首页期刊导航|Molecular Immunology
期刊信息/Journal information
Molecular Immunology
Pergamon Press
Molecular Immunology

Pergamon Press

0161-5890

Molecular Immunology/Journal Molecular ImmunologySCIISTP
正式出版
收录年代

    Splicing factor SRSF1 controls distinct molecular programs in regulatory and effector T cells implicated in systemic autoimmune disease

    Cassidy M.F.Herbert Z.T.Moulton V.R.
    10页
    查看更多>>摘要：? 2021 Elsevier LtdSystemic autoimmune diseases are characterized by hyperactive effector T cells (Teffs), aberrant cytokines and chemokines, and dysfunctional regulatory T cells (Tregs). We previously uncovered new roles for serine/arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in T cell signaling and cytokine production in human T cells. SRSF1 levels are decreased in T cells from patients with systemic lupus erythematosus (SLE), and low levels correlate with severe disease. Moreover, T cell-conditional Srsf1-deficient mice recapitulate the autoimmune phenotype, exhibiting CD4 T cell hyperactivity, dysfunctional Tregs, systemic autoimmunity, and tissue inflammation. However, the role of SRSF1 in controlling molecular programs in Teffs and Tregs and how these pathways are implicated in autoimmunity is not known. Here, by comparative bioinformatics analysis, we demonstrate that SRSF1 controls largely distinct gene programs in Tregs and Teffs in vivo. SRSF1 regulates 189 differentially expressed genes (DEGs) unique to Tregs, 582 DEGs unique to Teffs, and 29 DEGs shared between both. Shared genes included IL-17A, IL-17F, CSF1, CXCL10, and CXCR4, and were highly enriched for inflammatory response and cytokine-cytokine receptor interaction pathways. SRSF1 controls distinct pathways in Tregs, which include chemokine signaling and immune cell differentiation, compared with pathways in Teffs, which include cytokine production, T cell homeostasis, and activation. We identified putative mRNA binding targets of SRSF1 which include CSF1, CXCL10, and IL-17F. Finally, comparisons with transcriptomics profiles from lupus-prone MRL/lpr mice reveal that SRSF1 controls genes and pathways implicated in autoimmune disease. The target genes of SRSF1 and putative binding targets we discovered, have known roles in systemic autoimmunity. Our findings suggest that SRSF1 controls distinct molecular pathways in Tregs and Teffs and aberrant SRSF1 levels may contribute to their dysfunction and immunopathogenesis of systemic autoimmune disease.
      原文链接:
    • NSTL
    • Elsevier

    ECCO – A new initiative to support early-career researchers in the complement field

    Poppelaars F.Gaya da Costa M.Inkeri Lokki A.Mallah K....
    4页
    查看更多>>摘要：? 2021Research on the complement system, like most areas of immunology, has seen tremendous progress over the last decades. Further advances in the complement field will rely on the next generation of scientific leaders, which are today's early-career researchers (ECRs). ECRs are emerging scientists who obtained their PhD degree within the past five years. They represent a distinct population within the scientific community, and accordingly have unique needs. Unfortunately, ECRs are faced with significant challenges that require customized solutions. The current paper provides a snapshot of the major obstacles ECRs face, such as an unhealthy work-life balance, lack of mentor and peer support, and uncertain career prospects. Efforts must consequently be taken to ensure stability and success of ECRs, not only to benefit these researchers in the early stages of their career, but the entire field of complement research. The Early-Career Complementologists (ECCO) was, therefore, launched as a new Task Force to support ECRs in the complement field. This new initiative aims to support and connect ECRs in the complement field worldwide. Furthermore, ECCO is supported by both the International Complement Society (ICS) and the European Complement Network (ECN); two professional societies led by scientists investigating the complement system.
      原文链接:
    • NSTL
    • Elsevier

    The protective effects of Omarigliptin against Lipopolysaccharide (LPS)- induced inflammatory response and expression of mucin 5AC (MUC5AC) in human bronchial epithelial cells

    Ma L.Chang E.Ruan X.Zhang B....
    8页
    查看更多>>摘要：? 2021 Elsevier LtdThe epidemic of chronic inflammatory lung diseases such as asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) has become a global public health problem. Oxidative stress, inflammation, and overproduction of airway mucus play critical roles in the progression of these diseases. Omarigliptin, an oral dipeptidyl peptidase 4 (DPP-4) inhibitor, has been demonstrated to have anti-inflammatory effects in patients with type II diabetes. However, its role in chronic inflammatory lung diseases remains enigmatic. This study is to investigate whether Omarigliptin possesses a beneficial effect against Lipopolysaccharide (LPS)-induced injuries in human BEAS-2B bronchial epithelial cells. Our results show that Omarigliptin suppressed LPS-induced oxidative stress by attenuating the generation of mitochondrial reactive oxygen species (ROS) and decrease in reduced glutathione (GSH) in BEAS-2B cells. Additionally, Omarigliptin mitigated inflammatory response by inhibiting the expression of pro-inflammatory mediators, including interleukin-1β (IL-1β), interleukin-12 (IL-12), and macrophage chemoattractant protein-1 (MCP-1) in LPS-challenged BEAS-2B cells. Moreover, Omarigliptin mitigated the LPS-induced overproduction of MUC5AC by rescuing the expression of the suppressor of cytokine signaling 1(SOCS1). Importantly, we found that this process is mediated by the Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Based on these findings, we conclude that Omarigliptin might be a promising agent for the treatment of chronic inflammatory lung diseases.
      原文链接:
    • NSTL
    • Elsevier

    MiR-142-5p directly targets cyclin-dependent kinase 5-mediated upregulation of the inflammatory process in acquired middle ear cholesteatoma

    Fan X.Zhang X.Wang N.Zhang H....
    10页
    查看更多>>摘要：? 2021 The Author(s)MicroRNAs (miRNAs) play important roles in the regulation of cell proliferation, differentiation, apoptosis, and inflammatory responses. MiR-142-5p is an important inflammation-associated miRNA, whose abnormal expression has been associated with a variety of inflammation-related diseases. However, the role and signaling pathways targeted by miR-142-5p in acquired middle ear cholesteatoma (AMEC) have not been fully elucidated. Cyclin-dependent kinase 5 (CDK5), a special member of the CDK family compared with classic cyclins that plays a critical role in the inflammatory response. In this study, we investigated the roles of miR-142-5p and CDK5 in inflammatory responses in AMEC. Our results revealed that the expression of miR-142-5p was significantly reduced in AMEC, and was negatively correlated with the expression of CDK5 (r=-0.5451). We also found that miR-142-5p can inhibit CDK5 expression by directly target 3’ untranslated region (UTR) of CDK5. Additionally, our findings indicated that the increased expression of CDK5 induces the secretion of inflammatory cytokines. In order to further confirm the involvement of miR-142-5p in the regulation of the inflammatory response in AMEC through its inhibitory effect on CDK5 expression, we studied the inflammatory response in HaCaT cells transfected with small interfering RNA against CDK5 (si-CDK5) and a miR-142-5p inhibitor. The results confirmed that miR-142-5p regulates the inflammatory response in AMEC by downregulating CDK5. In summary, miR-142-5p directly inhibits the CDK5-mediated upregulation of inflammatory cytokines in AMEC, which makes it a potential therapeutic target in this disease.
      原文链接:
    • NSTL
    • Elsevier

    Mesenchymal stem cell therapy attenuates complement C3 deposition and improves the delicate equilibrium between angiogenic and anti-angiogenic factors in abortion-prone mice

    Shahgaldi S.Rezaei Kahmini F.Moazzeni S.M.
    11页
    查看更多>>摘要：? 2021Immunological disorders are one of the main causes of recurrent spontaneous abortions (RSA). A rapidly expanding body of evidence indicates that excessive activation of the complement system is critically involved in the development of miscarriages. In the CBA/J × DBA/2 murine model of recurrent miscarriage, exaggerated and unrestrained complement activation is reported to be the underlying cause of angiogenic factor imbalance and persistent inflammation. We have previously shown that mesenchymal stem cell (MSC) therapy can significantly reduce the abortion rate in abortion-prone mice through regulating the feto-maternal immune response. In the present study, we hypothesized that MSCs might improve the balance of angiogenic factors at the feto-maternal unit of CBA/J × DBA/2 mice by restraining complement activation and deposition. To explore this hypothesis, autologous adipose tissue-derived mesenchymal stem cells (AD-MSCs) were administered intra-peritoneally to abortion-prone mice on the 4.5th day of gestation. Control mice received PBS as vehicle. On day 13.5 of pregnancy, deposition of the complement component C3 and expression levels of Crry, CFD (adipsin), VEGF, PlGF and FLT-1 were measured at the feto-maternal interface by immunohistochemistry and real-time PCR, respectively. Decidual cells were also cultured in RPMI 1640 medium for 48 h and VEGF and sFLT-1 protein levels were quantified in supernatants using enzyme-linked immunosorbent assay (ELISA). Our results indicated that MSC therapy significantly reduced C3 deposition and adipsin transcription in the fetal-maternal interface of abortion-prone mice. Furthermore, administration of MSCs robustly upregulated the mRNA expression levels of Crry, VEGF, PlGF and FLT-1 in the placenta and decidua of CBA/J × DBA/2 mice. Consistently, the in vitro results demonstrated that decidual cells obtained from MSC-treated dams produced increased concentrations of VEGF in culture supernatants, with concomitant decreased levels of sFLT-1 protein. Here, we show for the first time that adoptive transfer of MSCs rectifies the disturbed balance of angiogenic factors observed at the feto-maternal unit of CBA/J × DBA/2 mice, in part at least, through inhibiting excessive complement activation and promoting the production of angiogenic factors. Collectively, these alterations seem to play a pivotal role in reducing the abortion rate and improving the intrauterine condition for the benefit of the fetus.
      原文链接:
    • NSTL
    • Elsevier

    Reply to “Identification of thermodynamic quantities of the stability of peptide-MHC I complex using nanoscale differential scanning fluorimetry” by Jakob Harris and Jonghoon Kang

    Springer S.
    10页
      原文链接:
    • NSTL
    • Elsevier

    Passive immunization with anti- chimeric protein PilQ/PilA –DSL region IgY does not protect against mortality associated with Pseudomonas aeruginosa sepsis in a rabbit model

    Zamani K.Irajian G.Zahedi Bialvaei A.Zahraei Salehi T....
    7页
    查看更多>>摘要：? 2021 Elsevier LtdBackground: Pseudomonas aeruginosa sepsis is associated with unacceptably high mortality and, for many of those who survive, long-term morbidity. The aims of this study were to production of IgY against chimeric protein pilQ-pilA-DSL region and killed- whole cell Pseudomonas aeruginosa O1 (PAO1) strain and their efficacy for immunoprophylaxis of sepsis caused by P. aeruginosa in a rabbit model. Methods: Specific IgY was obtained by immunization of hens. The purity of IgY was determined by SDS-PAGE analysis. The effect of IgY on growth and hydrophobicity of P. aeruginosa were performed through time-kill assay and microbial adhesion to hydrocarbons test (MATH), respectively. The efficacy of specific IgYs was examined against P. aeruginosa sepsis in a rabbit model. The rabbits were monitored for 72 h to record physiological characters and survival. Hematologic factors, C-reactive protein, pro-inflammatory cytokines, and bacterial count from blood and solid organs were measured, periodically. Results: We found that the growth inhibitory effect of the anti- killed whole cell IgY was higher than anti-pilQ-pilA IgY (P < 0.001). The hydrophobicity effect of PAO1 increased when bacteria were opsonized by anti- killed whole cell IgY while the hydrophobicity activity was decreased following incubation of PAO1 with anti-pilQ-pilA IgY in a broth medium (P < 0.001). Following intravenous (IV) administration of produced IgYs, no significant difference was observed in the survival, decrease in inflammatory mediators and clinical symptoms between the groups 48h post infection (P > 0.05). Moreover, no considerable decrease was observed in the bacterial load of blood, lungs and kidneys in rabbits treated with specific IgYs and control groups (P > 0.05). No bacteria were found in the spleen and liver samples from infected rabbits. Conclusion: Although produced IgYs had a good immunoreactivity, IV immunization of IgYs was not protective against P. aeruginosa sepsis in the rabbit model. Further studies are needed to assess the immune response and decreasing mortality rate using the rabbit sepsis model.
      原文链接:
    • NSTL
    • Elsevier

    Feedback regulation of antioxidant transcription factor NFE2L1 and immunostimulatory factor 41BBL mediates the crosstalk between oxidative stress and tumor immunity

    Qiu L.Ning H.Zhu Y.Yang Q....
    8页
    查看更多>>摘要：? 2021 Elsevier LtdTargeting the immune checkpoint to inhibit tumor immune escape, which is one of the fundamental causes of cancer, has become an important strategy for cancer treatment. The molecular mechanism of tumor immune escape involved in the process of spontaneous hepatocellular carcinoma after specifically knocking out NFE2L1, the core regulator of redox homeostasis, in the mouse liver is still unclear. Transcriptome data showed that the immunostimulatory TNFSF9/41BBL was significantly reduced in NFE2L1 knockdown hepatocarcinoma HepG2 cells, and this suggests that 41BBL may be an oxidative stress-responsive immune checkpoint. The results of the promoter activity experiment showed that NFE2L1 can promote 41BBL gene transcription activation through the ARE element in the promoter region. In addition, cell biology experiments have found that overexpression of 41BBL can inhibit cell proliferation and promote senescence. Importantly, reactive oxygen species in cells significantly increased after overexpression of 41BBL, whereas NFE2L1 was inhibited, indicating that 41BBL has the effect of feedback regulating oxidative stress in cells. In conclusion, in this study, the transcriptional activation effect of NFE2L1 on 41BBL and the feedback inhibition relationship of 41BBL on NFE2L1 was clarified. The NFE2L1/41BBL axis might be an important pathway that mediates the crosstalk between oxidative stress and the tumor immune response.
      原文链接:
    • NSTL
    • Elsevier

    Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically

    Thomas A.M.Chaban V.Pischke S.E.Orrem H.L....
    7页
    查看更多>>摘要：? 2021 The AuthorsBackground: Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone. Materials and methods: Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean. Results: Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio. Conclusion: C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically.
      原文链接:
    • NSTL
    • Elsevier

    The relationship between the efficacy of talazoparib and the functional toll-like receptors 3 and 9 in triple negative breast cancer

    Guney Eskiler G.Deveci Ozkan A.
    7页
    查看更多>>摘要：? 2021Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cell death by inhibiting the repair of DNA strand breaks binding to PARP and regulate immune cells functions. Toll-like receptors (TLRs) mediate the tumor microenvironment through the modulation of proinflammatory cytokines and chemokines. In this context, this study addressed the relationship between the efficacy of talazoparib (TAL) as a PARPi and the activation of TLR3 or TLR9 by Polyinosinic:polycytidylic acid (Poly I:C) or CpG oligodeoxynucleotides (CpG-ODN) stimulation, respectively in triple negative breast cancer (TNBC). TAL alone and the combination of TAL with Poly I:C or CpG-ODN induced cell death were analyzed by water-soluble tetrazolium salt 1 (WST-1), Annexin V analysis, acridine orange staining and mRNA levels of caspase-3 and caspase-8 in HCC1937 and HCC1937-R (TAL resistant) TNBC cells. Additionally, the expression of TLR3, TLR9 and interferon regulatory factor 7 (IRF7) was observed with immunofluorescence staining and western blot analysis. Our findings showed that TAL induced TLR3 and TLR9 activation and acted in synergy with TLR3 and TLR9 agonists in TNBC cells. The stimulation of TLR3 or TLR9 and TAL treatment caused significantly more apoptosis in TNBC cells through the over-expression of caspase-3 and caspase-8. Additionally, TAL combined with Poly I:C or CpG-ODN more increased TLR3, TLR9 and IRF7 protein levels in HCC1937 cells and treatment with TAL and Poly I:C had greater potential for overcoming TAL resistance. In conclusion, the combination of PARPi with TLR agonists may be a new therapeutic combined strategy for the effective immunotherapy of TNBC.
      原文链接:
    • NSTL
    • Elsevier