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关键词： Succinate   Type 2 immunity   IL-4   Hif-1 alpha   Colitis  

摘要： Inflammatory bowel disease (IBD) remains a pressing global health challenge, necessitating novel therapeutic strategies. Succinate, a metabolite known for its role in type 2 immunity and tuft cell activation in the small intestine, presents its potential in IBD management. However, its impact on colonic inflammation has not been explored. Here, we demonstrate that succinate administration induces a type 2 immune response, significantly alleviating dextran sulfate sodium (DSS)-induced colonic inflammation. Succinate enhances antibacterial capacity, reduces intestinal permeability, and reshapes the colonic cytokine milieu. Mechanistically, succinate promotes myeloid cell expansion in peripheral blood, mesenteric lymph nodes, and the colonic lamina propria. The protective effects of succinate were abolished in Ccr2-/- mice, confirming the role of monocyte recruitment, but persisted in Rag1- /- mice, indicating independence from adaptive immunity. Adoptive transfer of monocytes from succinate-treated donors mitigated intestinal inflammation in recipient mice. Transcriptomic analysis revealed heightened expression of Il1b and Il6, and higher lactate production in monocytes upon lipopolysaccharide (LPS) stimulation, highlighting a reprogrammed pro-inflammatory trained immunity phenotype. Finally, we identify the IL-4R alpha/Hif-1 alpha axis is critical for succinate-mediated protection. These findings reveal the ability of succinate to reprogram monocytes into protective intestinal macrophages via induction of type 2 response, restoring homeostasis through enhanced barrier function and immune modulation. Our study positions thus uncover succinate as a promising therapeutic candidate for IBD.

关键词： Cell signaling  

摘要： Persisting programmed cell death-1 (PD-1) signaling impairs T cell effector function, which is highly associated with T cell exhaustion and immunotherapy failure. However, the mechanism responsible for PD-1 deubiquitination and T cell dysfunction remains unclear. Here, we show that ubiquitin-specific peptidase 24 (USP24) promotes PD-1 protein stability by removing K48-linked polyubiquitin. Increased interleukin-6 level transcriptionally activates the USP24 expression, which leads to PD-1 stabilization. Furthermore, USP24 deficiency reduces PD-1 levels in CD8+ T cells and attenuates EgfrL858R-driven lung tumorigenesis in Usp24C1695A catalytic deficient mice. Targeting PD-1 stability with the USP24-specific inhibitor USP24-i-101 boosts cytotoxic T cell activity, restrains lung tumor growth, and achieves superior therapeutic effects when combined with anti-CTLA4 immunotherapy. Clinically, patients with lung cancer exhibiting high USP24 expression in tumor-infiltrating CD8+ T cells display exhausted features and show unfavorable responses to immunotherapy. Our findings dissect the mechanism for regulating enhanced PD-1 stability in tumor-infiltrating CD8+ T cells and reveal USP24 as a potential target of antitumor immunotherapy.

关键词： Inflammatory bowel disease   Phellodendrine   IL-17 signaling pathway   Intestinal mucosal barrier   Inflammation  

摘要： Background: Phellodendrine (PHE) has anti-inflammatory and antioxidant effects. However, the function of PHE in treating inflammatory bowel disease (IBD) has not been fully elucidated. The aim of this study was to investigate the effects and mechanisms of PHE on IBD with in vivo and in vitro assays. Materials and Methods: Bioinformatics was used to identify hub genes associated with IBD pathogenesis. Virtual screening was applied to predicting the natrual compounds targeting hub genes. A mouse model with colitis was established by oral administration of 3 % dextran sulfate (DSS), and the mice were treated with normal saline or PHE (30 mg/kg/day or 80 mg/kg/day). On day 14, the mice were sacrificed and their colons were collected for measurement and histological analysis. The pathological change and inflammation of the tissues in different groups also were evaluated. In addition, the intestinal epithelial Caco-2 cell line was treated with lipopolysaccharide (LPS) to establish an in vitro intestinal inflammation model. CCK-8 assay and flow cytometry were used to detect the effects of PHE (10 mu M or 40 mu M) on cell viability and apoptosis. Western blot was used to the investigate the regulatory effects of PHE on the expression levels of zonula occludens 1 (ZO-1), occludin, claudin1, collagen type I alpha 1 (COL1A1), vascular cell adhesion molecule 1 (VCAM1), interleukin-17 A (IL-17 A), phosphorylated AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). Results: COL1A1 and VCAM1 were identified as therapeutic targets in IBD. PHE was identified as a natural drug simultaneously targeting COL1A1 and VCAM1. PHE treatment alleviates the weight loss and symptoms of mice induced by acute colitis. PHE treatment reduced myeloperoxidase (MPO) activity and pro-inflammatory cytokine levels in colonic tissues, and inhibited expression levels of COL1A1, VCAM1 and IL-17 A, and promoted expression levels of ZO-1, occludin and claudin-1. In vitro, PHE treatmen

关键词： Allergic rhinitis   The aryl hydrocarbon receptor   M2 macrophage  

摘要： Background: Epidemiological evidence suggests that environmental pollutants precipitate the occurrence of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR), a receptor or sensor for various contaminants, is closely related to immunomodulation and the polarization of M2 macrophages. However, the mechanisms involving AhR and M2 macrophages in AR remain unclear. Methods: Bioinformatics analysis of GEO datasets (GSE180697 and GSE180697) assessed AhR and IL4I1 expression levels, which were then verified in the nasal mucosa, monocytes and serum of patients with AR using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Primary human mononuclear cells were isolated from peripheral blood using a magnetic separation technique, and THP-1 cell lines with IL4I1 overexpression or downexpression were established through lentiviral constructs. M2 macrophages were induced with the cytokines CSF, IL4 and IL13 and then treated with the AhR agonist FICZ or inhibitor CH223191. The polarization of M2 macrophages was measured by flow cytometry and western blotting. Furthermore, primary nasal epithelial cells and macrophages were co-cultured to assess the epithelial-mesenchymal transition (EMT) in epithelial cells. The AR murine model was established using ovalbumin (OVA). Inflammation within the nasal mucosa and lung tissue was examined after CH223191 or IL4I1 treatment. Results: Nuclear translocation of AhR and upregulation of IL4I1 was observed in peripheral mononuclear cells and nasal mucosal tissue of patients with AR. Through the activation of AhR, IL4I1 promoted M2 macrophage polarization. Furthermore, modulation of the IL4I1/AhR axis regulated the migratory impact of OVA on T-M2 cells. The IL4I1/AhR axis was involved in the regulation of M2 macrophage-associated EMT and contributed to the expression of IL-33 and STAT6 phosphorylation in epithelial cells. In AR mice, increased A

关键词： Abdominal aortic aneurysm   Macrophages   M1 macrophage polarization   IL-7/IL-7R   NF-kappa B pathway  

摘要： BackgroundAbdominal aortic aneurysm (AAA) is a common degenerative disease of the abdominal aorta, which can result in extremely high mortality owing to the rupture of the abdominal aorta. The activation of IL-7R has been shown to modulate the inflammatory responses, which play an important role in the progression of AAAs. However, the mechanism of IL-7/IL-7R axis in AAAs is still *** study aims to investigate the effects of IL-7R on AAAs and the underlying mechanisms ***-type C57BL/6 and IL-7R knockout mice were used as experimental subjects. ELISA analysis, histological staining, western blotting and qPCR were performed to explore effects of IL-7R deficiency in the formation and development of elastase-induced AAAs. Transwell, CCK8, and immunofluorescence assays detected the migration and polarization of RAW264.7 macrophages in *** demonstrated that IL-7R was elevated in mice with AAAs. Blocking IL-7R can inhibit the formation of AAAs and reduce aortic dilatation, elastic layer degradation, and inflammatory cell infiltration. Knockout of IL-7R suppressed the migration, infiltration and M1 polarization of macrophages. Moreover, inhibition of the NF-kappa B signaling pathway by BAY 11-7082 attenuated the macrophage-mediated inflammatory responses caused by IL-7R *** short, this study showed that IL-7R promotes the infiltration and migration of macrophages by regulating M1 macrophage polarization, possibly in part via activation of the NF-kappa B pathway, which may be associated with the development of AAAs.

关键词： amino acid residues   Aves   beta-2-microglobulin   birds   Carduelis   codons   diseases   HLA   hydrogen bound   intron   malaria   Marek's disease   MHC (Major Histocompatibility Complex)   molecules   Passeriformes   Serinus   Spinus   vertebrates   wild birds  

摘要： There are about 5000 species of Passeriformes birds, which are half of the extant ones. Their class I MHC molecules are found to be different from all other studied vertebrates, including other bird species;i.e., amino acid residues 10 and 96 are not the seven canonic residues extant in all other vertebrate molecules. Thus, the canonic residues in MHC class I vertebrate molecules are reduced to five. These differences have physical effects in MHC (Major Histocompatibility Complex) class I alpha chain interaction with beta-2-microglobulin but have yet unknown functional effects. Also, introns show specific Passeriformes distinction both in size and invariance. The studies reviewed in this paper on MHC structure have been done in wild birds that cover most of the world's passerine habitats. In this context, we are going to expose the most commonly occurring bird diseases with the caveat that MHC and disease linkage pathogenesis is not resolved. In addition, this field is poorly studied in birds;however, common bird diseases like malaria and Marek's disease are linked to MHC. On the other hand, the main established function of MHC molecules is presenting microbial and other antigens to T cells in order to start immune responses, and they also may modulate the immune system through NK receptors and other receptors (non-classical class I MHC molecules). Also, structural and polymorphic differences between classical class I molecules and non-classical class I molecules are at present not clear, and their definition is blurred. These passerine exceptional MHC class I molecules may influence linkage to diseases, transplantation, and other MHC presentation and self-protection functions. Further studies in more Passeriformes species are ongoing and needed.

关键词： Ovarian cancer   Tumor microenvironment   Macrophage polarization   IL-33   TRIM28  

摘要： The tumor microenvironment provides optimal condition for the growth of ovarian cancer. Macrophages display a highly functional plasticity to respond various signals. Switching macrophages' phenotype is a potential therapeutic strategy for the treatment of cancer. We used RNA-sequencing(RNA-Seq) and Chromatin immunoprecipitation-sequencing(ChIP-Seq) analyses in bone-marrow-derived macrophages (BMDMs) from wildtype (WT) and its receptor interleukin-1 receptor like-1 (IL1RL1 or ST2) knockout(ST2-/-) mice revealed that the interaction between IL-33 and TRIM28, which plays an antioxidant role, regulates glycolysis in BMDMs by promoting the PI3K/Akt pathway in ST2-independent manner, thereby reducing M2 polarization of macrophages is a way to inhibit ovarian cancer growth.

关键词： 粪拟杆菌   过敏性哮喘   卵清蛋白特异性免疫球蛋白E   细胞因子   肠道菌群  

摘要： 目的： 利用优化的小鼠过敏性哮喘模型，体内评价一株粪拟杆菌IM01的抗哮喘功能及对肠道菌群的影响。方法： 对比不同激发方式优化卵清蛋白（OVA）诱导的哮喘小鼠模型。将雌性BALB/c小鼠随机分为磷酸盐缓冲溶液、OVA模型组和IM01干预组。IM01干预组经口给予1×109菌落形成单位/只IM01活菌，连续21d，第22天采集肺部组织。检测血清OVA特异性免疫球蛋白E（IgE）及肺白细胞介素（IL）-4、IL-5、IL-13水平，并进行肺组织苏木精-伊红染色和粪便16S rRNA基因测序分析。结果：OVA雾化激发方式建模更优；口服IM01显著降低哮喘小鼠血清IgE及肺部IL-4、IL-5、IL-13水平，减轻肺病理炎性细胞浸润；IM01调节肠道菌群结构（增高有益菌/降低有害菌丰度）。结论： IM01经口干预可缓解哮喘小鼠肺部炎症及病理损伤，并调节肠道菌群组成。

关键词： coal dust exposure   dyslipidemia   lipid metabolism   FMO3 (flavin monooxygenase 3)   IL-6 (interleukin-6)  

摘要： Background: This study aims to investigate the impact of coal dust (silicon dioxide) exposure on dyslipidemia and its underlying mechanisms, with a focus on the association between coal dust exposure and hepatic metabolic disorders. Methods: Clinical data were collected from 5433 coal mine workers to compare the incidence of dyslipidemia between the dust-exposed group and the non-exposed group. A mouse model of silicon dioxide exposure was established to observe hepatic fat accumulation and pathological changes. Liver tissue sequencing was performed to screen for key differential genes. In vitro cell experiments were utilized to identify the molecular mechanisms underlying hepatocyte metabolic abnormalities induced by silicon dioxide exposure. Results: Clinical data revealed that 69.2% of miners in the dust-exposed group developed dyslipidemia, which was higher than the 30.7% in the non-exposed group. Animal data showed that silicon dioxide exposure led to hepatic fat deposition and pathological damage, with the degree of injury positively correlated with exposure time. Liver sequencing identified a significant upregulation of the FMO3 (flavin monooxygenase 3) gene in mouse liver tissue following silicon dioxide exposure, accompanied by enhanced inflammatory responses. Mechanistic studies demonstrated that silicon dioxide activates Kupffer cells to secrete IL-6 (interleukin-6), which induces high expression of FMO3 in hepatocytes through the PKC/YY1 signaling pathway, thereby disrupting lipid metabolism. Conclusions: Silicon dioxide exposure can promote the upregulation of FMO3 expression in hepatocytes by activating Kupffer cells to release IL-6 via the PKC/YY1 pathway, ultimately leading to lipid metabolic disorders and dyslipidemia