scholarly journals Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium

2014 ◽  
Vol 82 (5) ◽  
pp. 1949-1958 ◽  
Author(s):  
Sara M. Dann ◽  
Christine Le ◽  
Barun K. Choudhury ◽  
Houpu Liu ◽  
Omar Saldarriaga ◽  
...  
Keyword(s):  
Immune Responses ◽  
Intestinal Inflammation ◽  
Acute Infection ◽  
Interleukin 10 ◽  
Mucosal Inflammation ◽  
Immune Functions ◽  
Citrobacter Rodentium ◽  
Microbial Infection ◽  
Content Type ◽  
Deficient Mice

ABSTRACTInterleukin-10 (IL-10) curtails immune responses to microbial infection and autoantigens and contributes to intestinal immune homeostasis, yet administration of IL-10 has not been effective at attenuating chronic intestinal inflammatory conditions, suggesting that its immune functions may be context dependent. To gain a broader understanding of the importance of IL-10 in controlling mucosal immune responses to infectious challenges, we employed the murine attaching and effacing pathogenCitrobacter rodentium, which colonizes primarily the surfaces of the cecum and colon and causes transient mucosal inflammation driven by Th17 and Th1 T helper cells. Infection induced macrophage and dendritic cell production of IL-10, which diminished antibacterial host defenses, because IL-10-deficient mice cleared infection faster than wild-type controls. In parallel, the mice had less acute infection-associated colitis and resolved it more rapidly than controls. Importantly, transientC. rodentiuminfection protected IL-10-deficient mice against the later development of spontaneous colitis that normally occurs with aging in these mice. Genome-wide expression studies revealed that IL-10 deficiency was associated with downregulation of proinflammatory pathways but increased expression of the anti-inflammatory cytokine IL-27 in response to infection. IL-27 was found to suppressin vitroTh17 and, to a lesser degree, Th1 differentiation independent of IL-10. Furthermore, neutralization of IL-27 resulted in more severe colitis in infected IL-10-deficient mice. Together, these findings indicate that IL-10 is dispensable for resolvingC. rodentium-associated colitis and further suggest that IL-27 may be a critical factor for controlling intestinal inflammation and Th17 and Th1 development by IL-10-independent mechanisms.

scholarly journals Gamma Interferon Produced by Antigen-Specific CD4+ T Cells Regulates the Mucosal Immune Responses to Citrobacter rodentium Infection

2010 ◽  
Vol 78 (6) ◽  
pp. 2653-2666 ◽  
Author(s):  
Hideyuki Shiomi ◽  
Atsuhiro Masuda ◽  
Shin Nishiumi ◽  
Masayuki Nishida ◽  
Tetsuya Takagawa ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Gamma Interferon ◽  
Immune Defense ◽  
Interleukin 4 ◽  
Mucosal Inflammation ◽  
Citrobacter Rodentium ◽  
Macrophage Phagocytosis ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the surface of intestinal epithelial cells and causes mucosal inflammation. This bacterium is an ideal model for investigating pathogen-host immune interactions in the gut. It is well known that gene transcripts for Th1 cytokines are highly induced in colonic tissue from mice infected with C. rodentium. However, it remains to be seen whether the Th1 or Th2 cytokines produced by antigen-specific CD4+ T cells provide effective regulation of the host immune defense against C. rodentium infection. To investigate the antigen-specific immune responses, C. rodentium expressing ovalbumin (OVA-C. rodentium), a model antigen, was generated and used to define antigen-specific responses under gamma interferon (IFN-γ)-deficient or interleukin-4 (IL-4)-deficient conditions in vivo. The activation of antigen-specific CD4+ T cells and macrophage phagocytosis were evaluated in the presence of IFN-γ or IL-4 in vitro. IFN-γ-deficient mice exhibited a loss of body weight and a higher bacterial concentration in feces during OVA-C. rodentium infection than C57BL/6 (wild type) or IL-4-deficient mice. This occurred through the decreased efficiency of macrophage phagocytosis and the activation of antigen-specific CD4+ T cells. Furthermore, a deficiency in antigen-specific CD4+ T-cell-expressed IFN-γ led to a higher susceptibility to mucosal and gut-derived systemic OVA-C. rodentium infection. These results show that the IFN-γ produced by antigen-specific CD4+ T cells plays an important role in the defense against C. rodentium.

scholarly journals Enhanced Susceptibility to Citrobacter rodentium Infection in MicroRNA-155-Deficient Mice

2012 ◽  
Vol 81 (3) ◽  
pp. 723-732 ◽  
Author(s):  
Simon Clare ◽  
Victoria John ◽  
Alan W. Walker ◽  
Jennifer L. Hill ◽  
Cei Abreu-Goodger ◽  
...  
Keyword(s):  
Immune Responses ◽  
Bacterial Pathogen ◽  
Citrobacter Rodentium ◽  
Wild Type ◽  
Content Type ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Control Gene Expression ◽  
Gastrointestinal Tissue ◽  
Deficient Mice

ABSTRACTMicroRNAs (miRNAs) are small noncoding molecules that control gene expression posttranscriptionally, with microRNA-155 (miR-155) one of the first to be implicated in immune regulation. Here, we show that miR-155-deficient mice are less able to eradicate a mucosalCitrobacter rodentiuminfection than wild-type C57BL/6 mice. miR-155-deficient mice exhibited prolonged colonization associated with a higherC. rodentiumburden in gastrointestinal tissue and spread into systemic tissues. Germinal center formation and humoral immune responses againstC. rodentiumwere severely impaired in infected miR-155-deficient mice. A similarly susceptible phenotype was observed in μMT mice reconstituted with miR-155-deficient B cells, indicating that miR-155 is required intrinsically for mediating protection against this predominantly luminal bacterial pathogen.

scholarly journals Dietary Selenium in Immune Mechanisms During an Enteric Bacterial Infection (OR12-08-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Shaneice Nettleford ◽  
Luming Zhao ◽  
James Fraser ◽  
Adwitia Dey ◽  
Dhimant Desai ◽  
...  
Keyword(s):  
Immune Responses ◽  
Trace Element ◽  
Lymphoid Cells ◽  
Nutritional Deficiencies ◽  
Enteric Infection ◽  
Bacterial Burden ◽  
Citrobacter Rodentium ◽  
T Helper 17 ◽  
Western Blots ◽  
Deficient Mice

Abstract Objectives Enteropathogenic Escherichia coli (EPEC) poses a great threat to developing countries, as EPEC can result in diarrhea and colitis in children. Interestingly, the effect of trace element nutritional deficiencies as well as their supplementation on disease pathogenesis is increasingly being recognized. We have previously reported that supplementation of mice with selenium (Se), a trace element that is incorporated into selenoproteins as the 21st amino acid, resulted in the amelioration of chemically induced colitis through the downregulation of pro-inflammatory mediators of the arachidonic acid pathway, including prostaglandin E2 (PGE2). Here we examined the effects of Se supplementation on immune responses during an enteric infection with Citrobacter rodentium, a natural murine enteropathogen. Methods C57BL/6 mice placed on Se-deficient (0.01 ppm Se), Se-adequate (0.08 ppm Se), or Se-supplemented (0.4 ppm Se) diets for 8 weeks were infected with Citrobacter rodentium, the murine equivalent of EPEC with a shared core set of virulence factors. Mice were euthanized, and colons were collected for further analysis including western blots and flow cytometry. Results Se-deficient mice experienced increased bacterial burden, mortality, and decreased colon length following infection, compared to Se-adequate and Se-supplemented mice. Studies revealed that there was an increase type 3 innate-lymphoid cells (ILC3s) and IL-22 producing T helper 17 (Th17) cells, but a decrease in regulatory T- cells (Tregs) and 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that preferentially oxidizes PGE2, in the colon of Se-deficient mice compared to Se-adequate and Se-supplemented mice. Treatment of Se-adequate mice with CAY10397, an inhibitor of 15-PGDH, increased the bacterial burden following infection. Infection of mice that lack expression of selenoproteins in macrophages (Trspfl/fl LysMCre) showed increased mortality despite being fed diets replete with Se. Conclusions Adequate to supplemental levels of dietary Se is required to maximize the expression of selenoproteins to effectively mediate resolution of enteric infections. Selenoproteins act through diverse mechanisms, including modulation of immune responses and inflammation through the oxidative metabolism of PGE2. Funding Sources National Institute of Health.

scholarly journals Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

2014 ◽  
Vol 82 (10) ◽  
pp. 4204-4211 ◽  
Author(s):  
Khatoun Al Moussawi ◽  
Barbara I. Kazmierczak
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Immune Responses ◽  
Bacterial Pathogen ◽  
Innate Immune ◽  
Immune Recognition ◽  
Content Type ◽  
Caspase 1 ◽  
Rapid Responses ◽  
Subsequent Activation ◽  
Deficient Mice

ABSTRACTThe bacterial pathogenPseudomonas aeruginosacauses acute infections associated with significant morbidity and mortality.P. aeruginosaelicits strong innate immune responses in immunocompetent hosts, and the resulting recruitment of neutrophils to the site of infection is necessary for bacterial clearance.P. aeruginosalipopolysaccharide and flagellin are recognized by extracellular Toll-like receptors, but the most rapid responses to infection occur when cytosolic receptors sense flagellin or type 3 secretion system (T3SS) structural proteins. The subsequent activation of the NLRC4 inflammasome and caspase-1 generates an interleukin-1β (IL-1β) signal that is required for the rapid neutrophilic response. A T3SS effector, exotoxin U (ExoU), can inhibit activation of the NLRC4 inflammasome and caspase-1. Thus, our observation that IL-1 receptor (IL-1R)-mediated signals were still required to initiate a response to ExoU-producing bacteria was unexpected. As both IL-1α and IL-1β signal via the IL-1R, we examined immune responses in mice lacking either of these cytokines. IL-1β-deficient mice responded to ExoU-producingP. aeruginosabacteria similarly to wild-type animals; however, IL-1α-deficient mice had an attenuated immune response. The situation was reversed following infections by ExoU-negative bacteria: here, IL-1α was dispensable for neutrophil recruitment, while IL-1β was required. IL-1α secretion by macrophages infected with ExoU-producingP. aeruginosaisolates was independent of both caspase-1 and caspase-11. This study documents distinct roles for IL-1α and IL-1β in the response toP. aeruginosainfection as a function of the T3SS effectors produced by the infecting strain. The redundancy of these two cytokines nonetheless allows the infected host to mount a response to ExoU-positive and -negative bacterial isolates.

scholarly journals Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Naresh S Redhu ◽  
Vasudevan Bakthavatchalu ◽  
Evan A Conaway ◽  
Dror S Shouval ◽  
Amy Tsou ◽  
...  
Keyword(s):  
Infant Development ◽  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Postnatal Period ◽  
Macrophage Function ◽  
Murine Colitis ◽  
Macrophage Depletion ◽  
Macrophage Dysfunction ◽  
Inflammatory Bowel ◽  
Deficient Mice

Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with clodronate inhibited the development of colitis, while the absence of IL10R specifically on macrophages sensitized infant mice to the development of colitis. These results indicate that IL10R-mediated regulation of macrophage function during the early postnatal period is indispensable for preventing the development of murine colitis.

scholarly journals Inflammation-Induced Acid Tolerance GenesgadABin Luminal Commensal Escherichia coli Attenuate Experimental Colitis

2013 ◽  
Vol 81 (10) ◽  
pp. 3662-3671 ◽  
Author(s):  
Sandrine Tchaptchet ◽  
Ting-Jia Fan ◽  
Laura Goeser ◽  
Alexi Schoenborn ◽  
Ajay S. Gulati ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune Responses ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Acid Tolerance ◽  
Experimental Colitis ◽  
Intestinal Epithelial ◽  
Content Type ◽  
E Coli ◽  
Chronic Intestinal Inflammation

ABSTRACTDysregulated immune responses to commensal intestinal bacteria, includingEscherichia coli, contribute to the development of inflammatory bowel diseases (IBDs) and experimental colitis. Reciprocally,E. coliresponds to chronic intestinal inflammation by upregulating expression of stress response genes, includinggadAandgadB. GadAB encode glutamate decarboxylase and protectE. colifrom the toxic effects of low pH and fermentation acids, factors present in the intestinal lumen in patients with active IBDs. We hypothesized thatE. coliupregulatesgadABduring inflammation to enhance its survival and virulence. Using real-time PCR, we determinedgadABexpression in luminalE. colifrom ex-germfree wild-type (WT) and interleukin-10 (IL-10) knockout (KO) (IL-10−/−) mice selectively colonized with a commensalE. coliisolate (NC101) that causes colitis in KO mice in isolation or in combination with 7 other commensal intestinal bacterial strains.E. colisurvival and host inflammatory responses were measured in WT and KO mice colonized with NC101 or a mutant lacking thegadABgenes (NC101ΔgadAB). The susceptibility of NC101 and NC101ΔgadABto killing by host antimicrobial peptides and their translocation across intestinal epithelial cells were evaluated using bacterial killing assays and transwell experiments, respectively. We show that expression ofgadABin luminalE. coliincreases proportionately with intestinal inflammation in KO mice and enhances the susceptibility of NC101 to killing by the host antimicrobial peptide cryptdin-4 but decreases bacterial transmigration across intestinal epithelial cells, colonic inflammation, and mucosal immune responses. Chronic intestinal inflammation upregulates acid tolerance pathways in commensalE. coliisolates, which, contrary to our original hypothesis, limits their survival and colitogenic potential. Further investigation of microbial adaptation to immune-mediated inflammation may provide novel insights into the pathogenesis and treatment of IBDs.

scholarly journals Haemophilus ducreyi-Induced Interleukin-10 Promotes a Mixed M1 and M2 Activation Program in Human Macrophages

2012 ◽  
Vol 80 (12) ◽  
pp. 4426-4434 ◽  
Author(s):  
Wei Li ◽  
Barry P. Katz ◽  
Stanley M. Spinola
Keyword(s):  
Macrophage Polarization ◽  
Interleukin 10 ◽  
Human Infection ◽  
Haemophilus Ducreyi ◽  
Mitogen Activated Protein Kinase ◽  
Surface Markers ◽  
Microbial Infection ◽  
Bacterial Killing ◽  
Content Type

ABSTRACTDuring microbial infection, macrophages are polarized to classically activated (M1) or alternatively activated (M2) cells in response to microbial components and host immune mediators. Proper polarization of macrophages is critical for bacterial clearance. To study the role of macrophage polarization duringHaemophilus ducreyiinfection, we analyzed a panel of macrophage surface markers in skin biopsy specimens of pustules obtained from experimentally infected volunteers. Lesional macrophages expressed markers characteristic of both M1 and M2 polarization. Monocyte-derived macrophages (MDM) also expressed a mixed M1 and M2 profile of surface markers and cytokines/chemokines upon infection withH. ducreyiin vitro. Endogenous interleukin 10 (IL-10) produced by infected MDM downregulated and enhanced expression of several M1 and M2 markers, respectively. Bacterial uptake, mediated mainly by class A scavenger receptors, and activation of mitogen-activated protein kinase and phosphoinositide 3-kinase signaling pathways were required forH. ducreyi-induced IL-10 production in MDM. Compared to M1 cells, IL-10-polarized M2 cells displayed enhanced phagocytic activity againstH. ducreyiand similar bacterial killing. Thus, IL-10-modulated macrophage polarization may contribute toH. ducreyiclearance during human infection.

scholarly journals Studies on the Interleukin-10 Gene in Animal Models of Colitis

2001 ◽  
Vol 15 (8) ◽  
pp. 557-558
Author(s):  
Hugh J Freeman
Keyword(s):  
Inflammatory Bowel Disease ◽  
Animal Models ◽  
Bowel Disease ◽  
Inflammatory Process ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Inflammatory Bowel ◽  
Deficient Mice

Cytokines play a role in the inflammatory process in colitis and may have therapeutic potential. Interleukin-10 (IL-10) has both immunomodulatory and anti-inflammatory properties. IL-10-deficient mice develop intestinal inflammation with increased tissue levels of other cytokines, including tumour necrosis factor-alpha. In patients with inflammatory bowel disease, impaired IL-10 production by lamina propria T cells occurs and human recombinant IL-10 improves clinical parameters in inflammatory bowel disease (eg, Crohn's disease). There seem to be conflicting results in differing animal models, and the timing of administration of IL-10 relative to onset of colitis may be critical, possibly due to rapid clearance of IL-10. Interestingly, in IL-10 gene-deficient mice raised in germ-free conditions, the intestinal inflammatory changes normally observed in conventional nongerm-free conditions are not detected, suggesting a role for luminal bacteria in the pathogenesis of the inflammatory process.

scholarly journals Norovirus Triggered Microbiota-driven Mucosal Inflammation in Interleukin 10-deficient Mice

2014 ◽  
Vol 20 (3) ◽  
pp. 431-443 ◽  
Author(s):  
Marijana Basic ◽  
Lydia M. Keubler ◽  
Manuela Buettner ◽  
Marcel Achard ◽  
Gerhard Breves ◽  
...  
Keyword(s):  
Interleukin 10 ◽  
Mucosal Inflammation ◽  
Deficient Mice

scholarly journals Necessary and Sufficient Role for T Helper Cells To Prevent Fungal Dissemination in Allergic Lung Disease

2011 ◽  
Vol 79 (11) ◽  
pp. 4459-4471 ◽  
Author(s):  
Paul C. Porter ◽  
Luz Roberts ◽  
Anna Fields ◽  
Morgan Knight ◽  
Yuping Qian ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Fungal Infections ◽  
Allergic Inflammation ◽  
T Helper ◽  
Content Type ◽  
Allergic Lung Disease ◽  
Th2 Cell ◽  
Rag 1 ◽  
Deficient Mice

ABSTRACTMucosal immune responses to fungal infection range from T helper type 2 (Th2) cell-directed allergic inflammation to Th1-predominant neutrophilic inflammation, but the mechanisms directing these divergent mucosal immune outcomes and the role of T cells in host defense against mucosal fungal infections are not known. Here we examined the mouse mucosal immune responses to 12 filamentous environmental fungal species over a broad range of exposure doses and determined the requirement of T cells for host defense. For all tested fungi, low-grade conidium exposures induced Th2- and eosinophil-predominant allergic lung disease, whereas higher exposures led to rapid conversion to neutrophil- and Th1 cell-predominant inflammation, a phenomenon we term immune phenotype switching. All fungal exposure doses were further linked to the secretion of interleukin-17A (IL-17A). Fungal infections withCurvularia lunataandAspergillus fumigatuswere typically confined to the airway during allergic inflammation but became locally invasive and disseminated to the brain at higher conidium challenge doses, in association with predominant Th1 responses. Fungal dissemination occurred at relatively low challenge doses with the conidia ofAspergillus fumigatusadministered to recombinase activating gene 1 (Rag-1)-deficient mice, which lack B and T cells, but B cell-deficient μMT mice and T helper cell-reconstituted Rag-1-deficient mice were comparable to wild-type mice in preventing fungal dissemination. Our findings demonstrate that Th2 cell-predominant allergic responses followed by immune phenotype switching and fungal dissemination are highly predictable outcomes with progressive fungal infectious burdens and that T helper cell responses are protective against lethal fungal dissemination.

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