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Molecular Immunology
Pergamon Press
Molecular Immunology

Pergamon Press

0161-5890

Molecular Immunology/Journal Molecular ImmunologySCIISTP
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    LINC00665 interacts with BACH1 to activate Wnt1 and mediates the M2 polarization of tumor-associated macrophages in GC

    Su K.Yang B.Sha G.Bai Q....
    8页
    查看更多>>摘要：? 2022 Elsevier LtdGastric cancer (GC) remains one of the prevalent causes of cancer-related deaths globally. Long non-coding RNAs (lncRNAs) have been associated with different cancers. The polarization of macrophages towards the M2 (alternatively activated) phenotype promotes immunologic tolerance and can induce gastric tumorigenesis. Thus far, lncRNAs have been shown to modulate the differentiation of immune cells. Here, we investigated the biological effects of LINC00665 on the progression of GC and explored the mechanisms underlying its ability to mediate the polarization of macrophages towards the M2 phenotype. We report that the levels of LINC00665 were increased in GC tissues. Furthermore, this increase in LINC00665 expression could be associated with decreased overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS). Using cell-based macrophage polarization models, we demonstrated that LINC00665 upregulation in GC cells facilitated the polarization of macrophages towards the M2 but not M1 (classically activated) phenotype. Furthermore, the loss of LINC00665 prevented the M2 polarization of macrophages. Mechanically, we identified that Wnt1 was the downstream target of LINC00665. Additionally, LINC00665 could directly interact with the transcription factor BTB domain and CNC homology 1 (BACH1). The interaction between LINC00665 and BACH1 resulted in the activation and binding of BACH1 to the Wnt1 promoters. Furthermore, BACH1 silencing could inhibit GC progression, which highlighted a crucial role for BACH1 in LINC00665-mediated Wnt1 activation. In addition, genetic Wnt1 overexpression effectively abolished the repression of Wnt signaling after BACH1 depletion and mediated GC development by supporting M2 macrophage polarization. In conclusion, we report that LINC00665 modulates M2 macrophage polarization and suggest that it may facilitate macrophage-dependent GC progression.
      原文链接:
    • NSTL
    • Elsevier

    Exploring the efficacy and contribution of Dupilumab in asthma management

    Alkholifi F.K.Alsaffar R.M.
    9页
    查看更多>>摘要：? 2022 Elsevier LtdIgG4 monoclonal antibody Dupilumab binds to the alpha chain (IL4R) of both types of the ligand-binding domains (IL4R/ IL13R1; equally IL4 and IL13 specific) of the IL-4 receptor. The current focus on precision medicine techniques to blocking pathways implicated in allergy disorders is crucial to the development of Dupilumab and broadening its therapeutic uses. Our review describes how the IL-4R complexes signaling pathway works, explores the probable mechanisms of Dupilumab activity and addresses its clinical usefulness and safety in asthma. The FDA (Food and Drug Administration) already licences it to treat Alzheimer's disease and moderate-to-severe asthma, and it has shown highly significant results in the management of chronic rhinosinusitis and Eosinophilic esophagitis (EoE). Previous investigations and clinical trials undertaken by various pharmaceutical firms are examined in this review article to assess the existing literature fully. The discovery of Dupilumab and the expanding range of therapeutic uses are pertinent to the current focus on precision medicine methods to blocking asthma-related pathways.
      原文链接:
    • NSTL
    • Elsevier

    MicroRNA-449c-5p alleviates lipopolysaccharide-induced HUVECs injury via inhibiting the activation NF-κb signaling pathway by TAK1

    Fu Q.Yu W.Fu S.Xu Z....
    9页
    查看更多>>摘要：? 2022 Elsevier LtdBackground: Acute kidney injury caused by sepsis has become a hotspot of scientific research in recent years. Since the kidney is the most abundant of all organs with vascular endothelium, activation and injury of vascular endothelial cells is a main reason to renal dysfunction. In our research, we identify that miRNA-449c-5p can alleviate HUVECs injury through inhibiting the NF-κb signaling pathway activation by targeting TAK1 with the method of bioinformatics and in vitro experiment. Methods: Datasets of GSE28750 and GSE94717 were obtained from the GEO database. Differential analysis was performed on the two data sets using the GEO2R tool of the GEO database, and the miRNA-mRNA network was further constructed. Lipopolysaccharide (LPS) against Human umbilical vein endothelial cells induced an in vitro model of AKI were used for verification. RT-PCR, Western blotting, ELISA, CCK8, EDU and luciferase reporter genes were used to verify whether miR-449c-5p could alleviate the apoptosis of vascular endothelial cells and the release of inflammatory factors during the progression of sepsis by inhibiting the expression of TAK1. Results: TAK1 was identified as a direct target of miR-449c-5p by luciferase reporter gene assay, and TAK1 expression was negatively regulated by miR-449c-5p. Overexpression of miR-449c-5p promoted cell viability, inhibited apoptosis rate and inhibited the expression of inflammatory cytokines in HUVECs after LPS stimulation. Moreover, miR-449c-5p deactivated NF-κB signaling by targeting TAK1. Conclusion: In cell model experiments, it was found that miRNA-449c-5p could inhibit the release of LPS induced inflammatory cytokine, inhibit the occurrence of apoptosis and promote cell proliferation by inhibiting the expression of TAK1. Therefore, thus miRNA-449c-5p played a protective role on vascular endothelial cells.
      原文链接:
    • NSTL
    • Elsevier

    OxLDL-stimulated macrophage exosomes promote proatherogenic vascular smooth muscle cell viability and invasion via delivering miR-186–5p then inactivating SHIP2 mediated PI3K/AKT/mTOR pathway

    Ren L.Chen S.Yao D.Yan H....
    11页
    查看更多>>摘要：? 2022 The AuthorsThe current study aimed to investigate the implication of microRNA (miRNA) profile in the linkage between oxidized low-density-lipoprotein (oxLDL)-stimulated-macrophages (MФ) exosomes and vascular smooth muscle cells (VSMCs) during atherosclerosis. VSMCs were treated by oxLDL-stimulated-MФ with/without GW4869. MiRNA profile in oxLDL-stimulated-MФ and untreated-MФ was detected by microarray, then candidate miRNAs were proposed to RT-qPCR and functional validation in VSMCs. MiR-186–5p mimic/inhibitor was transfected into oxLDL-stimulated-MФ, then its exosomes were used to VSMCs. Subsequently, miR-186–5p, SHIP2 and PI3K/AKT/mTOR pathway were modified alone or in combination in VSMCs. VSMCs viability, invasion and apoptosis were detected. OxLDL-stimulated-MФ induced VSMCs viability, invasion, but repressed apoptosis (all P < 0.01); while after GW4869 treatment to delete exosomes, its effect was weakened (all P < 0.05). Totally 45 dysregulated miRNAs were identified in oxLDL-stimulated-MФ versus untreated-MФ. The top-three dysregulated miRNAs (miR-186–5p, miR-21–5p, miR-320b) were elevated in VSMCs after oxLDL-stimulated-MФ treatment (all P < 0.001); while only miR-186–5p mimic greatly enhanced VSMCs viability and invasion (both P < 0.01). Furthermore, miR-186–5p-overexpressed oxLDL-stimulated-MФ exosomes promoted VSMCs viability, invasion, repressed apoptosis, while miR-186–5p-knockdown oxLDL-stimulated-MФ exosomes exhibited opposite effect (all P < 0.05). MiR-186–5p negatively regulated SHIP2 in VSMCs and bound SHIP2 via luciferase-reporter-gene assay (all P < 0.05). SHIP2 overexpression decreased VSMCs viability, invasion, PI3K/AKT/mTOR pathway, increased apoptosis, and attenuated miR-186–5p-overexpression's effect on these functions (all P < 0.05). Besides, PI3K activator (740 Y-P) weakened SHIP2-overexpression's effect on VSMCs viability, invasion and apoptosis (all P < 0.05). In conclusion, oxLDL-stimulated-MФ exosomes deliver miR-186–5p to inactivate SHIP2 mediated PI3K/AKT/mTOR pathway, then promote cell viability and invasion in VSMCs to accelerate atherosclerosis.
      原文链接:
    • NSTL
    • Elsevier

    Anti-inflammation and adhesion enhancement properties of the multifunctional LPxTG-motif surface protein derived from the Lactobacillus reuteri DSM 8533

    Xu H.Lao L.Ji C.Lu Q....
    8页
    查看更多>>摘要：? 2022 Elsevier LtdLPxTG-motif protein (LMP) is one kind of a precursor protein that contains a conserved LPxTG-motif at the C-terminus, which can be recognized by sortase A (SrtA) and covalently bind to the bacterial peptidoglycan. In this study, LMP derived from Lactobacillus reuteri (L. reuteri) was heterologous expressed and the tolerance and intestinal colonization ability of the LMP on L. reuteri were analyzed in simulated gastrointestinal fluid. Meanwhile, the anti-inflammatory activity of LMP was also evaluated in the LPS-stimulated RAW 264.7 cell model. The results indicated that LMP can promote the intestinal survival rate and adhesion characteristics of L. reuteri and enhanced the autoinducer-2 (AI-2) signaling molecule of the Lactobacillus strains in quorum sensing. Furthermore, LMP can inhibit the expressions of inflammatory cytokine TNF-α and IL-1β via ERK-JNK related MAPK signaling cascades. These findings provide a better understanding of the multifunctional LPxTG-motif surface protein derived from L. reuteri in the gastrointestinal tract environment.
      原文链接:
    • NSTL
    • Elsevier

    Potency measurements of the complement system facilitated by antibodies targeting the zymogen form of complement factor D (Adipsin)

    Thiel S.Henriksen M.Hansen S.W.K.Palarasah Y....
    4页
    查看更多>>摘要：? 2022 The AuthorsThe serine protease complement factor D is fundamental in the activation of the complement system. In addition, it was the first adipokine described (named Adipsin) and shown to improve beta cell function in diabetes. As part of an amplification loop of complement activation, factor D is a rate-limiting enzyme, and its accessibility contributes to the potency of complement activation. The dogma has been that conversion of the zymogen form, profactor D, to mature factor D occurred during secretion by adipocytes by uncharacterized proteases. However, recent findings demonstrated that the serine protease MASP-3 of the lectin pathway of the complement system mediated this conversion, suggesting that pattern recognition of pathogen/danger-associated molecular patterns could be a prior requirement for all complement activation. To facilitate studies addressing this hypothesis, we have developed monoclonal antibodies specific for human profactor D without binding to mature factor D. We demonstrate their applications in accessing the conversion of profactor D into mature factor D and in measuring levels of profactor D.
      原文链接:
    • NSTL
    • Elsevier

    IL-6 regulates induction of C-reactive protein gene expression by activating STAT3 isoforms

    Ngwa D.N.Pathak A.Agrawal A.
    7页
    查看更多>>摘要：? 2022 Elsevier LtdC-reactive protein (CRP) is synthesized in hepatocytes. The serum concentration of CRP increases dramatically during the acute phase response. In human hepatoma Hep3B cells, maximal CRP expression occurs in cells treated with the combination of IL-6 and IL-1β. IL-6 induces transcription of the CRP gene and IL-1β synergistically enhances the effects of IL-6. We investigated the role of IL-6-activated transcription factor STAT3, also known as STAT3α, in inducing CRP expression since we identified four consensus STAT3-binding sites centered at positions ? 72, ? 108, ? 134 and ? 164 on the CRP promoter. It has been shown previously that STAT3 binds to the site at ? 108 and induces CRP expression. We found that STAT3 also bound to the other three sites, and several STAT3-containing complexes were formed at each site, suggesting the presence of STAT3 isoforms and additional transcription factors in the complexes. Mutation of the STAT3 sites at ? 108, ? 134 or ? 164 resulted in decreased CRP expression in response to IL-6 and IL-1β treatment, although the synergy between IL-6 and IL-1β was not affected by the mutations. The STAT3 site at ? 72 could not be investigated employing mutagenesis. We also found that IL-6 activated two isoforms of STAT3 in Hep3B cells: STAT3α which contains both a DNA-binding domain and a transactivation domain and STAT3β which contains only the DNA-binding domain. Taken together, these findings raise the possibility that IL-6 not only induces CRP expression but also regulates the induction of CRP expression by activating STAT3 isoforms and by utilizing all four STAT3 sites.
      原文链接:
    • NSTL
    • Elsevier

    MicroRNA-200c-5p targets NIMA Related Kinase 7 (NEK7) to inhibit NOD-like receptor 3 (NLRP3) inflammasome activation, MODE-K cell pyroptosis, and inflammatory bowel disease in mice

    Wu G.Zhang D.Yang L.Wu Q....
    12页
    查看更多>>摘要：? 2022 The AuthorsInflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the lower gastrointestinal tract with unknown etiology. In our previous study, NOD-like receptor 3 (NLRP3) inflammasome activation requiring the interaction of NLRP3 with NIMA Related Kinase 7 (NEK7) had been reported to regulate MODE-K cell pyroptosis and dextran sulfate sodium (DSS)-induced murine colitis. In the present study, miR-200c was closely related to IBD using weighted gene correlation network analysis (WGCNA). MicroRNA-200c (miR-200c) expression was down-regulated in IBD samples and negatively correlated with NLRP3. In MODE-K cells, miR-200c overexpression inhibited cellular inflammation; under adenosine triphosphate (ATP) and lipopolysaccharides (LPS) co-stimulation, miR-200c overexpression attenuated ATP and LPS-induced cell pyroptosis. In the DSS-induced IBD mice model, miR-200c overexpression alleviated DSS-induced IBD symptoms and improved physiological and biochemical indexes. Through direct targeting, miR-200c inhibited NEK7 expression. In MODE-K cells, NEK7 overexpression promoted cellular inflammation and ATP and LPS-induced cell pyroptosis; when co-transduced into MODE-K cells, NEK7 overexpression partially attenuated miR-200c agomir effects on cellular inflammation and ATP and LPS-induced cell pyroptosis. In conclusion, miR-200c, through targeting NEK7, could decrease cellular inflammation levels and NLRP3 inflammasome-related MODE-K cell pyroptosis in vitro and improve DSS-induced murine IBD symptoms in vivo.
      原文链接:
    • NSTL
    • Elsevier

    Methylsulfonylmethane protects against lethal dose MRSA-induced sepsis through promoting M2 macrophage polarization

    Liu H.Li J.Liang X.Xiao H....
    9页
    查看更多>>摘要：? 2022 The AuthorsBackground: Multi-drug-resistant bacterial infections, which have become a global threat, lack effective treatments. The discoveries of non-antibiotics with different modes of antibacterial action, such as methylsulfonylmethane (MSM), are a promising new treatment for multi-drug-resistant pathogens. Methods: We constructed a mouse peritonitis infection model to evaluate the effects of MSM against methicillin-resistant Staphylococcus aureus (MRSA) infection. The time-kill kinetics of MSM against MRSA and the effect of MSM on the integrity of bacterial cell membrane were measured. Viability effects of MSM on THP1 cells were performed by CCK-8 cytotoxicity assay. Systematic inflammatory factor levels of mice were detected using ELISA. The immune response of peritoneal macrophages during MRSA-infection was evaluated using RNA sequencing. Gene Ontology function, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, and correlation analyses were applied to analysis RNA sequencing data. RT-qPCR, western blotting and flow cytometry were performed to analysis the gene and protein expression levels of macrophages. Results: In in vitro experiments, MSM did not show significant killing effects on the growth of MRSA directly and did not destroy bacterial membrane integrity. MSM also displayed no significant effects on the proliferative capacity of THP1 cells. However, MSM treatment protected mice against a lethal dose MRSA-infection and decreased systemic inflammation. MSM upregulated metabolic pathway in peritoneal macrophages, especial glycolysis, during MRSA infection. MSM increased the expression of M2 markers (such as Arg1), promoted phosphorylation of STAT3 (which regulates M2 polarization), and decreased the expression of M1 markers in peritoneal macrophages. Additionally, MSM treatment increased the expression of H3K18 lactylation specific target genes, including Arg1. GNE-140, the LDHA-specific inhibitor of glycolysis, blocked the MSM-induced Arg1 expression in this disease model. Conclusions: MSM protects against MRSA infection through immunomodulation. MSM promotes the expression of Arg1 by lactate-H3K18la pathway to control macrophage to M2 polarization; it firstly provides therapeutic potential for drug-resistant infections and sepsis.
      原文链接:
    • NSTL
    • Elsevier

    Maresin-2 alleviates allergic airway inflammation in mice by inhibiting the activation of NLRP3 inflammasome, Th2 type immune response and oxidative stress

    Yu C.-X.Shi Z.-A.Ou G.-C.Nie X.-J....
    9页
    查看更多>>摘要：? 2022Asthma is a chronic inflammatory disease of the respiratory system. Maresin-2 (MaR2) is biosynthesized from docosahexaenoic acid (DHA) by macrophages, display strong anti-inflammatory and pro-resolving activity. To investigate the therapeutic effect and mechanism of MaR2 on asthmatic mice induced by ovalbumin (OVA) in conjunction with the adjuvant aluminum hydroxide. Twenty four female BALB/c mice were randomly divided into control, OVA, OVA + MaR2, and OVA + dexamethasone (Dexa) groups. MaR2 or Dexa were given as a treatment for OVA-induced asthma. Serum, bronchoalveolar alveolar lavage fluid (BALF) and lung tissue were collected for further analysis. The Pathological changes of lung tissue, proportion of inflammatory cells in BALF, levels of inflammatory cytokines in BALF or serum, oxidative stress indices, and the protein concentration of ASC, MPO, Ly-6G, ICAM-1, NLRP3 and Caspase-1 in lung tissues were evaluated. Compared with the OVA group, both OVA + MaR2 and OVA + Dexa group had reduced inflammation and mucus secretion in lung tissue, number of inflammatory cells in BALF, levels of related inflammatory cytokines in serum or BALF, and expressions of ASC, MPO, Ly-6G, ICAM-1, NLRP3 and Caspase-1 proteins in lung tissue. In addition, the oxidative stress was alleviated as indicated by decreased MDA, and elevated SOD and GSH. MaR2 has an obvious protective effect on OVA-induced bronchial asthma in mice, in a similar manner as Dexa. The mechanism may be related to the inhibition of the Th2 type immune response, the NLRP3 inflammasome activation and oxidative stress.
      原文链接:
    • NSTL
    • Elsevier