Search Results (637)

Trained immunity (TI) represents a form of immune memory in innate immune cells, driven by sustained epigenetic and metabolic reprogramming that potentiates innate immune responses. Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by persistent alveolar injury and pathological tissue remodeling. Given the central role of macrophages in IPF pathogenesis, we hypothesized that inducing TI could functionally reprogram these cells and attenuate fibrosis. In a murine model of pulmonary fibrosis induced by bleomycin, prior induction of TI via β-glucan enhanced autophagic activity in macrophages and reduced pathological collagen deposition. This trained response restricted bleomycin-triggered mitochondrial DNA release and suppressed the mitochondrial apoptosis pathway, thereby promoting macrophage survival. The protective effects were diminished by administration of the AMPK inhibitor Compound C. Our findings indicate that TI promotes mitophagy correlating with the AMPK-ULK1 signaling axis, thereby reducing alveolar macrophage apoptosis and uncovering a potential therapeutic strategy for pulmonary fibrosis. Full article

Mucosal microbiota contribute broadly to host defense and immune homeostasis, while the lung and gut microbiota form a particularly important bidirectional ecological and immunological network that shapes pulmonary host defense, inflammatory injury, and tissue repair. In pneumonia, loss of colonization resistance and altered microbial metabolite production may weaken innate and adaptive immunity; respiratory infection, antibiotics, and critical-care exposures can, in turn, remodel both microbial communities. In acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), intestinal barrier failure, circulating microbial products, immune cell trafficking and, in selected settings, lymphatic or hematogenous dissemination of gut-derived organisms may aggravate alveolar–capillary injury. Alveolar macrophages integrate these signals through pattern-recognition, metabolic, and epigenetic pathways, linking microbial ecology to pathogen clearance and inflammatory resolution. The evidence, however, remains uneven. Mechanistic causality rests largely on animal studies, most human data are associative, and trials of microbiota-directed interventions are heterogeneous and strain-specific. This Review examines bacterial and viral pneumonia, sepsis-associated ALI and ventilator-associated injury; separates mechanistic, observational, and interventional evidence; and evaluates probiotics, live biotherapeutic products, microbial metabolites, and dietary approaches. Translation will depend on longitudinal sampling, source-resolved microbial tracking, metabolite-informed patient stratification, and adequately powered trials with clinically relevant endpoints. Full article

Porcine reproductive and respiratory syndrome (PRRS), caused by porcine reproductive and respiratory syndrome virus (PRRSV), is a major infectious disease that poses a severe threat to the global swine industry. To investigate the role of miRNAs in the infection and susceptibility of PRRSV, four miRNA libraries were constructed and sequenced from PRRSV-infected and mock-infected of Tibetan pigs and Large White pigs at 7 days post-infection. A novel miRNA, miR-novel-80, was differentially expressed between PRRSV-infected and mock-infected porcine alveolar macrophages from 2 pig breeds. Importantly, the over-expression of miR-novel-80 inhibited the replication of a PRRSV-1 strain and multiple lineages (L1, L5, and L8) of PRRSV-2 strains in a dose-dependent manner. Bioinformatic predictions and experimental validation demonstrated that miR-novel-80 restricts viral replication through a dual antiviral mechanism. Directly, it targets the PRRSV nsp1-coding region within the ORF1a to suppress viral proliferation. Indirectly, miR-novel-80 specifically down-regulates the expression of host factor CXXC finger protein 4 (CXXC4). This reduction relieves the suppression of the Wnt/β-catenin signaling pathway, which in turn activates NF-κB-dependent innate immune responses to further inhibit PRRSV infection. Collectively, this study investigates the biological characteristics of miR-novel-80 and unveils its underlying molecular mechanisms in restricting PRRSV infection in vitro. However, its biological function and anti-PRRSV therapeutic effect in vivo need further investigation. Full article

African swine fever virus (ASFV) causes African swine fever (ASF), a highly lethal disease in pigs. Vietnam has approved two ASF live-attenuated vaccines (LAVs), but their efficacy and safety remain controversial, and no reliable, highly effective commercial ASF vaccine is available yet. Humoral immunity plays an important role in protection against ASFV infection. However, there is still controversy regarding whether ASFV infection can induce antibodies with neutralizing activity. Antibody-dependent cellular cytotoxicity (ADCC), as an antibody-mediated protective mechanism, offers a novel perspective for screening protective ASFV antigens. This study evaluated five structural proteins (pCP312R, pA104R, pA151R, p17, and pF317L) as subunit vaccine candidates based on their ability to induce antibodies that inhibit viral replication and mediate ADCC. The recombinant proteins were expressed in Escherichia coli, purified, and used to immunize pigs. Immune sera collected two weeks after the third immunization were tested for their ability to inhibit ASFV replication in porcine alveolar macrophages (PAMs) using rASFV-Gluc/EGFP. ADCC activity was assessed using a stable HEK293T-p17 cell line as target cells and porcine peripheral blood mononuclear cells (PBMCs) as effectors, with cytotoxicity measured by lactate dehydrogenase release. All five recombinant proteins were successfully expressed and purified. Immunization with pCP312R, pA104R, p17, and pF317L induced the production of specific antibodies in pigs, but only anti-p17 antibodies significantly inhibited ASFV replication in PAMs. The p17 is highly conserved across different ASFV genotypes and is predicted to contain a transmembrane domain. Anti-p17 antibodies effectively mediated PBMCs to specifically kill target cells, demonstrating significant ADCC activity. Moreover, the HEK293T-p17 cell line was specifically recognized by anti-ASFV sera. These findings indicate that p17 is a dual-functional antigen capable of eliciting antibodies that both inhibit viral replication and mediate ADCC in vitro. Furthermore, we have developed an in vitro platform for screening protective ASFV antibodies based on viral inhibition and ADCC, providing candidate targets for the development of next-generation ASF subunit vaccines. Full article

Immune checkpoint inhibitor-related pneumonitis (CIP) is an uncommon but clinically relevant toxicity in renal cell carcinoma (RCC), where immune checkpoint inhibitors are frequently used either as dual immunotherapy or in combination with VEGF-targeted tyrosine kinase inhibitors. In RCC, CIP poses specific diagnostic challenges because respiratory symptoms and computed tomography findings may overlap with pulmonary metastases, infections, thromboembolic events, heart failure, and TKI-related lung toxicity. This review summarizes the incidence of CIP across pivotal RCC trials and real-world cohorts, compares its epidemiology with non-small cell lung cancer, and discusses clinical presentation, radiological patterns, differential diagnosis, and current management strategies. Particular attention is given to RCC-specific mechanisms, including immune-mediated alveolar injury, T cell activation, cytokine dysregulation, macrophage activation, GSDME-mediated pyroptosis, and the potential contribution of VEGF pathway inhibition to pulmonary inflammation. We also review risk factors, steroid-refractory disease, second-line immunosuppression, and the unresolved issue of ICI rechallenge after pneumonitis. A better understanding of these mechanisms and clinical features may improve early recognition, guide multidisciplinary management, and support safer use of immunotherapy-based combinations in patients with RCC. Full article

Periodontitis, a chronic inflammatory disease driven by plaque biofilm, is a leading cause of tooth loss in adults worldwide. Effective treatment requires not only infection and inflammation control but, more critically, functional regeneration of the periodontal ligament, cementum, and alveolar bone. Periodontal regeneration, however, is a highly ordered, multi-stage biological cascade involving temporally coordinated phases of blood clot formation, inflammatory regulation, tissue formation, and remodeling. Conventional single-drug or mixed-delivery strategies cannot distinguish the distinct demands of each healing phase and fail to replicate this natural rhythm. Sequential controlled-release systems address this gap by delivering multiple bioactive agents (antimicrobials, immunomodulators, and growth factors) in a programmed order tailored to the healing cascade, enabling precise modulation of the periodontal microenvironment and orderly tissue regeneration. This review systematically summarizes advances in these systems, classifying material platforms into four categories: (1) diffusion-barrier and degradation-kinetics systems, including multilayer films, core–shell fibers, porous microspheres, and microneedle arrays; (2) stimuli-responsive systems triggered by pH, matrix metalloproteinases, reactive oxygen species, or exogenous physical stimuli; (3) cell and extracellular vesicle-based systems exploiting the inflammatory tropism of M2 macrophage-derived exosomes for targeted immune reprogramming; and (4) asymmetric structural designs achieving spatiotemporal coordination of physical and biochemical signals through hierarchical architectures. These systems follow an anti-infection/anti-inflammation first, osteogenesis later therapeutic logic, circumventing temporal antagonism among bioactive factors. However, significant challenges hinder clinical translation, including individualized prediction of release kinetics, long-term biocompatibility of carrier materials, material retention under dynamic oral conditions, translational limitations of animal models, and precise regulation of complex factor networks. Future progress will likely depend on multi-responsive and logic-gated systems, deeper integration of biotechnology and immunomodulation, personalized precision medicine, AI-driven material design, and robust clinical translational research. Full article

A bidirectional relationship has been observed between COVID-19 and respiratory disorders, where respiratory comorbidities increase severity, and COVID-19 induces respiratory sequelae. The underlying biological and genetic mechanisms remain unclear. While previous studies have identified overlapping genetic loci, few have systematically disentangled the genetic factors shared between these conditions versus those specific to COVID-19, particularly at a multi-omics level. We developed and applied a unified analytical framework to compare three COVID-19 phenotypes with eight respiratory disorders (including asthma, COPD, IPF, and pneumonia). Utilizing the cofdr method for shared genetic signal analysis and DDx/mtCOJO for differentiation, we integrated genome-wide association statistics with multi-omics data (transcriptome, splicing, and proteome). This approach allowed for the simultaneous identification of shared genetic signals (concordant or discordant) and disease-specific variants across expression (TWAS), alternative splicing (spTWAS), and protein abundance (PWAS). We delineated a comprehensive atlas of 214 differential and numerous shared loci across 24 pairwise comparisons. The shared genetic architecture was characterized by pleiotropic effects in genes such as ATP11A (exhibiting opposing effects in COVID-19 vs. IPF) and GSDMB (shared with COPD). Crucially, differentiation analysis revealed that severe COVID-19 is genetically distinct from other respiratory infections (e.g., pneumonia and influenza) through dysregulated Type I/III interferon signaling and specific defects in alveolar epithelial and macrophage function, as well as GM-CSF/surfactant metabolism pathways. These findings provide human genetic evidence consistent with the therapeutic rationale underlying GM-CSF modulators and interferon-lambda for COVID-19, both of which have entered clinical trials. Furthermore, multi-trait conditional analysis prioritized FYCO1 and HCN3 as potential COVID-19-specific risk genes. Splicing analysis underscored the critical role of alternative splicing in both shared and differential architectures, highlighting IFNAR2 isoform regulation as a key discriminator between COVID-19 and other respiratory traits. This study provides the first genome-wide, multi-omics map revealing the shared and differential genetic landscapes of COVID-19 and other respiratory phenotypes. By uncovering specific molecular mechanisms that distinguish COVID-19 pathology, specifically involving surfactant homeostasis and interferon pathways, our findings offer novel insights for targeted drug repurposing and precision risk stratification. Full article

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, causes substantial economic losses in the swine industry. Because viral variability and host genetic complexity limit conventional control, identifying host genetic factors associated with PRRS resistance through genomic approaches is important for disease-resistant breeding. In this study, 699 pigs were immunized with a PRRSV vaccine, 135 were selected for PRRSV infection experiments, and 133 were retained for whole-genome resequencing after two-stage phenotypic screening based on post-immunization and post-infection profiles. Genome-wide selection-signal analysis identified 12 highly differentiated regions (F_st > 0.15), annotated to 11 candidate genes: NFXL1, NIPAL1, CHIC2, LOC100623351, LOC100513671, LOC100513484, CENPC, STAP1, UBA6, GNRHR, and LOC100512727. The original exploratory GWAS identified candidate association signals, including signals annotated to PYGM, NFXL1, KIAA1324L, and FLNC; after PC1/PC2 adjustment, NFXL1 retained exploratory support, and additional exploratory signals were observed. Public PRRSV-related transcriptomic datasets provided additional expression-level evidence, with NIPAL1 and PYGM showing increased expression in PRRSV-infected porcine alveolar macrophages. Functional enrichment and variant-level analyses supported the biological relevance of the prioritized candidate gene set, particularly the chromosome 8 NFXL1 region, where the A-C-G haplotype was more frequent in resistant pigs. These findings provide useful genetic clues for further validation and PRRS resistance breeding. Full article

As a major occupational hazard, crystalline silica (SiO₂) poses a severe risk of pulmonary toxicity. While the irreversible fibrosis of late-stage silicosis has been extensively studied, the cellular and molecular mechanisms by which SiO₂ reprograms macrophage metabolism to drive early pathogenesis remain poorly understood. To elucidate this early immune-inflammatory response, we combined targeted metabolomics, pharmacological treatments, and nutrient deprivation in murine alveolar macrophages. Our results demonstrate that SiO₂ exposure severely impairs the master antioxidant regulator, nuclear factor erythroid 2-related factor 2 (Nrf2), triggering excessive reactive oxygen species (ROS) accumulation and upregulated glutamine catabolism to drive pro-inflammatory M1 macrophage polarization. We demonstrated that Nrf2 activation with tert-butylhydroquinone (TBHQ) redirected glutamine metabolic flux from pro-inflammatory catabolism to antioxidant anabolism, significantly attenuating SiO₂-induced M1 polarization. Conversely, Nrf2 inhibition via ML385 exacerbated the inflammatory response. Furthermore, introducing a glutamine deprivation (−Gln) model revealed that restricting glutamine availability significantly attenuated the ability of Nrf2 to reverse M1 polarization, suggesting that its immune-protective effects largely depend on an intact glutamine metabolic pathway. Ultimately, our findings underscore the severe risks of silica exposure and identify the Nrf2–glutamine metabolic axis as a promising target, providing novel mechanistic insights and a robust basis for “antioxidant–metabolic” dual-target interventions in early-stage silicosis. Full article

(TB) induces a pronounced thromboinflammatory state during active disease, characterized by elevated fibrinogen, D-dimer, and thrombin-related activity, reduced levels of endogenous anticoagulants, impaired fibrinolysis, platelet activation, and endothelial dysfunction. Although many of these abnormalities improve after treatment initiation, accumulating evidence suggests that microbiological cure may not fully restore vascular, immune, and hemostatic homeostasis. This raises the possibility that TB leaves a persistent thromboinflammatory imprint after cure. This narrative synthesizes current evidence on tuberculosis-associated hypercoagulability during active disease and after treatment, and proposes a conceptual framework for post-tuberculosis thromboinflammatory memory grounded in cellular persistence, tissue remodeling, and extracellular vesicle-mediated signaling. Candidate storage compartments include hematopoietic stem and progenitor cells, monocyte/macrophage lineages, alveolar macrophages, remodeled pulmonary endothelium, and fibrotic post-TB lung tissue. EVs may function as mobile vectors that transfer procoagulant phospholipids, tissue factor, inflammatory proteins, and regulatory microRNAs between these compartments, thereby linking local post-TB remodeling to systemic vascular and coagulation pathways. A mechanistic evidence ladder is proposed, encompassing phenotypic persistence, EV cell-of-origin attribution, molecular persistence, paired longitudinal validation, functional transfer, and clinical outcome linkage. Current data support the biological plausibility of this framework but remain insufficient to establish post-TB thromboinflammatory memory as a defined clinical entity. Direct evidence in long-term TB survivors is still lacking, particularly with respect to persistent EV signatures, cell-specific reservoirs, and the functional transfer of procoagulant phenotypes. Longitudinal, cell-resolved, multi-omic, and functionally validated studies are required to determine whether TB leaves a durable thromboinflammatory memory, where it is stored, and whether it contributes to long-term thrombotic and cardiovascular risk. This article should be interpreted as a narrative review with a conceptual framework rather than as evidence that post-tuberculosis thromboinflammatory memory is already a formally established clinical entity. Full article

Dysregulated activation of the NLRP3 inflammasome is a key driver in the pathogenesis of numerous inflammatory disorders. This study aimed to evaluate the protective effect of Platycodon grandiflorus polysaccharide (PGPS_t) against NLRP3-inflammasome-mediated inflammation and elucidate its underlying mechanisms. An in vitro inflammatory model was established in porcine alveolar macrophages (3D4/21) using LPS/ATP co-stimulation. The effects of PGPS_t were assessed by measuring inflammasome activation, intracellular reactive oxygen species (ROS) generation, and pro-inflammatory cytokine secretion. Molecular docking, alongside inhibitors (NAC, MCC950) and siRNA targeting NEK7, was employed to probe the involved mechanisms. PGPS_t significantly suppressed NLRP3 inflammasome assembly and activation, reduced caspase-1 cleavage, and decreased the maturation and release of IL-1β and IL-18. It exerted its inhibitory effects through dual mechanisms: scavenging intracellular ROS and directly binding to NEK7 and NLRP3 to disrupt their interaction, as supported by molecular docking. The anti-inflammatory effect was diminished upon NEK7 knockdown. In conclusion, PGPS_t is an effective natural inhibitor of the NLRP3 inflammasome, functioning through ROS clearance and direct interference with the NLRP3–NEK7 interaction. These findings propose PGPS_t as a promising therapeutic candidate and further validate NEK7 as a potential target for treating NLRP3-driven inflammatory diseases. Full article

Periodontitis is a chronic inflammatory disease characterized by alveolar bone loss driven by dysregulated immune responses. We previously showed that extracellular vesicles derived from retinoic acid-induced regulatory T lymphocytes (RA-Treg EVs) suppress pathogenic CD4⁺ T-lymphocyte responses and reduce alveolar bone loss during periodontitis. Herein, we investigated whether RA-Treg EVs also modulate macrophage and CD8⁺ T-lymphocyte responses during experimental periodontitis. Ligature-induced periodontitis was generated in mice, followed by local administration of RA-Treg EVs. Alveolar bone loss was analyzed by micro-computed tomography, and periodontal tissues and cervical lymph nodes were analyzed by flow cytometry to quantify antigen-presenting cells, macrophages, macrophage subsets, and CD8⁺ T lymphocytes. The direct effects of RA-Treg EVs on macrophage phenotype and CD8⁺ T-cell proliferation and activation were assessed in vitro. RA-Treg EV treatment attenuated alveolar bone loss and preserved trabecular microarchitecture. This effect was associated with reduced macrophage infiltration into periodontal tissues, modulation of macrophage polarization, and restoration of CD8⁺ T-cell abundance in periodontal tissues and draining cervical lymph nodes, without major changes in CD8⁺IFN-γ⁺ or CD8⁺RANKL⁺ cells. In vitro, RA-Treg EVs induced heterogeneous macrophage phenotypes distinct from the classical M1/M2 polarization states while markedly enhancing CD8⁺ T-cell proliferation and activation. These findings indicate that RA-Treg EVs preserve alveolar bone during experimental periodontitis while selectively modulating macrophage and CD8⁺ T-lymphocyte responses. Full article

Hemorrhagic pneumonia is a severe and often fatal disease in captive forest musk deer (Moschus berezovskii), but the pathogen remains incompletely understood. Based on incomplete statistics, the estimated incidence in captive populations ranges from 20% to 80%, with the disease occurring mainly in autumn, winter, and early spring. The disease has an acute onset and rapid progression. Due to the species’ strong stress response, affected animals rarely show behavioral changes, making early detection difficult. In this study, we investigated a mortality case presenting with oral bleeding and hematemesis on a forest musk deer farm. Postmortem examination revealed diffuse hemorrhagic pneumonia, and lung tissue samples were collected for histopathology, bacterial isolation, full-length 16S rRNA gene sequencing, and DNA/RNA virome sequencing. Histological examination showed extensive alveolar hemorrhage, fibrinous exudate, and macrophage infiltration. Bacterial culture and 16S rRNA gene sequencing identified Bergeyella zoohelcum as the predominant bacterium, accounting for 100% of the bacterial community in the lung tissue. Virome analysis revealed predominantly DNA bacteriophages (e.g., Cirlivirales, Cremevirales, Microviridae) and no known pathogenic RNA viruses; only seven low-abundance, unclassified RNA viral contigs of low completeness were detected. These results indicate that B. zoohelcum is the likely causative agent of hemorrhagic pneumonia in this case, with no evidence of viral involvement. This study provides the first direct association of B. zoohelcum with hemorrhagic pneumonia in forest musk deer, highlighting its pathogenic potential and the importance of monitoring this bacterium in captive populations. Full article

Old murine bone marrow-derived monocytes and macrophages (BMMs) display enhanced CD38 protein, a nicotinamide adenine dinucleotide (NAD⁺) glycohydrolase, and reduced NAD⁺ level after infection with oral pathogens compared to young controls. We aimed to determine whether treatment with a CD38-specific inhibitor (78c) in mice with experimental periodontitis could alleviate alveolar bone loss and enhance NAD⁺ levels in tissues compared with vehicle treatment. Twenty young (2-month-old) and twenty old (18-month-old) male C57BL/6J mice with experimental periodontitis were treated with either vehicle or 78c twice daily via intraperitoneal injection for 4 weeks. The liver, spleen, and right maxillary tissues were harvested to analyze NAD⁺ levels. The left maxillary tissues were scanned by micro-CT. Then, the left maxillary tissues were processed for tissue sectioning and stained with hematoxylin and eosin (H&E) and tartrate−resistant acid phosphatase (TRAP). Treatment with 78c significantly enhanced NAD⁺ levels in the liver and spleen of both young and old mice, and significantly increased NAD⁺ in the right maxilla of old mice compared with vehicle treatment. Additionally, treatment with 78c alleviated alveolar bone loss in both young and old mice. Our results support the notion that 78c is a promising therapeutic strategy for treating periodontal disease. Full article

Porcine reproductive and respiratory syndrome (PRRS) is an immunosuppressive disease caused by PRRS virus (PRRSV). PRRSV infection not only compromises the host immune defenses, but also predisposes the host to secondary infections by other pathogens, of which PRV is one of the common secondary infection pathogens. Porcine alveolar macrophages (PAMs) are the primary target cells of PRRSV, and their phagocytic function is critical for immune defense, homeostasis maintenance, and disease regulation. However, PRRSV disrupts PAMs phagocytosis, impairing the host’s ability to combat infection. This study used PRV-pAb complexes as phagocytic indicators, investigated the effect of PRRSV infection on PAMs phagocytosis and its underlying molecular mechanisms. We found that PRRSV infection interfered with phagosome maturation—a process regulated by Rab7 and other regulators, thereby blocking phagocytic degradation and significantly suppressing PAMs phagocytic activity. Further analysis revealed that reactive oxygen species (ROS) play a key role in this process. Elevated ROS levels damaged lysosomal membrane integrity, ultimately inhibiting phagosome-lysosome fusion. Notably, phagocytosis of PRRSV-infected PAMs was partially restored with N-acetylcysteine (NAC) by reducing ROS levels. These findings offer novel insights into PRRSV-induced immunosuppression and secondary infections while providing a theoretical foundation for developing more effective PRRSV prevention and control strategies. Full article