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Molecular Immunology
Pergamon Press
Molecular Immunology

Pergamon Press

0161-5890

Molecular Immunology/Journal Molecular ImmunologySCIISTP
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    TBK1 participates in glutaminolysis by mediating the phosphorylation of RIPK3 to promote endotoxin tolerance

    Yang, LianYi, ZhujunZhang, WenfengGong, Jianping...
    14页
    查看更多>>摘要：TRAF-associated NF-kappa B activator (TANK)-binding kinase 1 (TBK1), a nonclassical I kappa B kinase (IKK), and its effect on inflammation have not been entirely clarified. Here, we identified that TBK1 participates in the catabolism of glutamine by mediating the phosphorylation of receptor-interacting protein kinase 3 (RIPK3) and promoting macrophage endotoxin tolerance (ET). We found that the TBK1 protein directly interacts with the RIPK3 protein and mediates the phosphorylation of RIPK3 in macrophages. Activated RIPK3 can directly bind to glutamate dehydrogenase 1 (GLUD1), which is known to be a critical enzyme for catalyzing glutamine decomposition, to improve its catalytic activity and increase the production of alpha-ketoglutarate (alpha-KG) in macrophages. alpha-KG generated from glutaminolysis can promote M2 activation and restrict M1 polarization, which plays a crucial role in promoting lipopolysaccharide (LPS)-induced ET. As a result of TBK1 regulating the phosphorylation level of RIPK3, overexpressed TBK1 could enhance the tolerance of macrophages to endotoxin through glutaminolysis. Overall, these findings reveal a novel mechanism for the metabolic control of inflammation and for the induction of ET by modulating glutamine metabolism.
      原文链接:
    • NSTL
    • Elsevier

    Allergic inflammation in lungs and nasal epithelium of rat model is regulated by tissue-specific miRNA expression

    Langwinski, WojciechSzczepankiewicz, DawidNarozna, BeataStegmayr, John...
    11页
    查看更多>>摘要：Introduction: Atopic asthma and allergic rhinitis are common chronic inflammatory diseases affecting lower airways and nasal mucosa, respectively. Several reports demonstrated frequent co-occurrence of these two diseases, however, the exact molecular mechanism has not been described. The present study aimed to investigate if small non-coding RNA might be responsible for the co-occurrence of asthma and allergic rhinitis in an animal model of allergic airway inflammation.& nbsp;Materials and methods: As an in vivo model of allergic airway inflammation, we used Brown Norway rats exposed intranasally to house dust mite (HDM). Histological analysis, total IgE concentration, eosinophil counts and iNOS gene expression were determined to confirm inflammatory changes. Small RNA sequencing in the lung tissue and nasal epithelium was performed with TruSeq Small RNA Library Preparation Kit and analyzed using the Base-Space tool. Validation of sequencing results was performed using qPCR. To assess the functional role of hsa-miR-223-3p, we transfected normal human bronchial epithelial (NHBE) cells with specific LNA-inhibitor and measured phosphorylated protein level of NF-kB with ELISA. Expression analysis of NF-kB pathway-related genes was performed using qPCR with SYBR Green and analyzed in DataAssist v3.01. Statistical analysis were done with STATISTICA version 13.& nbsp;Results: We found 9 miRNA genes differentially expressed in the lungs of allergic rats. In nasal epithelium, only rno-miR-184 was upregulated in animals exposed to HDM. Validation with qPCR confirmed increased expression only for rno-miR-223-3p in the lungs from allergic rats. The expression of this miRNA was also increased in normal bronchial epithelial ALI cell culture stimulated with IL-13, but not in cells cultured in monolayer due to the low mRNA level of IL13RA1 and IL13RA2. Transfecting NHBE cells with hsa-miR-223-3p inhibitor increased the amount of phosphorylated NF-kB protein level and expression of MUC5AC, CCL24 and TSLP genes.& nbsp;Conclusions: These findings suggest that miRNAs that regulate allergic inflammation in the lungs and nasal epithelium are specific for upper and lower airways. Furthermore, our study provides new insight on the role of hsa-miR-223-3p, that via targeting NF-kB signaling pathway, regulates the expression of MUC5AC, CCL24 and TSLP. Taken together, our study suggests that miR-223-3p is a regulator of allergic inflammation and could potentially be used to develop novel and targeted therapy for asthma.
      原文链接:
    • NSTL
    • Elsevier

    Preconditioning with procyanidin B2 protects MAC-T cells against heat exposure-induced mitochondrial dysfunction and inflammation

    Yang, LiangYan, PeishiWei, ShengjuanWang, Hongzhuang...
    10页
    查看更多>>摘要：Heat stress (HS) induced by high environmental temperature is a main factor causing mastitis and reduced milk production in dairy cows. Procyanidin B2 (PB2) is a phenolic compound with strong anti-inflammatory and antioxidant properties. By using the MAC-T (mammary alveolar cells-large T antigen) cells as the in vitro cell model, this study determines PB2 effects on HS-induced MAC-T mitochondrial dysfunction, cell apoptosis, and inflammation. Cells were divided into three groups: Con (37 degrees C), HS (42 degrees C), and PB2 +HS. Results show that, under HS-exposure, MAC-T cells exhibited an increased accumulation of reactive oxygen species (ROS) and Ca2+, a decreased mitochondrial membrane potential (Delta psi) and ATP content. Besides, HS markedly induced cell apoptosis, as evidenced by flow cytometry and significantly increased mRNA and protein expressions of apoptosis-related genes, including cytochrome C (Cyto-c) and cleaved caspase-3, etc. HS also led to mitochondrial fission and fusion dynamic disorder. Meanwhile, HS induced a significant inflammatory response by activating the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-kappa beta) signaling pathway and the NOD-like receptor with pyrin domain containing-3 (NLRP3) inflammasome. Notably, preconditioning of PB2 alleviated the accumulation of ROS and Ca2+ concentration induced by HS, increased Delta psi and ATP content, and maintained the dynamic balance of mitochondrial fission and fusion, thus improving mitochondrial function. PB2 also blocked the HS-induced mitochondrial caspase apoptosis pathway. Furthermore, PB2 preconditioning inhibited HSinduced activation of the TLR4/NF-kappa beta signaling pathway and the NLRP3 inflammasome, as well as IL-1 beta release, reversing HS-induced inflammation. In conclusion, PB2 has an important protective effect against the mitochondrial dysfunction, inflammatory response, and apoptosis of MAC-T cells induced by HS.
      原文链接:
    • NSTL
    • Elsevier

    Scorpion venom exhibits adjuvant effect by eliciting HBsAg-specific Th1 immunity through neuro-endocrine interactions

    Santhosh, Kambaiah NagarajRamesh, DhatriRamesh, DhanyaNagaraj, Urmila...
    11页
    查看更多>>摘要：The Hottentotta rugiscutis scorpion venom (Hrv) contains neurotoxins, which elicit a strong innate immune response through the activation of the Hypothalamus-pituitary-adrenal axis, which could improve the quality of adaptive immunity. Hence, the Hrv was used as an adjuvant for the Hepatitis-B virus surface antigen (HBsAg) and assessed its ability in the activation of innate (NGF, CORT, cellularity, NO) and adaptive (IgM, IgG, IgG1/IgG2a/ IgG2b/IgG3, Th1/Th2 cytokines, avidity) immunity. Here, the Hrv and HBsAg were given in the mixed form (HBsAg-Hrv) as well as in a separate form (HBsAg+Hrv). The NGF levels in plasma/spleen and CORT in plasma were found to be elevated optimally at 5 h and 6 h post-Hrv injection, respectively. Further studies showed that CORT and NGF levels were also highly upregulated in the HBsAg-Hrv group. The HBsAg-specific IgM titer was found to be increased in the HBsAg+Hrv group and total IgG was relatively similar among alum and Hrv-test groups, but IgG2a/IgG2b/IgG3 levels were higher along with IL-1 beta in HBsAg-Hrv groups. The study showed that the venom from H. rugiscutis acts as a vaccine adjuvant for HBsAg to develop strong antigen-specific Th1 immunity. The Hrv also enhances the antibody-avidity which may improve the neutralizing ability of antibodies with systemic infectious agents. The study also elucidated that the venom acts by neuroendocrine-immune mechanism and majorly impacts splenocytes through NGF and corticosterone.
      原文链接:
    • NSTL
    • Elsevier

    The analysis of dynamic gene expression patterns in peripheral blood of multiple sclerosis patients indicates possible diagnostic and prognostic biomarkers

    Razia, RabatMajeed, FazeelAmin, RehabMukhtar, Shahid...
    10页
    查看更多>>摘要：Introduction: Among numerous invasive procedures for the research of biomarkers, blood-based indicators are regarded as marginally non-invasive procedures in the diagnosis and prognosis of demyelinating disorders, including multiple sclerosis (MS). In this study, we looked into the blood-derived gene expression profiles of patients with multiple sclerosis to investigate their clinical traits and linked them with dysregulated gene ex-pressions to establish diagnostic and prognostic indicators. Methods: We included 51 patients with relapsing-remitting MS (RRMS, n = 31), clinically isolated syndrome (CIS, n = 12), primary progressive MS (PPMS, n = 8) and a control group (n = 51). Using correlational analysis, the transcriptional patterns of chosen gene panels were examined and subsequently related with disease duration and the expanded disease disability score (EDSS). In addition, principal component analysis, univariate regression, and logistic regression analysis were employed to highlight distinct profiles of genes and prognosticate the excellent biomarkers of this illness. Results: Our findings demonstrated that neurofilament light (NEFL), tumor necrosis factor alpha (TNF-alpha), Tau, and clusterin (CLU) were revealed to be increased in recruited patients, whereas the presenilin-1 (PSEN1) and cell-surface glycoprotein-44 (CD44) were downregulated. Principal Component Analysis revealed distinct patterns between the MS and control groups. Correlation analysis indicated co-dependent dysregulated genes and their differential expression with clinical findings. Furthermore, logistic regression demonstrated that Clusterin (AUC=0.940), NEFL (AUC=0.775), TNF-alpha (AUC=0.817), Tau (AUC=0.749), PSEN1 (AUC=0.6913), and CD44 (AUC=0.832) had diagnostic relevance. Following the univariate linear regression, a significant regression equation was found between EDSS and IGF-1 (R-2 adj = 0.10844; p= 0.0060), APP (R-2 adj = 0.1107; p= 0.0098), and PSEN1 (R-2 adj = 0.1266; p=0.0102). Conclusion: This study exhibits dynamic gene expression patterns that represent the significance of specified genes that are prospective diagnostic and prognostic biomarkers for multiple sclerosis.
      原文链接:
    • NSTL
    • Elsevier

    Treponema pallidum delays the apoptosis of human polymorphonuclear neutrophils through the intrinsic and extrinsic pathways

    Wang, JianyeLu, SiminZheng, KangHe, Zhangping...
    13页
    查看更多>>摘要：Treponema pallidum is a "stealth pathogen" responsible for infectious sexually transmitted diseases. Although neutrophils are usually present in skin lesions of early syphilis, the role of these cells in T. pallidum infection has barely been investigated. Neutrophils are short-lived cells that undergo constitutive apoptosis, and phagocytosis usually accelerates this process. Here, we demonstrated that human polymorphonuclear neutrophils (hPMNs) could phagocytose T. pallidum in vitro. An unexpected discovery was that T. pallidum inhibited hPMNs apoptosis markedly in an opsonin-independent manner. Furthermore, this phenomenon was not affected by bacterial viability, as detected by annexin V, morphology studies, and TUNEL staining. Exploration of the underlying mechanism showed that expression of the cleaved forms of caspase-3,-8, and-9 and effector caspase activity were diminished significantly in T. pallidum-infected hPMNs. T. pallidum also impaired staurosporine-and antiFas-induced signaling for neutrophil apoptosis. Of note, these effects were accompanied by inducing the autocrine production of the anti-apoptotic cytokine IL-8. Taken together, our data revealed that T. pallidum could inhibit the apoptosis of hPMNs through intrinsic and extrinsic pathways and provide new insights for understanding the pathogenicity mechanisms of T. pallidum.
      原文链接:
    • NSTL
    • Elsevier

    A new cysteine protease allergen from Ambrosia trifida pollen: proforms and mature forms

    Ling, Xiao-JingZhou, Yan-JunYang, Yong-ShiXu, Zhi-Qiang...
    10页
    查看更多>>摘要：Giant ragweed (Ambrosia trifida) pollen is closely associated with respiratory allergy in late summer and autumn, and the prevalence of giant ragweed pollen allergy progressively increases. Compared with short ragweed (Ambrosia artemisiifolia), allergenic components from giant ragweed pollen are poorly investigated. To promote component resolved diagnosis and treatment for giant ragweed pollen allergy, it becomes necessary to identify and characterize unknown allergens from giant ragweed pollen. In the present study, we identified and characterized a new cysteineprotease (CP) allergen from giant ragweed pollen, named as Amb t CP. The cloned Amb t CP gene encoded 387 amino acids. Recombinant Amb t CP (rAmb t CP) and natural Amb t CP (nAmb t CP) were purified by high-affinity Ni2+ resin and immunoaffinity chromatography respectively. During refolding, purified rAmb t CP could autocatalytically converted to its mature forms displaying a higher enzymatic activity. Moreover, the autocatalytic conversion of proforms to mature forms of nAmb t CP could cause their amount to change in giant ragweed pollen extracts. Then, the allergenicity of Amb t CP was characterized: 23 (33.8%) of 68 Chinese patients with ragweed pollen allergy showed positive IgE binding to nAmb t CP by enzyme-linked immunosorbent assay (ELISA); the result of subsequent ELISA showed that IgE-binding activity of proforms and mature forms of rAmb t CP was different, with positive rate of 39.1% (9/23) and 47.8% (11/23) respectively; Amb t CP showed IgE cross-reactivity with the CP components from short ragweed, Artemisia annua and Artemisia sieversiana pollen. Our findings will help to promote component-resolved diagnosis and treatment for giant ragweed pollen allergy, standardize allergen products and individualize allergen specific immunotherapy.
      原文链接:
    • NSTL
    • Elsevier

    A comprehensive analysis of the components of common weed pollen and related allergens in patients with allergic diseases in southern China

    Xu, LinaLuo, WentingLu, YanhongHuang, Zhifeng...
    7页
    查看更多>>摘要：Background: Pollen allergens are vital contributors to allergic diseases. The frequency and coreactivity pattern of allergens are closely related to geographical distribution. Objective: In this study, we aimed to characterize the prevalence of the molecular components of the common weed pollen allergens, birch pollen, walnut, and cross-reactive carbohydrate determinant (CCD), as well as investigate the relationship between the allergens and CCD in Chinese pollen-sensitized patients with allergic diseases. Methods: Based on previous vegetation surveys, serum samples from 165 pollen-sensitized patients with allergic diseases in Guangdong Province in southern China were used to test 19 crude allergen extracts, their components, and CCD using component-resolved diagnosis (CRD). Moreover, the potential associations among CCD, allergens, and their components were described. Results: In the 165 samples, the most common sensitized allergens were goosefoot (43.0%), ragweed (40.6%), walnut (37.6%), walnut tree (37.6%), and mugwort (37.0%), followed by platane (35.2%), cocklebur (27.9%), and birch (24.2%). The positivity rate of CCD was 39.4%. Among the samples positive for mugwort, 11 (18.0%), 15 (24.6%), and 15 (24.6%) were positive for Art v 1, Art v 2, and Art v 3, respectively. Among the 67 patients sensitized to ragweed, only five (7.5%) were positive for Amb a 1. In the 40 patients sensitized to birch, Bet v 2 had the highest positivity rate (40.0%). There were 62 patients who were sensitized to walnut. Their components had a lower positivity rate (less than 15%). The hierarchical clustering and optimal scale analysis showed that Art v 4 and Bet v 2 were closely related, and 91.9% of CCD-positive samples were polysensitized. Meanwhile, Spearman's rank correlation method showed that CCD was closely correlated with the sensitization of crude allergen extracts, and there was a low correlation between CCD and allergen components. CCD was highly correlated with goosefoot, ragweed, and walnut trees (r > 0.8). Moreover, there was a strong relationship between the levels of Jug r 3 and Art v 3 (r = 0.78; P < 0.001). Conclusions: In southern China, the weed pollens (ragweed, cocklebur, and goosefoot) exhibited higher positivity rates in adults and had a stronger relationship with CCD but not with mugwort. The positivity rate of allergen components was not high. CCD-positive samples were always polysensitized.
      原文链接:
    • NSTL
    • Elsevier

    3,4,5-O-tricaffeoylquinic acid with anti-radiation activity suppresses LPS-induced NLRP3 inflammasome activation via autophagy in THP-1 macrophages

    Liu, JiajunChen, JingyunXu, BaixueLin, Long...
    12页
    查看更多>>摘要：Damage to normal tissues caused by excessive ionizing radiation (IR) exposure is the major side effect of radiotherapy. Several recent studies have shown that IR-induced damage to tissues leads to a systemic immune response and NLRP3 inflammasome activation in immune cells. 3,4,5-O-tricaffeoylquinic acid (tCQA), extracted from the natural plant Azolla imbricata, relieves inflammation and has radioprotective function. Here, we aimed to investigate the inhibitory effect and molecular mechanism of tCQA on IR-induced NLRP3 inflammasome activation. First, the results of ELISA and qPCR assays showed that tCQA has anti-inflammatory effects in THP-1 cell line and healthy human peripheral blood mononuclear cells. Western blotting and ELISA suggested tCQA could inhibit NF-kappa B/MAPK signaling pathway, NLRP3 expression and the secretion of IL-1 beta in lipopolysaccharide (LPS)-stimulated THP-1 macrophages. Then, flow cytometry, LDH assay and western blotting demonstrated that tCQA could inhibit LPS-and nigericin-induced Caspase-1 activation and gasdermin D cleavage, thereby suppressing inflammatory cell death. Furthermore, we found that the autophagy inhibitor chloroquine, not the proteasome inhibitor MG132, could counteract the promoting effect of tCQA on NLRP3 degradation and the inhibitory effect on cell death. Western blotting and autophagosome staining results suggested tCQA could significantly enhance LPS-induced autophagic flux in macrophages and ATG5/ATG7 knockdown reverses the inhibitory effect of tCQA on NLRP3 expression and Caspase-1 activation, indicating that tCQA induces NLRP3 degradation via autophagy. Finally, THP-1 macrophages and BALB/c mice were irradiated with 137Cs gamma-rays and tCQA could inhibit IR-induced NLRP3 inflammasome activation both in vitro and in vivo. To conclude, tCQA controls inflammation and NLRP3 inflammasome activation in vitro via NF-kappa B/MAPK signaling pathway and autophagy, meanwhile inhibits IR-induced NLRP3 inflammasome activation in vivo. Overall, our study provides an experimental and theoretical basis for the application of tCQA as a radioprotectant in clinical radiotherapy.
      原文链接:
    • NSTL
    • Elsevier

    Influence of SARS-CoV-2 inactivation by different chemical reagents on the humoral response evaluated in a murine model

    Barbosa, Emerson de CastroAndrade, Adriana de SouzaDuarte, Myrian MoratoFaria, Gilson...
    10页
    查看更多>>摘要：Viral inactivation for antibody induction purposes, among other applications, should ensure biosafety, completely avoiding the risk of infectivity, and preserving viral immunogenicity. beta-propiolactone (BPL) is one of the most used reagents for viral inactivation, despite its high toxicity and recent difficulties related to importation, experienced in Brazil during the SARS-CoV-2 pandemic. In this context, the main objectives of this work were to test different inactivation procedures for SARS-CoV-2 and to evaluate the induction of neutralizing antibodies in mice immunized with antigenic preparations obtained after viral treatment with formaldehyde (FDE), glutaraldehyde (GDE), peroxide hydrogen (H2O2), as well as with viral proteins extract (VPE), in parallel with BPL. Verification of viral inactivation was performed by subsequent incubations of the inactivated virus in Vero cells, followed by cytopathic effect and lysis plaques observation, as well as by quantification of RNA load using reverse transcription-quantitative real time polymerase chain reaction. Once viral inactivation was confirmed, cell culture supernatants were concentrated and purified. In addition, an aliquot inactivated by BPL was also subjected to viral protein extraction (VPE). The different antigens were prepared using a previously developed microemulsion as adjuvant, and were administered in a four-dose immunization protocol. Antibody production was comparatively evaluated by ELISA and Plaque Reduction Neutralization Tests (PRNT). All immunogens evaluated showed some level of IgG anti-SARS-CoV-2 antibodies in the ELISA assay, with the highest levels presented by the group immunized with FDE-inactivated viral antigen. In the PRNT results, except for VPEantigen, all other immunogens evaluated induced some level of neutralizing anti-SARS-CoV-2 antibodies, and the FDE-antigen stood out again with the most expressive values. Taken together, the present work shows that FDE can be an efficient and affordable alternative to BPL for the production of inactivated SARS-CoV-2 viral antigen.
      原文链接:
    • NSTL
    • Elsevier