group, Dram1 expression was upregulated approximately 121 times, Bmf1 expression was upregulated approximately 18 times, and Bnip3 was significantly downregulated, whereas Bnip3l expression remained unchanged. Overall, RTP-2 exhibited a more pronounced and coherent macrophage-stimulating profile in vitro, supporting its potential as a macrophage-targeted immunostimulatory ingredient. Full article

Autoinflammatory diseases involve recurrent systemic inflammation caused by dysregulated innate immunity, arising from genetic or multifactorial mechanisms, as seen in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. About 10% of PFAPA patients show autosomal dominant inheritance. We describe a three-generation family with a PFAPA-like recurrent fever syndrome displaying clear autosomal dominant transmission. All affected individuals tested negative on a diagnostic panel of 13 known autoinflammatory genes. Whole-exome sequencing was performed in two distantly related affected members, followed by variant filtering, segregation analysis, and phenotype-based prioritization. A single heterozygous missense variant in RXFP1, c.154G>A p.(Asp52Asn), co-segregated with disease in all affected relatives. This variant is extremely rare in population databases, absent from ClinVar, present in COSMIC, and predicted as damaging by REVEL and CADD. RXFP1, not previously implicated in autoinflammatory or innate immune disorders, encodes the relaxin family peptide receptor 1, a G protein–coupled receptor involved in extracellular matrix regulation, anti-fibrotic pathways, and modulation of inflammatory cytokine production. Protein network analysis showed interactions with RLXN1-3, inflammatory mediators, PTGDR, ADORA2B, and C1QTNF8, supporting an immunomodulatory function. This is the first report linking RXFP1 variation to a hereditary recurrent fever syndrome, identifying relaxin signalling as a potential immune regulatory pathway. Full article

RhoA (Ras homolog A) is a prominent member of the Rho GTPase family, playing a key role in various cellular processes such as cytoskeletal dynamics, cell migration, and immune responses. However, its function in red swamp crayfish remains unclear. In this study, it is proposed that RhoA may regulate the innate immune response in P. clarkii. The gene was fully characterized as PcRhoA in P. clarkii. The results showed that the open reading frame (ORF) of PcRhoA is 663 bp, encoding a 220-amino acid protein with a conserved Rho domain of 174 amino acids. Phylogenetic analysis placed PcRhoA close to Cherax quadricarinatus RhoA. RT-qPCR analysis revealed high expression levels of the PcRhoA gene in the hepatopancreas, muscle, heart, ovary, and stomach, with lower expression in the blood, intestine, gills, and tentacle gland. Furthermore, PcRhoA mRNA transcript was significantly upregulated in the intestine following LPS and Poly I:C challenges. Knockdown of PcRhoA suppressed the expression of downstream genes in the immune signaling pathway. These results indicate that PcRhoA appears to play a pivotal role in regulating the immune response of crayfish. Full article

Vitamin D is a steroid hormone whose relevant immunomodulatory role has been widely described. Therefore, its contribution to the pathogenesis of immune-mediated diseases is an important and ongoing matter of research. Specifically, the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, through the interaction with its receptor, exerts different activities on the innate and adaptive immune system, among which are suppression of inflammation and promotion of tolerogenic responses. Indeed, vitamin D insufficiency/deficiency has been related to the pathogenesis and/or disease activity of several autoimmune diseases, including, amongst others, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus. Based on these premises, in this review, we will describe the main molecular mechanisms modulated by vitamin D in the regulation of immune responses, including the induction of immune tolerance. Moreover, we will focus on the current knowledge regarding the contribution of vitamin D depletion to the aforementioned autoimmune diseases, seeking to provide evidence as to why its supplementation in the context of these immune-mediated disorders may potentially ameliorate disease activity and its related clinical manifestations. Full article

Patients with inflammatory bowel disease (IBD) frequently fail to achieve protective immunity after hepatitis B vaccination, even with intensified vaccination schedules. In this observational real-world study, 18 patients with IBD who were seronegative for hepatitis B virus (HBV) received three standard doses of the Engerix-B^® vaccine (at 0, 1, and 6 months). After immunisation, patients were classified into responders and non-responders according to their serological response. Blood samples were collected before the first dose and after completion of the vaccination schedule. Responders activated pathways that supported durable protection, including conventional dendritic cells type 1 mobilisation, expansion of IgG plasmablasts, and preservation of B- and T-cell memory. In contrast, non-responders displayed a more inflammatory innate profile, characterised by enrichment of CCR2⁺ monocytes. They also showed higher baseline Treg frequencies, which may suppress effective effector responses, together with impaired natural killer (NK) activation and progressive loss of memory potential. This study shows that hepatitis B vaccine failure in inflammatory bowel disease reflects a convergence of excessive immune regulation, inflammatory activation, and loss of memory potential, underscoring that no single pathway can explain the impaired response. Full article

Rapid weight loss (RWL) is a common strategy among combat sports athletes aiming for a competitive advantage. However, it imposes significant immunological stress that compromises both innate and adaptive immune defenses. This systematic review synthesizes current experimental and mechanistic evidence on the effects of RWL in combat sports, focusing on cellular immunity, neuroendocrine regulation, and inflammatory pathways. Acute RWL activates the hypothalamic–pituitary–adrenal axis, elevating plasma cortisol and suppressing lymphocyte proliferation, T-cell function, and natural killer cell cytotoxicity. Although neutrophil counts increase, their phagocytic and oxidative burst capacities decline, reflecting impaired host defense. Monocyte and macrophage systems shift toward proinflammatory phenotypes, while mucosal immunity is weakened by reductions in secretory immunoglobulin A, leading to increased upper respiratory tract infection risk. The magnitude and speed of weight loss are critical determinants of immune dysfunction, with reductions exceeding 5% of body mass producing particularly severe consequences. Evidence-based intervention strategies—including gradual weight management, nutritional optimization, and biomarker monitoring—are essential to mitigate immunosuppression and safeguard athlete health. This review highlights key gaps in combat sports-specific protocols and proposes integrated approaches to preserve immune competence and optimize performance. Full article

Melatonin, an ancient and evolutionarily conserved indolamine, has long attracted attention for its multifunctional roles in redox homeostasis. More recently, it has been studied in relation to immune regulation and cancer biology. Beyond its well-known circadian function, melatonin modulates oxidative stress by directly scavenging reactive oxygen and nitrogen species and by upregulating antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase. At the same time, it exerts wide-ranging immunomodulatory functions by influencing both innate and adaptive immune responses. All these actions converge within the tumor microenvironment, where oxidative stress and immune suppression drive cancer progression. Although the antitumoral effects of melatonin have traditionally been interpreted through its actions on T cells and NK cells, recent studies identify macrophages as an underappreciated and pivotal target. Notably, melatonin influences macrophage polarization, favoring antitumor M1 phenotypes over pro-tumoral M2 states, while attenuating chronic inflammation and restoring mitochondrial function. This review summarizes current knowledge on melatonin’s antioxidant and immunoregulatory mechanisms, highlighting its impact on the tumor immune microenvironment, with a particular focus on the growing recognition of macrophages as a compelling new axis through which melatonin may exert anticancer effects. Full article

Beyond their traditional role as short-lived antimicrobial cells, neutrophils are increasingly recognized as key regulators of adaptive immunity and tumor progression. This AI-assisted integrative review investigated the neutrophil–T-cell axis, particularly the role of Galectin-9 (Gal-9), across adult T-cell leukemia/lymphoma (ATL), Sézary syndrome (SS), coronavirus disease 2019 (COVID-19), and psoriasis. Leveraging AI tools (GPT-5 and Adobe Acrobat AI Assistant) for literature synthesis (2000–2025) and expert validation, we aimed to identify common immunological mechanisms. Across all conditions, neutrophils displayed persistent activation, elevated Gal-9 expression, and modulated T-cell interactions. In ATL and SS, neutrophilia correlated with poor survival and TCR signaling dysregulation, suggesting Gal-9-mediated immune modulation. In COVID-19 and psoriasis, neutrophil-derived Gal-9-linked innate hyperactivation to T-cell exhaustion and IL-17-driven inflammation. These findings define a recurring neutrophil–Gal-9 regulatory module connecting innate and adaptive immune responses. This study underscores the feasibility of combining AI-driven literature synthesis with expert review to identify unifying immunological mechanisms and therapeutic targets across malignancy and inflammation. Full article

The complement system is crucial for immune defense, linking innate and adaptive immunity. In the classical and lectin pathways, C4 is split into C4b, triggering opsonization, lysis, and the removal of pathogens and damaged cells. Dysregulated activation of C4 and other components of the classical pathway can lead to tissue damage and heightened inflammation, whereas appropriate regulation of C4b activity serves to mitigate excessive inflammation and prevent injury. ELISA analysis demonstrated C4 activation and cleavage during the co-incubation of PRRSV with fresh porcine serum. Immunoelectron microscopy revealed that porcine red blood cells could immunologically adhere to PRRSV, and C4b was involved in this adhesion process. BLAST (NCBI BLAST+ 2.14.1) analysis revealed that porcine CR1-like CCPs 1-3, CR1-like CCPs 12-14, and CR1-like CCPs 19-21 share high similarity with the CCP 1-3 region of human CR1, which mediates C4b binding. Yeast two-hybrid assays confirmed that all three CR1-like fragments bind C4b. To elucidate the interaction mechanism, homology models of C4b and CR1-like fragments were constructed, followed by molecular docking and dynamics simulations, identifying 18 key amino acids in porcine CR1-like involved in C4b binding. Surface plasmon resonance further validated the binding affinity of CR1-like CCPs 1-3, its mutant 118I, and C4b. These results enhance our understanding of complement regulation and provide a foundation for developing therapeutic strategies targeting complement-related diseases. Full article

Porcine epidemic diarrhea virus (PEDV) is an enteric alphacoronavirus that causes severe diarrhea and high mortality in neonatal pigs, leading to substantial economic loss in the porcine industry. Previous studies have primarily focused on the spike protein because of its role in viral entry and induction of neutralizing antibody responses. However, accumulating evidence indicates that other viral components also contribute to host immune modulation and pathogenesis. This review summarizes the current knowledge on PEDV structural proteins, with an emphasis on membrane proteins as regulators of porcine innate immune responses. The molecular characteristics and intracellular localization of membrane proteins were described, and the reported effects on interferon signaling, inflammatory pathways, and cellular stress responses were examined. Findings from related coronaviruses were incorporated to highlight the conserved features and virus-specific differences in membrane protein-mediated host modulation. Available evidence suggests that membrane protein-associated interference with innate immune signaling may contribute to intestinal immune dysregulation and disease severity in neonatal piglets. The implications of these observations on PEDV pathogenesis and intervention strategies are also discussed. By shifting attention from spike-centered frameworks to structural protein-driven host interactions, this review highlights membrane proteins as an underexplored but biologically relevant factor in porcine coronavirus research. Full article

Aging is an inevitable biological process that affects the function of various organs, including the immune system. Immunosenescence is characterized by diminished immune cell function, weakened immune responses, and imbalances in immune components, which together reduce the body’s resistance to pathogens and increase the risk of age-related diseases in older adults. These conditions pose direct threats to health and significantly impact quality of life and longevity. Therefore, effective strategies to delay aging and maintain immune function are critical areas of research. Emerging evidence suggests that moderate physical activity can significantly enhance immune system functionality, serving as an effective intervention for mitigating immunosenescence. Exercise is known to remodel the metabolism of carbohydrates, fats, and proteins, strengthen communication between organs and the immune system, regulate the functions of both innate and adaptive immune cells, and decrease age-related chronic inflammation. Furthermore, exercise aids in restoring the functionality of aging immune cells through mechanisms such as autophagy activation, mitochondrial optimization, and epigenetic reprogramming. Importantly, a dose–response relationship exists between various exercise modalities and the attenuation of immunosenescence in older adults, with the cumulative amount of lifelong physical activity profoundly influencing the pace of immunosenescence. Full article

In higher vertebrates, Tripartite Motif (TRIM) proteins modulate the immune response by coordinating processes related to inflammation such as antiviral restriction, autophagy and inflammasome activation. In fish, TRIM proteins have been reported mainly in cyprinids (e.g., carp—Cyprinus carpio and zebrafish—Danio rerio) and salmonids (i.e., rainbow trout—Oncorhynchus mykiss). However, their molecular mechanisms and functions are still being described in aquatic animals. Thus, our study focused on characterizing novel TRIM proteins involved in the innate immunity of gill cells from rainbow trout (RTgill-W1 and primary cultures) stimulated with lipopolysaccharide (LPS) or polyinosinic–polycytidylic acid (poly I:C). Furthermore, an in vivo experiment with rainbow trout was performed to detect TRIM proteins after the challenge with Flavobacterium psychrophilum (a major bacterial pathogen affecting Chilean salmonid industry). In vitro results showed that OmTRIM25 triggered an LPS-induced expression of pro-inflammatory cytokines such as TNF-α2 and IL-1β. Moreover, in the fish experiment, OmTRIM25 and finTRIM2 were up-regulated in the gills two days post-infection (dpi), whereas IL-1β and TNF-α2 had a higher gene expression at four and six dpi, respectively. To investigate the immunological role of OmTRIM25, a gene silencing strategy using RNA interference (RNAi) was used, confirming the immunomodulatory function of OmTRIM25. Full article