Search Results (3,516)

Growing evidence implicates neuroinflammation, gut-derived endotoxemia, and dysregulated lipid metabolism in the pathogenesis of Parkinson’s disease (PD). However, the relationships among circulating lipopolysaccharide (LPS), LPS-handling proteins, systemic inflammatory activation, and lipid fractions remain insufficiently characterized. The aim of this study was to compare LPS levels, LPS-related inflammatory mediators, and plasma lipid parameters between PD patients and matched controls, and to explore correlations among these biomarkers. Twenty PD patients and twenty matched controls underwent fasting venous sampling. Circulating LPS, lipopolysaccharide binding protein (LBP), soluble cluster of differentiation 14 (sCD14), high-sensitivity C-reactive protein (hsCRP), and phospholipid transfer protein (PLTP) were quantified via LAL assay and ELISAs. Serum cholesterol, HDL cholesterol (HDL-C), phospholipids (PLs), HDL-PLs and triacylglycerols (TAGs) were assessed using validated biochemical techniques. LPS concentrations did not differ between groups. However, PD patients showed elevated sCD14 and hsCRP levels, reduced LBP, and increased PLTP. Lipid profiling revealed lower total cholesterol and reduced HDL-associated cholesterol and phospholipids in PD, while TAG levels remained unchanged. Correlation analyses indicated coordinated associations between inflammatory markers and lipid fractions, with distinct interaction patterns in PD compared with controls. These findings support a mechanistic interplay among endotoxemia, innate immune activation, and lipid dysregulation in the pathophysiology of PD. Full article

Asthma is a chronic respiratory disease characterized by airway hyperresponsiveness, obstruction, and persistent inflammation, arising from complex interactions among genetic, epigenetic, immune, and environmental factors. To elucidate the stage-specific molecular mechanisms underlying asthma progression, we constructed candidate genome-wide genetic and epigenetic networks (GWGENs) of human cells through large-scale biological database mining. Using a system order detection scheme, false-positive interactions were pruned to identify real GWGENs corresponding to three clinical stages of asthma: quiet, exacerbation, and follow-up. Core GWGENs were subsequently extracted from each real network using the principal network projection (PNP) method to highlight dominant regulatory structures and pathogenic pathways. Based on the inferred core networks, key stage-specific biomarkers were identified and further explored as potential drug targets. Drug–target relationships were investigated by integrating gene expression perturbation profiles from the Connectivity Map (cMap), comprising microarray data for 14,207 genes across 1327 compounds. This network-guided analysis enabled the qualitative design of multi-molecule drug combinations tailored to each disease stage. Our results suggest that asthma onset is associated with reduced innate immunity, increased disease susceptibility, and impaired endothelial barrier recovery influenced by microenvironmental factors such as cigarette smoke and lipopolysaccharides, together with genetic and epigenetic alterations. During the exacerbation stage, enhanced differentiation of T cells toward the T helper 2 lineage contributes to airway inflammation and tissue injury. In the follow-up stage, T helper 1–mediated responses are linked to mucus hypersecretion, airway obstruction, and sustained inflammation. Collectively, these findings demonstrate that a systems-level, network-based framework can uncover stage-specific pathogenic mechanisms of asthma and provide hypothesis-generating insights for network-informed drug repurposing strategies. Full article

Steroid-sensitive cancers (e.g., breast, ovarian, uterine, and prostate cancers) are difficult to control and frequently metastasize to lymph nodes, bone, or lung. Although endocrine research has greatly advanced our identification of the direct roles of steroid sex hormones such as androgens and estrogens on tumor cells in promoting metastasis or recurrence (e.g., treatment with gonadotropin releasing hormone agonists/antagonists, aromatase inhibitors, and estrogen and androgen receptor antagonists), mechanistic insight regarding indirect effects of steroid hormones, including how the innate immune system responds to cancer and is influenced by steroid hormones, is lacking. Despite technological advances in engineering more robust adaptive immunity to combat tumor growth (e.g., CART or checkpoint inhibitors), there remains a relative lack of investigation into the role of innate immunity as a key defense system. Here we discuss recent studies that highlight the significance of neutrophils and their response to tumorigenic conditions with or without steroid hormones in animal models of cancer. We will describe relationships between steroid hormones and neutrophils, with a specific focus on neutrophil extracellular traps (NETs), and how these interactions modulate tumor growth and invasion. Together, these data indicate that combinatorial regulation of both innate and adaptive immunity in the context of tumorigenesis may improve outcomes in cancer therapies. Full article

The central nervous system (CNS), comprising the brain and spinal cord, represents the core regulatory hub of the body. Damage to the CNS often leads to irreversible structural and functional impairments of neural tissues, posing a major global public health challenge. Immune memory encompasses two states: immune training and immune tolerance, which are characterized by enhanced or attenuated immune responses, respectively, following initial exposure to external stimuli in immune cells such as monocytes and macrophages. Microglia, the resident immune cells of the CNS, can be rapidly activated by external stimuli. Accumulating evidence indicates that microglial immune memory plays a critical role in sustaining states and neuroinflammatory responses in CNS disorders. Specifically, the immune training state promotes amyloid-β (Aβ) accumulation in the brains of Alzheimer’s disease (AD) model mice, thereby exacerbating neuronal damage, whereas the immune tolerance state suppresses pro-inflammatory cytokine expression and alleviates neuroinflammation. This review focuses on two immune memory states in microglia—training and tolerance—and what triggers them. We summarize their roles and mechanisms in CNS diseases. Specifically, we break down how epigenetic and metabolic reprogramming control microglial immune memory, with an emphasis on how these two processes interact during memory formation and maintenance. Our goal is to fill key knowledge gaps about their combined effects and to suggest new therapeutic targets. Evidence shows that immune memory acts as a “double-edged sword” in the CNS: it can either fuel harmful inflammation and worsen damage, or, when moderately activated, protect nerves. Therefore, precisely balancing these two states could help reduce harmful inflammation while preserving the protective functions of microglia, offering a new, reversible immunotherapy for CNS diseases. Full article

A phage is a virus that targets bacteria with high precision. While phage therapy provides a targeted alternative to broad-spectrum antibiotics, it is not completely free from the challenges of antimicrobial resistance, as phages can facilitate the horizontal transfer of resistance genes through transduction and promote the growth of phage-resistant strains. Nonetheless, within the One Health framework, the strategic use of phages remains a vital and promising tool for addressing the global antimicrobial resistance crisis. This paper reviews current research on phage therapy for gastrointestinal diseases such as cirrhosis, enteritis, and Helicobacter pylori infection. It also details how phages help regulate gut microecological balance and discusses how phage dysbiosis can lead to innate immune dysfunction and worsen conditions like inflammatory bowel disease. The review summarizes both the therapeutic potential and limitations observed in clinical trials and fundamental studies. Transitioning from laboratory research to clinical practice is hindered by multiple complex challenges, including the stomach’s extreme acidity, physical entrapment by the intestinal mucus layer, the rapid co-evolution of bacterial resistance, and ecological risks associated with temperate phages. To overcome challenges like gastrointestinal barrier tolerance and address ethical, technical, and practical hurdles for clinical use, the paper outlines treatment strategies for specific conditions and highlights future directions, providing guidance for employing phages in digestive system disease management. These future innovations focus on integrating artificial intelligence-driven precision matching, advanced bioengineering for durable delivery systems, and multimodal combination therapies to safely modulate the intestinal microecology. Full article

C. burnetii (Cb) is an obligate intracellular bacterial pathogen that replicates within alveolar macrophages following aerosol infection. Unlike most intracellular bacteria, Cb establishes a lysosome-derived replicative niche (Coxiella-containing vacuole or CCV) through the action of its Type IVB secretion system (T4BSS). This system translocates a large repertoire of effector proteins into the host cytoplasm after phagosome acidification. These effectors interfere with diverse signaling pathways to co-opt host processes, such as vesicle trafficking, ubiquitylation, gene expression and lipid metabolism, promoting pathogen survival without triggering robust proinflammatory signaling or host cell death pathways. This effector-triggered immune silencing is particularly unique given the central role of macrophages as innate immune sentinels. In this review, we examine Cb T4BSS effectors that have been characterized as central determinants of innate immunity modulation. We discuss innate immune sensing pathways potentially engaged during infection, including Toll-like receptors, NOD-like receptors, RIG-I-like receptors, inflammasomes, and interferon signaling pathways, and highlight evidence indicating that these pathways are actively suppressed. Emphasis is placed on effector-mediated regulation of NF-κB signaling, type I interferon responses, and inflammasome activation. Finally, we address unresolved questions related to effector-triggered immunity, redundancy in immune suppression, and discrepancies between in vitro and in vivo infection models. Full article

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus responsible for sporadic outbreaks of severe disease with high case fatality rates in South and Southeast Asia. Human infection occurs through spillover from natural reservoirs, primarily fruit bats, or via human-to-human transmission, and is characterized by a broad clinical spectrum ranging from asymptomatic infection to acute respiratory disease and fatal encephalitis. Following entry via ephrin-B2 and ephrin-B3 receptors, NiV exhibits marked endothelial and neuronal tropism, leading to systemic vasculitis, disruption of the blood–brain barrier, and direct infection of the central nervous system. Disease progression is driven by a complex interplay between viral replication strategies and host immune responses. NiV effectively counteracts innate immunity through multiple viral proteins that inhibit interferon signaling, while simultaneously inducing dysregulated inflammatory responses that contribute to tissue damage and multi-organ failure. Neurological involvement represents the most severe manifestation, often resulting in acute or relapsing encephalitis with long-term sequelae among survivors. Despite the severity of the disease, no licensed antiviral therapies or human vaccines are currently available. Therapeutic development has focused on neutralizing monoclonal antibodies targeting viral glycoproteins and small-molecule antivirals that inhibit viral RNA synthesis, both of which show promising results in preclinical models, but remain limited by timing and translational challenges. In parallel, several vaccine platforms—including viral vectors, mRNA-based constructs, and recombinant protein subunits—have advanced to early-phase clinical trials, demonstrating encouraging immunogenicity. Beyond biomedical interventions, effective outbreak containment relies on integrated public health strategies. The “Kerala model” highlights the importance of rapid case identification, isolation, contact tracing, and community engagement within a One Health framework to mitigate transmission and reduce mortality. This review synthesizes the current knowledge on NiV pathogenesis, immune evasion, clinical manifestations, and emerging therapeutic and vaccine strategies, while highlighting critical gaps and future directions for improving the preparedness and response to this high-consequence emerging pathogen. Full article

Alphaviruses are mosquito-borne viruses that can infect the central nervous system (CNS) and cause encephalomyelitis, which is a rare but dangerous complication from infection. In mice, this can be studied in a model of infection with Sindbis virus (SINV), which infects neurons and causes neurological disease. Due to the non-renewable nature of neurons, the immune response in the CNS is specialized to prevent neuronal damage or death, even if they are infected. Therefore, insights into the nuances of antiviral immunity in the CNS provide a better understanding of disease pathogenesis and mechanisms of recovery. Type I interferons (IFNs) are critically important for survival; they are an innate antiviral defense mechanism that consists mainly of IFNα and IFNβ. Although both use the same receptor, type-specific differences between IFNα and IFNβ have been described in other contexts. To this end, Ifnb^−/− mice were used to elucidate the role of IFNβ in recovery from alphavirus encephalomyelitis. IFNβ-deficient mice have intact IFNα expression and downstream signaling, but symptomatic disease occurs earlier and is more severe. This is accompanied by increased virus replication in the early stages of infection. Microgliosis is reduced in Ifnb^−/− mice compared to wildtype, but inflammatory cytokine/chemokine levels are higher and associated with alterations in monocyte and NK cell recruitment into the CNS. Ifnb^−/− mice have no deficiencies in the expression of factors known to be required for viral clearance. Therefore, IFNβ modulates the early stages of the immune response and facilitates restriction of virus replication, contributing to delayed disease onset. Full article

Natural killer (NK) cells are effector cells of the innate immune system. The cytokine microenvironment influences NK cell function. Dysregulation of NK cell cytotoxicity can manifest in reproductive disorders and is also observed in tumor-transformed tissues. The search for immunotherapies capable of regulating NK cell activity is therefore relevant. This study aimed to evaluate the effect of the TGFβ signaling pathway inhibitor and the cyclin-dependent kinase (CDK) 7/12/13 inhibitor on the transcriptional profile of NK-92 cell line. In the study, the cytokines TGFβ1, IL-12, IL-15, IL-18, and TNFα, and the TGFβ receptor type 1 (TGFβR1) inhibitor LY3200882 and the CDK7/12/13 inhibitor THZ1 were used. The cells were cultured sequentially in the presence of inhibitors and cytokines, followed by assessment of the gene expression of NCR2, NCR3, AHR, NCAM1, B3GAT1, EOMES, GATA3, KLRC1, KLRC2, CCL5, IL10 and TBX21. We observed direct effects of the inhibitors on NK cells. LY3200882 increased the expression of KLRC1 and B3GAT1, and reduced NCAM1. THZ1 increased the expression of KLRC1, KLRC2, AHR and EOMES, while it reduced IL-10 and NCR2. IL-12, IL-15, IL-18, and TNFα modified the gene expression of some phenotypic and cytotoxic receptors and transcription factors. TGFβ1 increased the expression of KLRC1, NCAM1, and B3GAT1. Blocking TGFβ-dependent signaling with LY3200882 abolished TGFβ1 effects. We assessed CD56 presence on NK-92 cell membrane and found its increase in the presence of LY3200882. After LY3200882 treatment, in the presence of TGFβ1 and choriocarcinoma cell line JEG-3, the expression of CD56 receptor on NK cell membrane decreased. Pretreating NK cells with THZ1 decreased the expression of NCAM1, B3GAT1, and EOMES in the presence of TGFβ1. Thus, LY3200882 partially neutralized TGFβ1 effects on the expression of NK cell receptor genes. THZ1 followed by TGFβ1 treatment promoted NK cell transcriptional profile characteristic for CD56dim NK cells. Both LY3200882 and THZ1 affected the NK cell transcription even without cytokine treatment. The independent effects of synthetic inhibitors on NK cells, as well as their influence in the presence of tumor cells, should be considered. Full article

Candida albicans is a ubiquitous commensal fungus that may be lethal once it gains access to the bloodstream, following a breach in protective barriers such as skin or gut lining. Intravenous injection of C. albicans (4.5 × 10⁴ yeasts/gm of mouse) leads reproducibly to systemic infection with a median survival of about 75 h. We studied the effects of two human innate immune effectors on the course of systemic infections. The soluble human pentraxin serum amyloid P component (hSAP) retards death in murine disseminated candidiasis. In contrast, another soluble pentraxin, human C-reactive protein (hCRP), hastens death. To examine the pathological basis for these differences, necropsies were performed, and the right kidney was removed for study. Candidiasis caused abundant collagen deposition (the precursor to fibrosis) and loss of contrast between the kidney medulla and cortex. Daily administration of subcutaneous hSAP following the intravenous injection of C. albicans preserved the discrete histological difference between cortex and medulla and lessened host collagen deposition. Yeasts and hyphae within abscesses were decorated with hSAP. Contrastingly, kidneys from animals administered C. albicans and hCRP showed extensive collagen deposition and loss of the boundary between the cortex and the medulla of the kidney. hCRP did not bind to fungi but bound to damaged tissue surrounding abscesses, leading to a more destructive infection with loss of tissue. Staining cells with antibodies to CD45 (to detect T-lymphocytes, myelocytes, monocytes, and macrophages) and antibodies to Ly-6G (neutrophils, and granulocytes) showed that hSAP retarded infiltration of inflammatory cells into diseased areas. The results are consistent with the hypothesis that early administration of hSAP represses the migration of inflammatory cells, dampens the production of collagen by fibroblasts, and dampens the overall immune response of the host to infection. In doing so, hSAP prolonged life, whereas hCRP facilitated the infectious process and hastened death. Full article

Trained immunity is a concept that is currently in development and refers to the long-term functional reprogramming of innate immune cells in response to microbial or inflammatory stimuli. This process serves a dual purpose in the gastrointestinal tract, contributing to chronic inflammatory conditions like inflammatory bowel disease and maintaining host defense. The production of pro-inflammatory mediators is augmented by epigenetic and metabolic changes that are induced by the persistent activation of innate immune cells, which is triggered by microbial components and damage-associated signals. Although this increased responsiveness may initially be protective, sustained activation leads to tissue damage, epithelial barrier dysfunction, and chronic inflammation. These mechanisms are significant contributors to colorectal carcinogenesis, particularly in colitis-associated cancer. Through the activation of oncogenic signaling pathways, the establishment of a pro-tumorigenic microenvironment, and an increase in oxidative stress, trained immunity also influences tumor development. Additionally, the systemic reprogramming of hematopoietic progenitor cells has the potential to exacerbate inflammation and facilitate the progression of tumors. The identification of epigenetic and metabolic biomarkers associated with trained immunity can lead to novel diagnostic opportunities. Targeting metabolic and epigenetic pathways, as well as regulating the intestinal microbiota, is a promising therapeutic approach that could enhance the effectiveness of treatments for colorectal cancer while minimizing adverse effects on the immune system. Nevertheless, it is necessary to maintain a delicate equilibrium to suppress pathological inflammation without compromising protective immune responses. In general, trained immunity may represent a potentially relevant mechanistic link between chronic inflammation and colorectal cancer; however, its role remains context-dependent and not yet fully defined. Full article

Chronic pain is increasingly understood as a neuroimmune disorder rather than a purely neuronal condition, in which immune mediators and immune-like signaling within the nervous system regulate nociceptive gain across peripheral tissues, dorsal root ganglia (DRG), spinal cord, and supraspinal networks. Seminal and recent syntheses show that microglia, macrophages, cytokines/chemokines, and innate immune sensors can initiate and maintain maladaptive plasticity and central sensitization, helping explain the frequent clinical dissociation between structural pathology, systemic inflammatory markers, and pain severity. However, immune biology is bidirectional: alongside pronociceptive pathways, a growing literature describes active “pain-resolving” programs that terminate sensitization and restore homeostasis, including regulatory T cell (Treg)–IL-10 signaling and specialized pro-resolving mediators (SPMs). A structured search of PubMed/MEDLINE, supplemented by Europe PMC and PubMed Central, was performed, and citation chasing through broad scholarly indices was used to identify high-impact reviews, meta-analyses, and translational mechanistic studies. Systematic biomarker syntheses in low back pain, neck pain, and fibromyalgia indicate modest and heterogeneous systemic inflammatory signals, underscoring the need for mechanistic endotyping and stage-specific interventions. Based on this evidence, a clinically oriented framework is presented that distinguishes immune-driven pain amplification from impaired resolution and outlines practical implications for assessment, biomarker interpretation, and precision-oriented trial design. Full article

Dendritic cells (DCs) integrate innate immune sensing with adaptive immune priming through coordinated transcriptional programs that regulate antiviral defense, inflammatory signaling, and antigen presentation. However, the hierarchical organization and interdependence of these pathways following stimulation remain incompletely defined. Here, we performed an in silico re-analysis with full reproducibility of publicly available RNA-sequencing data (GSE108526) to characterize the temporal architecture and associations of immune transcriptional modules in human dendritic cells at 6 h and 16 h following innate immune activation. Principal component analysis revealed stimulation status as the dominant source of transcriptomic variance. Differential expression analysis confirmed robust induction of interferon-stimulated genes (ISGs) alongside modulation of inflammatory mediators and antigen presentation-associated genes. Module-level quantification showed that interferon signaling constituted the primary early transcriptional axis, whereas inflammatory cytokine programs displayed moderate induction and antigen presentation-associated genes exhibited distinct temporal dynamics. Association analysis demonstrated strong relationships between CIITA and downstream MHC class II genes, supporting coordinated antigen presentation regulation, while relationships between interferon and inflammatory modules were positive but non-proportional, indicating partial modular independence. Collectively, these findings reveal a structured yet non-uniform transcriptional organization in stimulated human dendritic cells, characterized by dominant interferon responses accompanied by context-dependent inflammatory activation and differentially associated antigen presentation programs. This integrative framework provides a reproducible systems-level approach for dissecting immune transcriptional architecture in human dendritic cell activation. Full article

Background: Non-typeable Haemophilus influenzae (NTHi) is a major cause of acute respiratory tract infections and chronic airway disease, despite its clinical importance, no licensed vaccine is available, largely due to the extensive genetic and antigenic diversity among circulating isolates. We previously identified conserved outer membrane proteins capable of inducing systemic protection against NTHi. Methods: In this study, we evaluated whether a multi-antigen protein vaccine composed of conserved NTHi antigens (P5 and P26) could protect against pulmonary infection. Transgenic mice expressing human transferrin and factor H were immunized via the intraperitoneal or intranasal route and challenged intranasally with a clinical NTHi isolate. Bacterial clearance, antigen-specific mucosal and systemic antibody responses, and recruitment of innate immune cells to the airways were assessed. Results: Both immunization routes significantly reduced bacterial loads compared with controls. Vaccination induced robust mucosal and systemic IgG and IgA responses and enhanced early recruitment of macrophages, monocytes, dendritic cells, and neutrophils to the airways. Intranasal immunization elicited strong mucosal antibody responses and was associated with improved local bacterial clearance. Conclusions: These findings demonstrate that multi-antigen vaccines targeting conserved NTHi proteins can elicit effective mucosal and systemic immunity and represent promising candidates for the prevention against NTHi respiratory infections. Full article

Liver diseases, ranging from chronic hepatitis and metabolic dysfunction to cirrhosis and hepatocellular carcinoma, represent a major global public health burden. As an immune-privileged organ, the liver harbors a unique and intricate immune microenvironment, which plays a dual role in pathogen clearance and chronicity. Kupffer cells (KCs), the primary resident macrophages in the liver, constitute the first line of defense in liver innate immunity and play complex and important roles in pathogen recognition, phagocytosis, and the regulation of liver inflammation and immune responses. The complement receptor of the immunoglobulin superfamily (CRIg) is a membrane receptor that is specifically expressed on KCs. It serves not only as a sentinel for the liver against pathogen invasion but also as a sophisticated regulator for maintaining immune homeostasis. As a key component of the liver’s immune system, CRIg can efficiently mediate the clearance of complement-opsonized particles, thereby playing multidimensional roles in pathogen clearance, antigen cross-presentation, and the establishment of immune tolerance, functioning as both a “pathogen catcher” and an “immune brake.” This review focuses on the CRIg molecule, detailing its mechanisms in the recognition and phagocytic clearance by KCs, and its subsequent impact on hepatic immune responses. Furthermore, we explored the potential involvement of CRIg in the pathological progression of diverse liver diseases, including persistent inflammation, fibrosis, and hepatocarcinogenesis. This synthesis provides novel insights into the immunopathology of liver diseases and establishes a theoretical foundation for developing CRIg-targeted therapeutic strategies. Full article