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  • Notch signaling represents an important checkpoint between follicular T-helper and canonical T-helper 2 cell fate
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-21
    Mark Dell’Aringa, R. Lee Reinhardt

    Type-2 immunity is regulated by two distinct CD4+ T-cell subsets. T follicular helper (Tfh) cells are required for humoral hallmarks of type-2 inflammation. T-helper type-2 (Th2) cells orchestrate type-2 inflammation in peripheral tissues, such as the lung and intestine. Given the importance of Notch signaling in the establishment of other CD4+ T-helper cell subsets, we investigated whether canonical Notch activation could differentially impact Tfh and Th2 cell fate during the induction of type-2 immunity. These studies show that Tfh cell, but not Th2 cell, generation and function is reliant on Notch signaling. While early Tfh cell specification is influenced by functional Notch ligands on classical dendritic cells, functional Notch ligands on cells other than dendritic cells, T cells, B cells, and follicular dendritic cells are sufficient to achieve full Tfh cell commitment. These findings identify Notch signaling as an early lineage-determining factor between Tfh and Th2 cell fate.

    更新日期:2018-02-22
  • Oral cholera vaccination promotes homing of IgA+ memory B cells to the large intestine and the respiratory tract
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-21
    M van Splunter, E van Hoffen, E G Floris-Vollenbroek, H Timmerman, E Lucas-van de Bos, B Meijer, L H Ulfman, B Witteman, J M Wells, S Brugman, H F J Savelkoul, R J J van Neerven

    Oral cholera vaccination is used to induce immune responses in the intestines to protect against cholera infection. However, oral vaccination may also affect immune responses in other mucosal tissues. To study this, tissue-specific homing potential and kinetics of B-cell responses were characterized after oral cholera vaccination. Healthy adult volunteers received two doses of Dukoral® and blood, saliva, nasal wash, and fecal samples were collected over time to detect vaccine-specific antibodies. Additionally, homing potential of lymphocytes to small intestine, colon, airways, skin, and periphery was measured by expression of Integrin β1 and β7, CCR9, CCR10, CCR7, and CLA. After vaccination, antibody responses to cholera toxin B (CTB) and Dukoral® were detected in serum and nasal wash. CTB-specific memory B cells in peripheral blood and tissue homing profiles of memory B cells peaked at day 18. IgA+ memory B cells expressed markers that enable homing to the airways and colon, while IgA− memory B cells primarily expressed small-intestine-homing markers. These data show that oral cholera vaccination has a differential effect on immune responses in various mucosal sites, including the respiratory tract.

    更新日期:2018-02-22
  • Vaccine-induced antigen-specific regulatory T cells attenuate the antiviral immunity against acute influenza virus infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-21
    Pin-Hung Lin, Weng-In Wong, Yi-Lan Wang, Meng-Ping Hsieh, Chia-wen Lu, Chieh-Yu Liang, Sung-Hsiang Jui, Fang-Yi Wu, Pei-Jer Chen, Hung-Chih Yang

    Peptide-based T cell vaccines targeting the conserved epitopes of influenza virus can provide cross-protection against distantly related strains, but they are generally not immunogenic. Foreign antigen-specific regulatory T (Treg) cells are induced under subimmunogenic conditions peripherally, although their development and role in vaccine-mediated antiviral immunity is unclear. Here, we demonstrated primary vaccination with peptides alone significantly induced antigen-specific Foxp3+ Treg cells, which were further expanded by repeated vaccination with unadjuvanted peptides. Certain adjuvants, including CpG, suppressed the induction and expansion of antigen-specific Treg cells by peptide vaccination. Interestingly, secondary influenza virus infection significantly increased the frequency of preexisting antigen-specific Treg cells, although primary infection barely induced them. Importantly, specific depletion of vaccine-induced antigen-specific Treg cells promoted influenza viral clearance, indicating their inhibitory role in vivo. Immunization with CpG-adjuvanted peptides by the subcutaneous prime–intranasal-boost strategy restricted the recruitment and accumulation of antigen-specific Treg cells in lung, and stimulated robust T cell immunity. Finally, subcutaneous prime–intranasal-boost immunization with CpG-adjuvanted peptides or whole-inactivated influenza vaccines protected mice from heterosubtypic influenza virus infection. In conclusion, antigen-specific Treg cells induced by peptide vaccines attenuate the antiviral immunity against influenza virus infection. CpG-adjuvanted peptide vaccines provide heterosubtypic influenza protection probably by inhibiting Treg development and enhancing T cell immunity.

    更新日期:2018-02-22
  • B cells are the predominant mediators of early systemic viral dissemination during rectal LCMV infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-19
    Martin Trapecar, Shahzada Khan, Benjamin L. Cohn, Frank Wu, Shomyseh Sanjabi

    Determining the magnitude of local immune response during mucosal exposure to viral pathogens is critical to understanding the mechanism of viral pathogenesis. We previously showed that vaginal inoculation of lymphocytic choriomeningitis virus (LCMV) fails to induce a robust innate immune response in the lower female reproductive tract (FRT), allowing high titer viral replication and a delay in T-cell-mediated viral control. Despite this immunological delay, LCMV replication remained confined mainly to the FRT and the draining iliac lymph node. Here, we show that rectal infection with LCMV triggers type I/III interferon responses, followed by innate immune activation and lymphocyte recruitment to the colon. In contrast to vaginal exposure, innate immunity controls LCMV replication in the colon, but virus rapidly disseminates systemically. Virus-induced inflammation promotes the recruitment of LCMV target cells to the colon followed by splenic viral dissemination by infected B cells, and to a lesser extent by CD8 T cells. These findings demonstrate major immunological differences between vaginal and rectal exposure to the same viral pathogen, highlighting unique risks associated with each of these common routes of sexual viral transmission.

    更新日期:2018-02-19
  • The impact of a helminth-modified microbiome on host immunity
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-16
    Tara P. Brosschot, Lisa A. Reynolds

    Intestinal helminths have well-characterized modulatory effects on mammalian immune pathways. Ongoing helminth infection has been associated with both the suppression of allergies and an altered susceptibility to microbial infections. Enteric helminths share a niche with the intestinal microbiota, and the presence of helminths alters the microbiota composition and the metabolic signature of the host. Recent studies have demonstrated that the helminth-modified intestinal microbiome has the capacity to modify host immune responses even in the absence of live helminth infection. This article discusses the mechanisms by which helminths modify the intestinal microbiome of mammals, and reviews the evidence for a helminth-modified microbiome directly influencing host immunity during infectious and inflammatory diseases. Understanding the multifaceted mechanisms that underpin helminth immunomodulation will pave the way for novel therapies to combat infectious and inflammatory diseases.

    更新日期:2018-02-17
  • Pulmonary antigen encounter regulates the establishment of tissue-resident CD8 memory T cells in the lung airways and parenchyma
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-16
    Sean R. McMaster, Alexander N. Wein, Paul R. Dunbar, Sarah L. Hayward, Emily K. Cartwright, Timothy L. Denning, Jacob E. Kohlmeier

    Resident memory CD8 T (TRM) cells in the lung parenchyma (LP) and airways provide heterologous protection against influenza virus challenge. However, scant knowledge exists regarding factors necessary to establish and maintain lung CD8 TRM. Here we demonstrate that, in contrast to mechanisms described for other tissues, airway, and LP CD8 TRM establishment requires cognate antigen recognition in the lung. Systemic effector CD8 T cells could be transiently pulled into the lung in response to localized inflammation, however these effector cells failed to establish tissue residency unless antigen was present in the pulmonary environment. The interaction of effector CD8 T cells with cognate antigen in the lung resulted in increased and prolonged expression of the tissue-retention markers CD69 and CD103, and increased expression of the adhesion molecule VLA-1. The inability of localized inflammation alone to establish lung TRM resulted in decreased viral clearance and increased mortality following heterosubtypic influenza challenge, despite equal numbers of circulating memory CD8 T cells. These findings demonstrate that pulmonary antigen encounter is required for the establishment of lung CD8 TRM and may inform future vaccine strategies to generate robust cellular immunity against respiratory pathogens.

    更新日期:2018-02-17
  • Goblet cell associated antigen passages are inhibited during Salmonella typhimur/cium infection to prevent pathogen dissemination and limit responses to dietary antigens
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-14
    Devesha H. Kulkarni, Keely G. McDonald, Kathryn A. Knoop, Jenny K. Gustafsson, Konrad M. Kozlowski, David A. Hunstad, Mark J. Miller, Rodney D. Newberry

    Dietary antigen acquisition by lamina propria (LP) dendritic cells (DCs) is crucial to induce oral tolerance and maintain homeostasis. However, encountering innocuous antigens during infection can lead to inflammatory responses, suggesting processes may limit steady-state luminal antigen capture during infection. We observed that goblet cell (GC) associated antigen passages (GAPs), a steady-state pathway delivering luminal antigens to LP-DCs, are inhibited during Salmonella infection. GAP inhibition was mediated by IL-1β. Infection abrogated luminal antigen delivery and antigen-specific T cell proliferation in the mesenteric lymph node (MLN). Antigen-specific T cell proliferation to dietary antigen was restored by overriding GAP suppression; however, this did not restore regulatory T cell induction, but induced inflammatory T cell responses. Salmonella translocation to the MLN required GCs and correlated with GAPs. Genetic manipulations overriding GAP suppression, or antibiotics inducing colonic GAPs, but not antibiotics that do not, increased dissemination and worsened outcomes independent of luminal pathogen burden. Thus, steady-state sampling pathways are suppressed during infection to prevent responses to dietary antigens, limit pathogen entry, and lessen the disease. Moreover, antibiotics may worsen Salmonella infection by means beyond blunting gut microbiota colonization resistance, providing new insight into how precedent antibiotic use aggravates enteric infection.

    更新日期:2018-02-14
  • Alteration in nerves and neurotransmitter stimulation of lacrimal gland secretion in the TSP-1−/− mouse model of aqueous deficiency dry eye
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-14
    Sumit Bhattacharya, Laura García-Posadas, Robin R. Hodges, Helen P. Makarenkova, Sharmila Masli, Darlene A. Dartt

    The purpose of this study is to determine neural, vascular, protein secretion, and cellular signaling changes with disease progression in lacrimal glands of the thrombospondin-1−/− (TSP-1−/−) mouse model of dry eye compared to C57BL/6 wild-type (WT) mice. Neural innervation was reduced in TSP-1−/− lacrimal glands compared to WT controls, whereas the number of blood vessels was increased. Intracellular Ca2+ stores and the amount of lysosomes, mitochondria, and secretory granules, but not the endoplasmic reticulum, were reduced in TSP-1−/− compared to WT acini at 12 weeks of age. Ex vivo high KCl-evoked secretion was decreased in TSP-1−/− compared to WT lacrimal gland tissue pieces. The α1D-adrenergic agonist-stimulated response was increased in TSP-1−/− at 4 and 24 weeks but decreased at 12 weeks, and the ATP and MeSATP-stimulated peak [Ca2+]i responses were decreased at 24 weeks. These changes were observed prior to the appearance of mononuclear infiltrates. We conclude that in the lacrimal gland the absence of TSP-1: injures peripheral nerves; blocks efferent nerve activation; decreases protein secretion; and alters intracellular Ca2+ stores. Through these effects the absence of TSP-1 leads to disruption of ocular surface homeostasis and development of dry eye.

    更新日期:2018-02-14
  • GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-07
    Ye Zhao, Feidi Chen, Wei Wu, Mingming Sun, Anthony J Bilotta, Suxia Yao, Yi Xiao, Xiangsheng Huang, Tonyia D Eaves-Pyles, George Golovko, Yuriy Fofanov, Warren D'Souza, Qihong Zhao, Zhanju Liu, Yingzi Cong

    The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown to promote IEC expression of RegIIIγ and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIIIγ and β-defensins 1, 3, and 4 were lower in G protein-coupled receptor (GPR)43−/− mice compared to that of wild-type (WT) mice. Oral feeding with short-chain fatty acids (SCFA) promoted IEC production of RegIIIγ and defensins in mice. Furthermore, SCFA induced RegIIIγ and β-defensins in intestinal epithelial enteroids generated from WT but not GPR43−/− mice. Mechanistically, SCFA activated mTOR and STAT3 in IEC, and knockdown of mTOR and STAT3 impaired SCFA induction of AMP production. Our studies thus demonstrated that microbiota metabolites SCFA promoted IEC RegIIIγ and β-defensins in a GPR43-dependent manner. The data thereby provide a novel pathway by which microbiota regulates IEC expression of AMP and intestinal homeostasis.

    更新日期:2018-02-07
  • Lymphoid tissue-resident Alcaligenes LPS induces IgA production without excessive inflammatory responses via weak TLR4 agonist activity
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-07
    Naoko Shibata, Jun Kunisawa, Koji Hosomi, Yukari Fujimoto, Keisuke Mizote, Naohiro Kitayama, Atsushi Shimoyama, Hitomi Mimuro, Shintaro Sato, Natsuko Kishishita, Ken J Ishii, Koichi Fukase, Hiroshi Kiyono

    Alcaligenes are opportunistic commensal bacteria that reside in gut-associated lymphoid tissues such as Peyer’s patches (PPs); however, how they create and maintain their homeostatic environment, without inducing an excessive inflammatory response remained unclear. We show here that Alcaligenes-derived lipopolysaccharide (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 and promotes IL-6 production from dendritic cells, which consequently enhances IgA production. The inflammatory activity of Alcaligenes LPS was weaker than that of Escherichia coli-derived LPS and therefore no excessive inflammation was induced by Alcaligenes LPS in vitro or in vivo. Alcaligenes LPS also showed adjuvanticity, inducing antigen-specific immune responses without excessive inflammation. These findings reveal the presence of commensal bacteria-mediated homeostatic inflammatory conditions within PPs that produce optimal IgA induction without causing pathogenic inflammation and suggest that Alcaligenes LPS could be a safe and potent adjuvant.

    更新日期:2018-02-07
  • Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-07
    A Kalinowski, B T Galen, I F Ueki, Y Sun, A Mulenos, A Osafo-Addo, B Clark, J Joerns, W Liu, J A Nadel, C S Dela Cruz, J L Koff

    Respiratory syncytial virus (RSV) persists as a significant human pathogen that continues to contribute to morbidity and mortality. In children, RSV is the leading cause of lower respiratory tract infections, and in adults RSV causes pneumonia and contributes to exacerbations of chronic lung diseases. RSV induces airway epithelial inflammation by activation of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor. Recently, EGFR inhibition was shown to decrease RSV infection, but the mechanism(s) for this effect are not known. Interferon (IFN) signaling is critical for innate antiviral responses, and recent experiments have implicated IFN-λ (lambda), a type III IFN, as the most significant IFN for mucosal antiviral immune responses to RSV infection. However, a role for RSV-induced EGFR activation to suppress airway epithelial antiviral immunity has not been explored. Here, we show that RSV-induced EGFR activation suppresses IFN regulatory factor (IRF) 1-induced IFN-λ production and increased viral infection, and we implicate RSV F protein to mediate this effect. EGFR inhibition, during viral infection, augmented IRF1, IFN-λ, and decreased RSV titers. These results suggest a mechanism for EGFR inhibition to suppress RSV by activation of endogenous epithelial antiviral defenses, which may be a potential target for novel therapeutics.

    更新日期:2018-02-07
  • Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-02-07
    R H M Raeven, J Brummelman, J L A Pennings, L van der Maas, K Helm, W Tilstra, A van der Ark, A Sloots, P van der Ley, W van Eden, W Jiskoot, E van Riet, C A C M van Els, G F A Kersten, W G H Han, B Metz

    Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination, Published online: 07 February 2018; doi:10.1038/mi.2017.110 Molecular and cellular signatures underlying superior immunity against Bordetella pertussis upon pulmonary vaccination

    更新日期:2018-02-07
  • Leptin receptor q223r polymorphism influences neutrophil mobilization after Clostridium difficile infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    S Jose, M M Abhyankar, A Mukherjee, J Xue, H Andersen, D B Haslam, R Madan

    Clostridium difficile is the leading cause of nosocomial infections in the United States. Clinical disease outcomes after C. difficile infection (CDI) are dependent on intensity of host inflammatory responses. Specifically, peak peripheral white blood cell (WBC) count >20 × 109 l−1 is an indicator of adverse outcomes in CDI patients, and is associated with higher 30-day mortality. We show that homozygosity for a common single nucleotide polymorphism (Q to R mutation in leptin receptor that is present in up to 50% of people), significantly increases the risk of having peak peripheral WBC count >20 × 109 l−1 (odds ratio=5.41; P=0.0023) in CDI patients. In a murine model of CDI, we demonstrate that mice homozygous for the same single nucleotide polymorphism (RR mice) have more blood and tissue leukocytes (specifically neutrophils), exaggerated tissue inflammation, and higher mortality as compared with control mice, despite similar pathogen burden. Further, we show that neutrophilia in RR mice is mediated by gut microbiota-directed expression of CXC chemokine receptor 2 (CXCR2), which promotes the release of neutrophils from bone marrow reservoir. Overall these studies provide novel mechanistic insights into the role of human genetic polymorphisms and gut microbiota in regulating the fundamental biological process of CDI-induced neutrophilia.

    更新日期:2018-01-24
  • Intestinal epithelial Toll-like receptor 4 prevents metabolic syndrome by regulating interactions between microbes and intestinal epithelial cells in mice
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    P Lu, C P Sodhi, Y Yamaguchi, H Jia, T Prindle Jr., W B Fulton, A Vikram, K J Bibby, M J Morowitz, D J Hackam

    Little is known about the pathogenesis of metabolic syndrome, although Toll-like receptor 4 (TLR4) has been implicated. We investigated whether TLR4 in the intestinal epithelium regulates metabolic syndrome by coordinating interactions between the luminal microbiota and host genes that regulate metabolism. Mice lacking TLR4 in the intestinal epithelium (TLR4ΔIEC), but not mice lacking TLR4 in myeloid cells nor mice lacking TLR4 globally, developed metabolic syndrome; these features were not observed in TLR4ΔIEC mice given antibiotics. Metagenomic analysis of the fecal microbiota revealed differences between TLR4ΔIEC and wild-type mice, while meta-transcriptome analysis of the microbiota showed that intestinal TLR4 affected the expression of microbial genes involved in the metabolism of lipids, amino acids, and nucleotides. Genes regulated by peroxisome proliferator-activated receptors (PPARs) and the antimicrobial peptide lysozyme were significantly downregulated in TLR4ΔIEC mice, suggesting a mechanism by which intestinal TLR4 could exert its effects on the microbiota and metabolic syndrome. Supportingly, antibiotics prevented both downregulation of PPAR genes and the development of metabolic syndrome, while PPAR agonists prevented development of metabolic syndrome in TLR4ΔIEC mice. Thus, intestinal epithelial TLR4 regulates metabolic syndrome through altered host-bacterial signaling, suggesting that microbial or PPAR-based strategies might have therapeutic potential for this disease.

    更新日期:2018-01-24
  • IFN-γ-dependent epigenetic regulation instructs colitogenic monocyte/macrophage lineage differentiation in vivo
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    Y Nakanishi, T Sato, K Takahashi, T Ohteki

    Colonic macrophages induce pathogenic inflammation against commensal bacteria, leading to inflammatory bowel disease (IBD). Although the ontogeny of colonic macrophages has been well studied in the past decade, how macrophages gain colitogenic properties during the development of colitis is unknown. Using a chemically induced colitis model, we showed that accumulated Ly6C+ cells consisting of inflammatory monocytes and inflammatory macrophages strongly expressed representative colitogenic mediators such as tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS). The interferon-γ–signal transducer and activator of transcription 1 (IFN-γ–Stat1) pathway was required for generating colitogenic macrophages, given that Stat1−/− mice had less severe colitis and fewer colitogenic macrophages. Notably, IFN-γ induced histone acetylation at the promoter regions of the Tnf and Nos2 loci in the monocyte and macrophage lineage, indicating that IFN-γ-dependent epigenetic regulation instructs the development of the colitogenic monocyte and macrophage lineage in vivo. Collectively, our results provide the essential mechanism by which dysregulated colitogenic monocytes/macrophages develop at the colon mucosa during inflammation, and suggest a new drug target for treating IBD.

    更新日期:2018-01-24
  • Noxa/HSP27 complex delays degradation of ubiquitylated IkBα in airway epithelial cells to reduce pulmonary inflammation
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    C Zhang, J T Jones, H S Chand, M G Wathelet, C M Evans, B Dickey, J Xiang, Y A Mebratu, Y Tesfaigzi

    IFN-γ is known as a pro-inflammatory cytokine, but can also block inflammation in certain chronic diseases although the underlying mechanisms are poorly understood. We found that IFN-γ rapidly induced Noxa expression and that extent of inflammation by repeated house dust mite exposure was enhanced in noxa−/− compared with noxa+/+ mice. Noxa expression blocked transforming necrosis factor alpha (TNF-α)-induced nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of pro-inflammatory cytokines. Noxa did not affect TNF-α-induced IκBα phosphorylation but the degradation of 48-chain-ubiquitylated IκBα. The Cys25 of Noxa was cross-linked with Cys137 of phospho-HSP27 and both proteins were required for blocking the degradation of ubiquitylated IκBα. Because phospho-HSP27 is present in airway epithelial cells and not in fibroblasts or thymocytes, we generated transgenic mice that inducibly expressed Noxa in airway epithelia. These mice showed protection from allergen-induced inflammation and mucous cell metaplasia by blocking nuclear translocation of NF-κB. Further, we identified a Noxa-derived peptide that prolonged degradation of 48-chain-ubiquitylated IκBα, blocked nuclear translocation of NF-κB, and reduced allergen-induced inflammation in mice. These results suggest that the anti-inflammatory role of the Noxa protein may be restricted to airway epithelial cells and the use of Noxa for therapy of chronic lung diseases may be associated with reduced side effects.

    更新日期:2018-01-24
  • Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-24
    J B Wechsler, A Szabo, C L Hsu, R A Krier-Burris, H A Schroeder, M Y Wang, R G Carter, T E Velez, L M Aguiniga, J B Brown, M L Miller, B K Wershil, T A Barrett, P J Bryce

    Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear as targeting histamine 1 receptor (H1R) or H2R is clinically ineffective. We hypothesized that histamine functioned instead through the other colon-expressed histamine receptor, H4R. In humans, UC patient biopsies exhibited increased H4R RNA and protein expression over control tissue, and immunohistochemistry showed that H4R was in proximity to immunopathogenic myeloperoxidase-positive neutrophils. To characterize this association further, we employed both the oxazolone (Ox)- and dextran sulfate sodium (DSS)-induced experimental colitis mouse models and also found upregulated H4R expression. Mast cell (MC)-derived histamine and H4R drove experimental colitis, as H4R–/– mice had lower symptom scores, neutrophil-recruitment mediators (colonic interleukin-6 (IL-6), CXCL1, CXCL2), and mucosal neutrophil infiltration than wild-type (WT) mice, as did MC-deficient KitW-sh/W-sh mice reconstituted with histidine decarboxylase–deficient (HDC−/−) bone marrow–derived MCs compared with WT-reconstituted mice; adaptive responses remained intact. Furthermore, Rag2−/− × H4R−/− mice had reduced survival, exacerbated colitis, and increased bacterial translocation than Rag2−/− mice, revealing an innate protective antibacterial role for H4R. Taken together, colonic MC-derived histamine initiates granulocyte infiltration into the colonic mucosa through H4R, suggesting alternative therapeutic targets beyond adaptive immunity for UC.

    更新日期:2018-01-24
  • Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells
    Mucosal Immunol. (IF 7.478) Pub Date : 
    Roland Lehmann, Mario M Müller, Tilman E Klassert, Dominik Driesch, Magdalena Stock, Anina Heinrich, Theresia Conrad, Christoph Moore, Uta K Schier, Reinhard Guthke, Hortense Slevogt

    Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells, Published online: 03 January 2018; doi:10.1038/mi.2017.100 Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells

    更新日期:2018-01-03
  • Epithelial Hes1 maintains gut homeostasis by preventing microbial dysbiosis
    Mucosal Immunol. (IF 7.478) Pub Date : 
    X-K Guo, J Ou, S Liang, X Zhou, X Hu

    Epithelial Hes1 maintains gut homeostasis by preventing microbial dysbiosis Epithelial Hes1 maintains gut homeostasis by preventing microbial dysbiosis, Published online: 03 January 2018; doi:10.1038/mi.2017.111 Epithelial Hes1 maintains gut homeostasis by preventing microbial dysbiosis

    更新日期:2018-01-03
  • T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection
    Mucosal Immunol. (IF 7.478) Pub Date : 
    Américo H López-Yglesias, Elise Burger, Alessandra Araujo, Andrew T Martin, Felix Yarovinsky

    T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection, Published online: 03 January 2018; doi:10.1038/mi.2017.102 T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection

    更新日期:2018-01-03
  • Immunity to gastrointestinal nematode infections
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-03
    D Sorobetea, M Svensson-Frej, R Grencis

    Immunity to gastrointestinal nematode infections Immunity to gastrointestinal nematode infections, Published online: 03 January 2018; doi:10.1038/mi.2017.113 Immunity to gastrointestinal nematode infections

    更新日期:2018-01-03
  • Oral-gut connection: one step closer to an integrated view of the gastrointestinal tract?
    Mucosal Immunol. (IF 7.478) Pub Date : 2018-01-03
    R Lira-Junior, E A Boström

    Although an enrichment of orally derived bacteria is reported in the gut microbiota of patients with several diseases, it is mostly unknown whether oral bacteria can colonize and induce intestinal inflammation. In a recent paper in Science, Atarashi et al.1 from Kenya Honda’s laboratory show that a subset of orally derived bacteria colonizes and persists in the gut, leading to activation of the intestinal immune system and subsequent chronic inflammation in a susceptible host. The impact of oral health status as a potential contributor to inflammatory diseases at distal sites of the body deserves consideration.

    更新日期:2018-01-03
  • Epithelial–mesenchymal transition in Crohn’s disease
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    H Jiang, J Shen, Z Ran

    Crohn’s disease (CD) is often accompanied by the complications of intestinal strictures and fistulas. These complications remain obstacles in CD treatment. In recent years, the importance of epithelial–mesenchymal transition in the pathogenesis of CD-associated fistulas and intestinal fibrosis has become apparent. Epithelial–mesenchymal transition refers to a dynamic change, wherein epithelial cells lose their polarity and adherence and acquire migratory function and fibroblast features. During formation of CD-associated fistulas, intestinal epithelial cells dislocate from the basement membrane and migrate to the lining of the fistula tracts, where they convert into transitional cells as a compensatory response under the insufficient wound healing condition. In CD-associated intestinal fibrosis, epithelial–mesenchymal transition may serve as a source of new fibroblasts and consequently lead to overproduction of extracellular matrix. In this review, we present current knowledge of epithelial–mesenchymal transition and its role in the pathogenesis of CD in order to highlight new therapy targets for the associated complications.

    更新日期:2017-12-20
  • Development of immune and microbial environments is independently regulated in the mammary gland
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    K Niimi, K Usami, Y Fujita, M Abe, M Furukawa, Y Suyama, Y Sakai, M Kamioka, N Shibata, E J Park, S Sato, H Kiyono, H Yoneyama, H Kitazawa, K Watanabe, T Nochi, H Aso

    Breastfeeding is important for mammals, providing immunological and microbiological advantages to neonates, together with the nutritional supply from the mother. However, the mechanisms of this functional diversity in the mammary gland remain poorly characterized. Here, we show that, similar to the gastrointestinal tract, the mammary gland develops immune and microbial environments consisting of immunoglobulin A (IgA) and the microflora, respectively, both of which are important for protecting neonates and the mother from infectious diseases. The IgA production and microflora development are coordinated in the gastrointestinal tract but seem to be independently regulated in the mammary gland. In particular, the chemokine (C–C motif) ligand 28 and poly-Ig receptor, crucial molecules for the IgA production in milk, were expressed normally in germ-free lactating mice but were almost undetectable in postweaning mothers, regardless of the microflora presence. Our findings offer insights into potentially improving the quality of breastfeeding, using both immunological and microbiological approaches.

    更新日期:2017-12-20
  • Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    S P Parihar, M Ozturk, M J Marakalala, D T Loots, R Hurdayal, D Beukes, M Van Reenen, D E Zak, S K Mbandi, F Darboe, A Penn-Nicholson, W A Hanekom, M Leitges, T J Scriba, R Guler, F Brombacher

    Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice, Published online: 20 December 2017; doi:10.1038/mi.2017.108 Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice

    更新日期:2017-12-20
  • Early treatment of SIV+ macaques with an α4β7 mAb alters virus distribution and preserves CD4+ T cells in later stages of infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    P J Santangelo, C Cicala, S N Byrareddy, K T Ortiz, D Little, K E Lindsay, S Gumber, J J Hong, K Jelicic, K A Rogers, C Zurla, F Villinger, A A Ansari, A S Fauci, J Arthos

    Integrin α4β7 mediates the trafficking of leukocytes, including CD4+ T cells, to lymphoid tissues in the gut. Virus mediated damage to the gut is implicated in HIV and SIV mediated chronic immune activation and leads to irreversible damage to the immune system. We employed an immuno-PET/CT imaging technique to evaluate the impact of an anti-integrin α4β7 mAb alone or in combination with ART, on the distribution of both SIV infected cells and CD4+ cells in rhesus macaques infected with SIV. We determined that α4β7 mAb reduced viral antigen in an array of tissues of the lung, spleen, axillary, and inguinal lymph nodes. These sites are not directly linked to α4β7 mediated homing; however, the most pronounced reduction in viral load was observed in the colon. Despite this reduction, α4β7 mAb treatment did not prevent an apparent depletion of CD4+ T cells in gut in the acute phase of infection that is characteristic of HIV/SIV infection. However, α4β7 mAb appeared to facilitate the preservation or restoration of CD4+ T cells in gut tissues at later stages of infection. Since damage to the gut is believed to play a central role in HIV pathogenesis, these results support further evaluation of α4β7 antagonists in the study and treatment of HIV disease.

    更新日期:2017-12-20
  • The cytosolic sensor STING is required for intestinal homeostasis and control of inflammation
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    M C C Canesso, L Lemos, T C Neves, F M Marim, T B R Castro, ÉS Veloso, C P Queiroz, J Ahn, H C Santiago, F S Martins, J Alves-Silva, E Ferreira, D C Cara, A T Vieira, G N Barber, S C Oliveira, A M C Faria

    STING (stimulator of interferon genes) is a cytosolic sensor for cyclic dinucleotides and also an adaptor molecule for intracellular DNA receptors. Although STING has important functions in the host defense against pathogens and in autoimmune diseases, its physiological relevance in intestinal homeostasis is largely unknown. In this study, we show that STING−/− mice presented defective protective mechanisms of intestinal mucosa, including decreased number of goblet cells, diminished mucus production, and lower levels of secretory IgA, when compared with wild-type (WT) mice. Fecal content and microbiota DNA could activate STING, indicating a role of this molecule in gut. Microbiota composition was altered in STING−/− mice toward a more inflammatory profile, evidencing a reduction in the Allobacolum and Bifidobacterium groups along with increase in Disulfovibrio bacteria. Absence of STING lead to decrease in induced intraepithelial lymphocytes (IEL) and to increase in group 1 innate lymphoid cell (ILC1) as well as ILC3 frequencies and decrease in ILC2 in the colon. Development and function of Foxp3+ and LAP+ regulatory T cells were also compromised in STING−/− mice. Moreover, these mice were highly susceptible to dextran sodium sulfate–induced colitis, T-cell-induced colitis, and enteric Salmonella typhimurium infection when compared with WT animals. Therefore, our results identify an important role of STING in maintaining gut homeostasis and also a protective effect in controlling gut inflammation.

    更新日期:2017-12-20
  • Macrophages regulate lung ILC2 activation via Pla2g5-dependent mechanisms
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    M Yamaguchi, S K Samuchiwal, O Quehenberger, J A Boyce, B Balestrieri

    Group V phospholipase A2 (Pla2g5) is a lipid-generating enzyme necessary for macrophage effector functions in pulmonary inflammation. However, the lipid mediators involved and their cellular targets have not been identified. Mice lacking Pla2g5 showed markedly reduced lung ILC2 activation and eosinophilia following repetitive Alternaria Alternata inhalation. While Pla2g5-null mice had Wt levels of immediate IL-33 release after one Alternaria dose, they failed to upregulate IL-33 in macrophages following repeated Alternaria administration. Unexpectedly, while adoptive transfer of bone marrow-derived (BM)-macrophages restored ILC2 activation and eosinophilia in Alternaria-exposed Pla2g5-null mice, exogenous IL-33 did not. Conversely, transfers of Pla2g5-null BM-macrophages reduced inflammation in Alternaria-exposed Wt mice. Mass spectrometry analysis of free fatty acids (FFAs) demonstrated significantly reduced FFAs (including linoleic acid (LA) and oleic acid (OA)) in lung and BM-macrophages lacking Pla2g5. Exogenous administration of LA or LA+OA to Wt mice sharply potentiated IL-33-induced lung eosinophilia and ILC2 expansion in vitro and in vivo. In contrast, OA potentiated IL-33-induced inflammation and ILC2 expansion in Pla2g5-null mice, but LA was inactive both in vivo and in vitro. Notably, Pla2g5-null ILC2s showed significantly reduced expression of the FFA-receptor-1 compared to Wt ILC2s. Thus, macrophage-associated Pla2g5 contributes significantly to type-2 immunity through regulation of IL-33 induction and FFA-driven ILC2 activation.

    更新日期:2017-12-20
  • Restricted access or access all areas? a new cadherin-like protein upregulated in the inflamed esophagus
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    D A Knight, P M Hansbro

    Restricted access or access all areas? a new cadherin-like protein upregulated in the inflamed esophagus Restricted access or access all areas? a new cadherin-like protein upregulated in the inflamed esophagus, Published online: 20 December 2017; doi:10.1038/mi.2017.56 Restricted access or access all areas? a new cadherin-like protein upregulated in the inflamed esophagus

    更新日期:2017-12-20
  • CD103+CD11b+ mucosal classical dendritic cells initiate long-term switched antibody responses to flagellin
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-20
    A Flores-Langarica, K Müller Luda, E K Persson, C N Cook, S Bobat, J L Marshall, M W Dahlgren, K Hägerbrand, K M Toellner, M D Goodall, D R Withers, I R Henderson, B Johansson Lindbom, A F Cunningham, W W Agace

    Antibody responses induced at mucosal and nonmucosal sites demonstrate a significant level of autonomy. Here, we demonstrate a key role for mucosal interferon regulatory factor-4 (IRF4)-dependent CD103+CD11b+ (DP), classical dendritic cells (cDCs) in the induction of T-dependent immunoglobulin G (IgG) and immunoglobulin A (IgA) responses in the mesenteric lymph node (MLN) following systemic immunization with soluble flagellin (sFliC). In contrast, IRF8-dependent CD103+CD11b− (SP) are not required for these responses. The lack of this response correlated with a complete absence of sFliC-specific plasma cells in the MLN, small intestinal lamina propria, and surprisingly also the bone marrow (BM). Many sFliC-specific plasma cells accumulating in the BM of immunized wild-type mice expressed α4β7+, suggesting a mucosal origin. Collectively, these results suggest that mucosal DP cDC contribute to the generation of the sFliC-specific plasma cell pool in the BM and thus serve as a bridge linking the mucosal and systemic immune system.

    更新日期:2017-12-20
  • iNOS- and NOX1-dependent ROS production maintains bacterial homeostasis in the ileum of mice
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-12-06
    C Matziouridou, S D C Rocha, O A Haabeth, K Rudi, H Carlsen, A Kielland

    iNOS- and NOX1-dependent ROS production maintains bacterial homeostasis in the ileum of mice iNOS- and NOX1-dependent ROS production maintains bacterial homeostasis in the ileum of mice, Published online: 06 December 2017; doi:10.1038/mi.2017.106 iNOS- and NOX1-dependent ROS production maintains bacterial homeostasis in the ileum of mice

    更新日期:2017-12-15
  • Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-29
    B M Wittig, R Sabat, P Holzlöhner, E Witte-Händel, K Heilmann, K Witte, J Triebus, A Tzankov, J D Laman, B Bokemeyer, L Terracciano, C Schwärzler, H Kohler, R Volkmer, C Loddenkemper, K Wolk, U Hoffmann, U Günthert

    Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis, Published online: 29 November 2017; doi:10.1038/mi.2017.98 Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis

    更新日期:2017-12-15
  • IL-15 supports the generation of protective lung-resident memory CD4 T cells
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-29
    T M Strutt, K Dhume, C M Finn, J H Hwang, C Castonguay, S L Swain, K K McKinstry

    IL-15 supports the generation of protective lung-resident memory CD4 T cells IL-15 supports the generation of protective lung-resident memory CD4 T cells, Published online: 29 November 2017; doi:10.1038/mi.2017.101 IL-15 supports the generation of protective lung-resident memory CD4 T cells

    更新日期:2017-12-15
  • Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-29
    J Li, J-L Casanova, A Puel

    Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation, Published online: 29 November 2017; doi:10.1038/mi.2017.97 Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation

    更新日期:2017-12-15
  • A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-15
    K Radulovic, S Normand, A Rehman, A Delanoye-Crespin, J Chatagnon, M Delacre, N Waldschmitt, L F Poulin, J Iovanna, B Ryffel, P Rosenstiel, M Chamaillard

    A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation, Published online: 15 November 2017; doi:10.1038/mi.2017.87 A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation

    更新日期:2017-12-15
  • Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-15
    H B Jijon, L Suarez-Lopez, O E Diaz, S Das, J De Calisto, M B Yaffe, M J Pittet, J R Mora, Y Belkaid, R J Xavier, E J Villablanca

    Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system, Published online: 15 November 2017; doi:10.1038/mi.2017.91 Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system

    更新日期:2017-12-15
  • Trigger-happy resident memory CD4+ T cells inhabit the human lungs
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-15
    A E Oja, B Piet, C Helbig, R Stark, D van der Zwan, H Blaauwgeers, E B M Remmerswaal, D Amsen, R E Jonkers, P D Moerland, M A Nolte, R A W van Lier, P Hombrink

    Trigger-happy resident memory CD4+ T cells inhabit the human lungs Trigger-happy resident memory CD4+ T cells inhabit the human lungs, Published online: 15 November 2017; doi:10.1038/mi.2017.94 Trigger-happy resident memory CD4+ T cells inhabit the human lungs

    更新日期:2017-12-15
  • Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection
    Mucosal Immunol. (IF 7.478) Pub Date : 2017-11-15
    Brenna E Kiniry, Shengbin Li, Anupama Ganesh, Peter W Hunt, Ma Somsouk, Pamela J Skinner, Steven G Deeks, Barbara L Shacklett

    Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection, Published online: 15 November 2017; doi:10.1038/mi.2017.96 Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection

    更新日期:2017-12-15
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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