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关键词： Chimeric antigen receptor - CAR   Natural killer - NK   Mitochondria   Lymphoma  

摘要： Background Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy has demonstrated safety and feasibility in clinical settings;however, limited efficacy due to intrinsic dysfunction and extrinsic suppression remains an unresolved issue. T cells provide multifaceted support to NK cell-mediated responses. Here, we aimed to design a novel CD19-targeted CAR-NK, engineered with secreted interleukin-15 and C-C motif chemokine ligand 21 (ie, 15x21 CAR-NK), capable of recruiting and cooperating with T *** We characterized 15x21 CAR-NK cells by performing experiments in vitro and in mouse models, and conducting RNA *** 15x21 CAR-NK cells exhibit strong capabilities in cytotoxicity, cytokine production, effector molecule expression, and T-cell recruitment in vitro. Cooperation with T cells promoted efficient tumor-cell elimination, alleviated mutual exhaustion phenotypes, and enhanced the expression of effector molecules/receptors. The recruitment and cooperative effects also result in effective tumor control in mouse models. In addition, 15x21 CAR-NK cells strongly enrich the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway - a key intracellular signaling cascade that is associated with enhanced downstream pro-survival signaling, anti-apoptotic ability, mitochondrial function, and *** Our study highlights the intrinsic advantages and extrinsic T-cell cooperative benefits of 15x21 CAR-NK cells, providing a promising strategy for NK-cell-based immunotherapy.

关键词： beta cells   butyrate   cytokine   inflammation   mitochondria   oxidative stress  

摘要： Butyrate, a gut microbiota-derived metabolite, supports cellular health. In pancreatic beta cells, inflammation and oxidative stress disrupt mitochondrial function, contributing to dysfunction. This study explores how butyrate influences mitochondrial function and redox balance to protect beta cells from interleukin-1beta (IL-1 beta)-induced stress. Pancreatic mouse islets were treated with IL-1 beta and/or butyrate for 10 days to model chronic inflammation in type 2 diabetes, and their effects on mitochondrial health and oxidative stress were studied. Butyrate protected against IL-1 beta-induced impairment of insulin secretion by enhancing mitochondrial function, as evidenced by an increased glucose-stimulated oxygen consumption rate and a higher mitochondrial membrane potential compared to IL-1 beta treatment alone. IL-1 beta increased mitochondrial mass, but the mitochondria appeared smaller and rounded, indicating fragmentation. In contrast, butyrate co-treatment promoted mitochondrial hyperfusion, as evidenced by elongated mitochondria, higher levels of fusion proteins Opa1 and Mfn2, and lower levels of fission protein Fis1 compared to IL-1 beta alone. Furthermore, butyrate reduced IL-1 beta-induced reactive oxygen species (ROS) production, antioxidant enzyme gene expression, and protein oxidation, indicating protection against oxidative stress. Butyrate co-treatment further enhanced redox balance by increasing reduced glutathione (GSH) levels and the ratio of GSH to oxidized glutathione (GSSG). These findings suggest that butyrate acts as a potent modulator of mitochondrial function and redox balance, counteracting IL-1 beta-induced dysfunction and providing a potential therapeutic strategy for improving insulin secretion in inflammatory conditions.

关键词： hepatitis B virus (HBV)   neutrophils   neutrophil extracellular traps   inflammation   interleukin (IL)-1b   liver fibrosis   cirrhosis  

摘要： Hepatitis B virus (HBV) infection is one of the most dangerous viral diseases, with innate immunity representing the first line of defense against the virus. In this branch of the immune system, neutrophils are considered key cellular mediators. To better understand the implication of neutrophils in the distinct stages of the disease, HBV-infected patients were enrolled in this study and categorized into three groups: patients with acute infection, chronic infection under treatment, and at early cirrhotic stage. To elucidate the role of inflammatory mediators and cellular mechanisms of neutrophilic origin in the course of the infection, both ex vivo and in vitro studies were performed. Increased levels of C-C motif chemokine ligand 2 (CCL2), interleukin (IL)-18, IL-33, and citrullinated histone H3 (CitH3)-an accurate marker of neutrophil extracellular traps (NETs)-were detected in the circulation of patients with acute infection or early cirrhosis. In parallel, sera from the aforementioned patient groups induced the formation of IL-1b-bearing NETs in neutrophils from healthy individuals. These inflammatory NETs affected primary fibroblasts towards acquiring a pro-fibrotic phenotype. These results suggest that NETs could be regarded as mediators in hepatitis B manifestations, while their therapeutic targeting could enhance the management of early-stage cirrhotic patients.

关键词： Pelvic organ prolapses   Adhesive   Exosomes   Immune response  

摘要： Pelvic organ prolapse (POP) is a prevalent condition among middle-aged women, resulting from weakened pelvic floor muscles and ligaments, which cause organ descent and associated dysfunctions. Surgical interventions utilizing polypropylene (PP) mesh are often limited by factors such as complex procedures and postoperative inflammation, leading to suboptimal outcomes. An innovative adhesive hydrogel (CAN-15) has been synthesized from carboxylated methacrylate polyvinyl alcohol (CMPVA), acrylic acid (AA), and acrylic acid N-hydroxysuccinimide ester (AA-NHS) through photopolymerization. This hydrogel exhibits a rapid photopolymerization rate (within 5 s) and robust adhesion (89.17 kPa), enabling the secure attachment of PP mesh to pelvic structures without sutures. Additionally, exosomes derived from interferon-gamma pre-treated adipose stem cells (IFN-gamma-Exos) demonstrate superior immunomodulatory capabilities compared to their non-pretreated counterparts (Exos). The integration of IFN-gamma-Exos with the CAN-15 hydrogel forms a functional adhesive (IFN-gamma-Exos@CAN-15) for POP surgeries. This adhesive facilitates a controlled release of exosomes, with IFN-gamma-Exos modulating the immune response by promoting macrophage polarization towards an anti-inflammatory M2 phenotype, thereby enhancing the local immunological microenvironment. In vivo, uterine prolapse mesh fixation experiments have shown secure mesh attachment and a markedly improved inflammatory response compared to suture methods. The IFN-gamma-Exos@CAN-15 adhesive represents a significant advancement in mesh-based pelvic floor repair surgeries.

关键词： aspartate   inflammation   malate-aspartate shuttle   noncommunicable diseases   sub-Saharan Africa   tumor necrosis factor-alpha   urbanization  

摘要： Urbanization in sub-Saharan Africa is characterized by a shift toward a proinflammatory state and rising rates of noncommunicable diseases. The biological mechanism(s) linking changes in environmental factors to health and disease are incompletely understood. We propose a TNF-hypersecreting phenotype described in rheumatoid arthritis patients also has a role in the inflammatory response differences observed between rural and urban populations living in Africa. The mechanism involves insufficient mitochondrial aspartate production, failed NAD+ regeneration, ER membrane expansion, and enhanced biogenesis of TNF-alpha. Supporting data show serum and stool aspartate levels decline with urbanization, and TNF-alpha production inversely correlates with stool aspartate levels across a spectrum of socioeconomic development. These findings suggest a new hypothesis for the inflammatory differences between rural and urban populations and their role in noncommunicable diseases like atherosclerosis.

关键词： Type-I interferon (IFN-I)   Periodontitis   Neutrophil   Interleukin-17 (IL-17)   Osteoclastogenesis   Monocytes   Single-cell analysis  

摘要： Type I interferons (IFNs-I), a group of pleiotropic cytokines, critically modulate host response in various inflammatory diseases. However, the role of the IFN-I pathway in periodontitis remains largely unknown. In this report, we describe that the IFN-(3 levels in the gingival crevicular fluid of human subjects were negatively associated with periodontitis and clinical gingival inflammation. Disruption of IFN-I signaling worsened alveolar bone resorption in a ligature-induced periodontitis murine model. Deficiency of the IFN-I pathway resulted in an exaggerated inflammatory response in myeloid cells and drastically increased the interleukin-17 (IL-17)-mediated neutrophil recruitment in the gingiva. We further identified that the myeloid lineage-specific IFN-I response was essential in safeguarding against periodontal inflammation by suppressing the IL-17-producing gamma S T cells in gingiva. IFN-I signaling also directly repressed osteoclastogenesis in monocytes, which are precursor cells for osteoclasts. Therefore, our findings demonstrate that an integral myeloid-specific IFN-I pathway protects against bone loss by keeping the IL-17-neutrophil axis in check and directly inhibiting osteoclast formation in periodontitis.

关键词： Pseudorabies virus   Resveratrol   Osteopontin   Antiviral activity   Immune response  

摘要： Pseudorabies virus (PRV) can infect most mammals and has caused significant economic losses in global pig production. The emergence of new mutants significantly reduces the protective effect of vaccination, indicating an urgent need for the development of specific therapeutic agents against PRV infection. In this study, we analyzed the changes in the cellular proteome after PRV infection in resveratrol-treated PK-15 cells using TMT quantitative proteomics combined with LC-MS/MS. The results identified the differential proteins osteopontin (iOPN) and interleukin-1 receptor accessory protein (IL-1RAP), which have significant biological implications. The regulation of OPN-IL-1 beta signaling by PRV infection was further studied through the OPN-ERK/JNK-IL-1 beta signaling axis. The transcriptional levels of OPN, C-JUN, IL-1RAP, and IL-1 beta, along with the protein levels of ERK, JNK, C-Jun, and their phosphorylated forms at 8, 12, and 16 h post-infection, were determined. The results showed that PRV infection inhibited the activation of this signaling axis, which was upregulated by resveratrol treatment. Down-regulation of OPN by siRNA increased PRV proliferation and inhibited the activation of the signaling axis, which was antagonized by resveratrol treatment. In PRV-infected mice, resveratrol treatment produced the same changes observed in vitro. The present study demonstrated that resveratrol can promote innate immune responses by regulating the OPN-ERK/JNK-IL-1 beta signaling axis, thereby activating host antiviral defenses against PRV infection. Significance: Resveratrol targets the OPN-ERK/JNK-IL-1 beta axis to enhance innate immunity, offering a novel antiviral strategy against PRV infection. This study identifies OPN as a key regulator of host defense, linking ERK/JNK signaling to IL-1 beta-mediated antiviral responses. In vivo validation demonstrates resveratrol's therapeutic potential, reducing PRV replication and mortality in mice via immune pathway activati

关键词： Ankylosing Spondylitis (AS)   Immunosenescence   Signal Transduction Pathways   Therapeutic Strategies  

摘要： BackgroundThis study aims to explore the common mechanisms between aging and the pathogenesis of ankylosing spondylitis (AS) and to identify potential therapeutic *** total of 87 patients with AS and matched controls were analyzed via multidimensional flow cytometry to examine the peripheral blood immune signature. Single-cell RNA sequencing was employed to characterize T-cell subsets. The infiltration of Ly49h + cells (the murine homolog of NKG2C) was observed in a collagen-induced arthritis mouse model, and functional experiments were conducted to validate the cytotoxicity of NKG2C + CD8 + T cells. The mechanisms were further confirmed via the use of HLA-B27 transgenic mice and *** peripheral blood immune signature of AS patients exhibited dysregulation similar to that observed during aging. NKG2C + CD8 + T cells activated the PI3K-Akt signaling pathway and increased phagocytosis in AS patients. HLA-B27 stimulation significantly increased the cytotoxicity of this subset, an effect that could be reversed by NKG2C blockade. In HLA-B27 transgenic mice, Ly49h + T cells exhibited significantly enhanced degranulation ability. RNA sequencing validated the activation of the PI3K-Akt pathway in NKG2C + CD8 + T cells by ***-B27 drives the cytotoxicity of aging-related NKG2C + CD8 + T cells via activation of the PI3K-Akt signaling pathway. Targeting NKG2C inhibition may represent a novel therapeutic strategy for AS. This study elucidates the association between immune aging and the pathogenesis of AS, providing theoretical evidence for clinical intervention.

摘要： BackgroundSpondyloarthritis (SpA) is a chronic inflammatory disorder with axial and peripheral manifestations. A strong association between HLA-B27 and SpA has been known for more than 50 years. Remarkably, HLA-B27 and human beta 2-microglubulin transgenic rats (B27 rat) develop manifestations recapitulating SpA, referred to as rat SpA. Antigen-presenting cells such as dendritic cells (DC) and CD4 T cells are mandatory to develop rat SpA. Serum levels of granulocyte macrophage-colony stimulating factor (GM-CSF), a key growth factor for DC generation and functions, are significantly increased during SpA. Conventional (c)DCs can be divided in two subsets implicated either in immune tolerance (cDC1) or in adaptive immune responses induction (cDC2). In this study, we aimed to determine the influence of GM-CSF on cDC subsets functions linked to T cell activation and differentiation, in the B27 rat *** subsets were isolated from spleens of B27 and nontransgenic (NTG) rats, primed with GM-CSF and tested for their ability to support CD4h T cell differentiation. RNA sequencing was performed on GM-CSF-primed cDC ***-CSF-primed cDC2 from B27 rat were strong inducers of TNF-producing proinflammatory CD4+ T cells. In contrast, whereas control cDC1 required GM-CSF to support T cell proliferation, HLA-B27+ cDC1 primed with GM-CSF failed to do so. RNA sequencing analysis demonstrated that HLA-B27 expression promoted endoplasmic reticulum stress and unfolded protein response in both cDC subsets. In addition, HLA-B27 expression promoted inflammatory cytokine synthesis by cDC2 and a signature interfering with regulation of cell adhesion and activation in ***, our study reveals a dual role of GM-CSF during SpA. In one hand, GM-CSF promotes proinflammatory functions of cDC2. On the other hand, GM-CSF is required for cDC1 to induce T cell proliferation, and those functions are blunted by HLA-B27 expression.