Immunological Investigations最新文献

Objective: To elucidate the role of the polypyrimidine tract-binding protein 1 (PTBP1)-tumor necrosis factor receptor-associated factor 6 (TRAF6) pathway in chronic obstructive pulmonary disease (COPD), with a particular focus on its regulatory effects on macrophage polarization and clearance of neutrophil extracellular traps (NETs).

Methods: A COPD-like mouse model was established via cigarette smoke (CS) exposure. Lung injury, macrophage polarization, and levels of NETs were assessed. The role of TRAF6 in macrophage polarization and NETs clearance was assessed through lentiviral modulation of TRAF6 expression. RNA immunoprecipitation-quantitative polymerase chain reaction (RIP-qPCR), RNA stability assays, and Western blotting were performed to investigate the regulatory mechanism of PTBP1 on TRAF6 expression.

Results: The COPD-like mouse model exhibited increased M1 and decreased M2 macrophage populations, along with elevated NETs formation. Both PTBP1 and TRAF6 were upregulated in lung tissues of the COPD-like mouse model and cigarette smoke extract (CSE)-treated macrophages. Mechanistically, PTBP1 bound to and stabilized TRAF6 mRNA, enhancing TRAF6 expression. Inhibition of the PTBP1-TRAF6 pathway alleviated lung injury, restored macrophage polarization balance, and promoted NETs clearance.

Conclusion: PTBP1 enhances TRAF6 expression by stabilizing its mRNA, promoting M1 macrophage polarization and impairing NETs clearance, ultimately aggravating COPD.

Introduction: Colorectal Cancer has been a significant health issue at a global level in terms of increasing incidence, high metastatic capacity, and inadequate treatment reactions in most patient groups. Though chemotherapy and targeted agents have given better survival chances, resistance to treatment, avoidance of the immune system as well as systemic toxicity still limit long-term efficacy. Immunotherapeutic strategies have developed as effective methods in the past few years to address these shortomings.

Methods: A comprehensive literature search was conducted across different electronics databases including Web of Science, PubMed, Scopus, and ScienceDirect utilizing keywords colorectal cancer immunotherapy, PD-1 / PD-L1, CAR-T cells, viral vector vaccines, carcinoembryonic antigen alone and in combinations.

Results: PD-1/PD-L1, CTLA-4, immune checkpoint inhibitors have shown long-term responses, especially in mismatch repair-deficient and microsatellite instability-high tumours, and cell-based therapies such as CAR -T cells and dendritic cell vaccines provide other opportunities of personalised immune modulation.

Discussion: This critical review summarizes the current developments in terms of immunotherapy and interventions of CRC with a focus on the mechanistic understanding of the issue, clinical outcomes, and combinatorial strategies aimed to improve antitumor immunity and surmount therapy resistance. Specific attention is paid to the optimization of the checkpoint blockade, innovations with vaccines and CAR-T engineering to accumulate and release tumor-specific cells and control the microenvironment. Finally, key translational challenges current clinical trials, and future perspectives are identified to promote the development of the next-generation multimodal therapies in the efficient and customized management of CRC.

Background: Adjuvants potentiate adaptive immunity by enhancing antigen-specific immune responses, yet many exhibit high toxicity for clinical use. Naloxone (NLx) and naltrexone (NLt) opioid receptor antagonists have emerged as promising adjuvants in preclinical vaccination models against intracellular pathogens.

Objective: This narrative review synthesizes evidence from 2000 to 2025 evaluating NLx/NLt as adjuvants against bacterial, viral, and parasitic infections, while examining proposed immunoregulatory mechanisms.

Methods: A comprehensive search of Web of Science, PubMed, Scopus, ScienceDirect, and ProQuest employed Boolean operators combining: (vaccine OR vaccination) AND (adjuvant) AND (naloxone OR naltrexone OR NLx OR NLt OR "opioid receptor antagonist") AND ("immune response" OR "cellular immunity" OR "Th1").

Results: Key findings demonstrate that NLx/NLt monotherapy or combinatorial use with Alum consistently, enhanced Th1 polarization and cellular immunity, Elevated pathogen clearance and protection rates, synergistically overcame Alum's Th2 bias. Mechanistically, μ-opioid receptor (MOR) antagonism disrupts tonic immunosuppression, reversing opioid-mediated inhibition of dendritic cell maturation, IL-12 production, and cytotoxic T-cell function.

Conclusions: This immunorestorative action positions NLx/NLt as strategic adjuvants for vaccines targeting intracellular pathogens requiring robust cell-mediated immunity. Future horizons include combinatorial platforms (e.g. DNA vaccines + low-dose naltrexone) and clinical translation.

Background: Obesity-induced metabolic stress impairs the efficacy of immune checkpoint blockade (ICB) therapy, but the mechanisms linking a high-fat diet (HFD) to immune suppression remain unclear.

Objective: To investigate how HFD-induced metabolic changes modulate the tumor immune microenvironment through the STAT3/CD155 axis.

Methods: Murine colorectal cancer models using control, CD155-overexpressing (CD155 OE), and STAT3 knockdown CT26 cells were established under normal or HFD conditions with anti - PD-L1 treatment. Tumor growth, immune infiltration, and gene expression were analyzed by flow cytometry, Western blotting, and chromatin immunoprecipitation.

Results: HFD impaired anti - PD-L1 efficacy and accelerated tumor growth. Mechanistically, HFD promoted STAT3 nuclear translocation and CD155 upregulation, reducing CD8⁺ T cell infiltration and enhancing regulatory T cell accumulation. Chromatin immunoprecipitation confirmed direct STAT3 binding to the CD155 promoter, while STAT3 knockdown reversed these effects and restored antitumor immunity in HFD-fed mice.

Conclusion: HFD-induced metabolic stress drives immune evasion via the STAT3/CD155 axis. Targeting this pathway may improve ICB efficacy in obesity-related cancers.

Introduction: The immunosuppressive microenvironment of hepatocellular carcinoma (HCC) is shaped by multiple oncogenic pathways, but howosteopontin (OPN), a molecule frequently overexpressed in HCC, regulates anti-tumor immunity remains unclear.

Methods: To define the mechanism by which OPN modulates the HCC immune microenvironment, with a focus on its regulation of CD155 and its impact on CD8⁺ T-cell - mediated anti-tumor responses.

Results: We identified that OPN activates the p65/NF-κB - c-Myc/CD155 signaling axis, leading to robust upregulation of CD155 and impaired intratumoral CD8⁺ T-cell infiltration and effector activity. These immunosuppressive effects occurred independently of changes in tumor stemness markers or Treg accumulation. Genetic suppression of p65 abrogated OPN-induced CD155 expression and mitigated tumor progression in vivo, demonstrating the pathway's functional requirement.

Discussion: OPN drives HCC progression by suppressing CD8⁺ T-cell immunity through the NF-κB (p65)/c-Myc/CD155 axis. Targeting this pathway may enhance anti-tumor immunity and represents a promising therapeutic strategy for HCC.

Background: Cardiomyopathies contribute substantially to heart failure, arrhythmias, and sudden cardiac death. Innate immune activation-particularly via Toll-like receptors (TLRs)-is increasingly recognized as a driver of pathological cardiac remodeling.

Objective: To evaluate how TLR expression and downstream signaling pathways (MyD88 and TRIF) shape distinct cardiomyopathy phenotypes and to assess therapeutic strategies targeting these mechanisms.

Methods: Evidence from studies of ischemic, viral, septic, diabetic, drug-induced, hypertrophic, and obesity-associated cardiomyopathies was surveyed to determine the roles of TLR subtypes and the impact of modulating their signaling pathways.

Results: Activation of TLR2, TLR3, TLR4, TLR7, and TLR9 consistently amplifies myocardial inflammation, fibrosis, and functional decline. However, context-dependent protective effects in certain settings highlight the complexity of uniformly suppressing TLR activity. Preclinical investigations demonstrate favorable outcomes from selective pathway modulation, including TLR4 antagonists (such as TAK-242 and eritoran), MyD88 pathway inhibitors, and nucleic-acid-directed TLR9 strategies.

Conclusions: Targeting TLR signaling has strong potential to limit inflammation, curb fibrotic remodeling, and preserve cardiac function across diverse cardiomyopathies. The most promising therapeutic direction involves developing subtype-specific and cell- or pathway-targeted interventions, supported by translational research to bridge preclinical findings with clinical application.

Background: This review aims to synthesize the structural and functional characteristics of DOCK2, as well as its mechanistic roles in various diseases, in order to provide a theoretical foundation for targeted therapies.

Methods: We systematically reviewed existing literature to summarize the molecular features and expression patterns of DOCK2, its regulation of cellular processes through both Rac-dependent and Rac-independent pathways, and its implications in inflammation, cancer, fibrosis, and related disorders.

Results: DOCK2, a member of the Dock-A subfamily of GEFs, is widely expressed across tissues and prominently in immune cells (e.g., dendritic cells, macrophages, T cells, B cells), where it regulates proliferation, differentiation, migration, and cytokine secretion primarily via Rac activation. Emerging evidence also links DOCK2 to non-immune cell types such as glial cells and vascular smooth muscle cells, highlighting its relevance in immune-related and broader pathological conditions including inflammatory diseases, cancer, atherosclerosis, idiopathic pulmonary fibrosis, and obesity.

Conclusion: As a critical GEF, DOCK2 plays a central role in immune and non-immune cellular processes through Rac and non-Rac signaling pathways. Dysregulation of DOCK2 is closely associated with multiple diseases. Further elucidation of its regulatory networks may reveal novel therapeutic targets for treating related disorders.

Background: Treating traumatic spinal cord injury (SCI) requires mitigating microglia-mediated inflammation and nerve damage. Phillyrin (phi) shows neuroprotective potential, but its effects on SCI are unknown. We investigated phi's impact on microglial activation, inflammation, neuronal apoptosis, and pyroptosis in mice after SCI.

Methods: A mouse contusion SCI model was used to assess phi efficacy. Functional recovery was assessed with BBB and LSS scales. Histological and TUNEL staining were used to evaluate tissue damage and neuronal survival. Microglial phenotypes, inflammation, pyroptosis, oxidative stress and Nrf2/HO-1 pathway were analyzed.

Results: Phi treatment accelerated motor function recovery, improved tissue pathology, increased live cells, and reduced apoptosis. Phi treatment showed a decrease in the proportion of M1 pro-inflammatory microglia characterized by iNOS, an increase in the proportion of M2 anti-inflammatory microglia characterized by Arg1 and a reduction in inflammatory factors. Phi enhanced Nrf2 expression in neurons and microglia, activated HO-1 and NQO1 expression, weaken oxidative stress, and improved pyroptosis.

Conclusion: Phi alleviates SCI by activating the Nrf2/HO-1 pathway, suppressing microglial activation-mediated neuroinflammation, neuronal apoptosis, oxidative stress and pyroptosis. This study provides the first evidence of the therapeutic effect of phi on traumatic SCI, providing theoretical support for its future clinical application in SCI.

Background: The gut microbiota plays an important role in systemic immune homeostasis and is increasingly implicated in autoimmune thyroid disease (AITD). Evidence suggests that gut dysbiosis, impaired intestinal barrier function, and altered microbial metabolites particularly short-chain fatty acids contribute to immune imbalance along the gut-thyroid axis. Although molecular mimicry between microbial and thyroid antigens has been proposed, current human evidence remains associative rather than causal.

Methods: This review synthesized current observational, translational, and preclinical studies evaluating microbial composition, barrier integrity, microbial metabolites, and immune pathways relevant to AITD. Mechanistic insights into T-lymphocyte regulation and microbial-host interactions were integrated with emerging interventional data.

Results: Gut dysbiosis in AITD is linked to reduced regulatory T-lymphocytes, expansion of Th17 cells, increased intestinal permeability, and the loss of short-chain-fatty-acid-producing taxa. Observational studies consistently report disease-associated taxonomic alterations, while preclinical models support causal pathways through barrier disruption and microbiota-driven immune activation. Early interventional approaches such as high-fiber dietary patterns, probiotics, prebiotics, and experimental fecal microbiota transplantation show modest reductions in thyroid autoantibodies in small trials, though effects are strain-specific, short-term, and not disease-modifying.

Conclusion: Despite largely associative human evidence, converging mechanistic findings highlight the gut microbiota as a modifiable contributor to thyroid autoimmunity. Future priorities include clarifying causality, identifying keystone microbial taxa and metabolites, and establishing standardized interventional frameworks to facilitate translation into endocrine practice.

Background: Periodontal disease is a prevalent chronic inflammatory condition of the tooth-supporting tissues characterized by progressive loss of connective attachment and alveolar bone. The IL-12 cytokine family-comprising IL-12, IL-23, IL-27, and IL-35-plays key yet divergent roles in shaping periodontal immune responses through heterodimeric subunits and distinct JAK-STAT signaling pathways. These cytokines differentially regulate inflammation, microbial interactions, and bone resorption.

Methods: This review integrates experimental and clinical evidence assessing IL-12 family members in saliva, gingival crevicular fluid, and periodontal tissues. Studies examining cytokine expression profiles, their correlation with disease activity, microbial dysbiosis, and treatment response were analyzed. Mechanistic data elucidating how IL-12 family signaling modulates inflammatory cascades and osteoclastogenic pathways were also evaluated.

Results: IL-12 and IL-23 predominantly amplify pro-inflammatory responses by promoting Th1/Th17 polarization, enhancing neutrophil recruitment, and driving osteoclastogenesis, thereby linking dysbiotic biofilms to tissue destruction. In contrast, IL-27 and IL-35 exhibit context-dependent immunoregulatory properties, inducing IL-10-mediated anti-inflammatory signaling and expanding regulatory T and B cell compartments to support the resolution of inflammation. Across clinical samples, cytokine levels consistently reflect disease severity and demonstrate modulation following periodontal therapy, underscoring their potential as adjunctive biomarkers.

Conclusion: Members of the IL-12 cytokine family exert both pathogenic and protective influences in periodontal disease. Therapeutic strategies that suppress IL-12/IL-23-driven inflammation while augmenting IL-27/IL-35-mediated regulation show promise as host-modulatory approaches in periodontal treatment. A deeper understanding of these immunologic dynamics may advance precision-based periodontal therapies.