Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells

Lotz, Michael; Gütle, Dominique; Walther, Sabrina; Ménard, Sandrine; Bogdan, Christian; Hornef, Mathias

doi:10.1083/jcb1732oia3

Cited by 137 publications

(214 citation statements)

References 10 publications

(10 reference statements)

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“…The enterocytes' tolerance to luminal bacteria and bacterial products may be a unique and intrinsic feature of the intestinal epithelium: indeed, fetal enterocytes are highly responsive to LPS stimulation whereas neonatal and adult enterocytes become unresponsive due to enhanced IRAK-1 degradation. The intestine of newborn mice is colonized rapidly by bacteria following their passage through the birth canal, and it is this event that likely initiates the rapid establishment of intestinal tolerance toward the luminal contents (49). It is possible that germfree mice in a similar manner rapidly respond to bacterial colonization by inducing TLR/NF-B signaling but that the signal is down-regulated through activation of intrinsic negative feedback loops and extrinsic regulatory factors.…”

Section: Discussionmentioning

confidence: 99%

Gnotobiotic IL-10−/−;NF-κBEGFP Mice Reveal the Critical Role of TLR/NF-κB Signaling in Commensal Bacteria-Induced Colitis

Karrasch

Kim

Mühlbauer

et al. 2007

The Journal of Immunology

109

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Commensal bacteria and TLR signaling have been associated with the maintenance of intestinal homeostasis in dextran sodium sulfate-induced intestinal injury. The aim of this study was to determine the in vivo role of TLR/NF-κB activation in a model of commensal bacteria-induced T cell-mediated colitis. A NF-κB reporter gene mouse (NF-κBEGFP) (EGFP, enhanced GFP) was crossed to the colitogenic susceptible strain IL-10−/− and derived into germfree conditions using embryo-transfer technology. Germfree IL-10wt/wt;NF-κBEGFP and IL-10−/−;NF-κBEGFP mice (wt, wild type) were dual associated with the nonpathogenic commensal bacteria strains Enterococcus faecalis and Escherichia coli. EGFP was detected using macroimaging, confocal microscopy, and flow cytometry. IL-10−/−;MyD88−/− mice were used to assess E. faecalis/E. coli-induced TLR-dependent signaling and IL-23 gene expression. Dual-associated IL-10−/−;NF-κBEGFP mice developed severe inflammation by 7 wk. Macroscopic analysis showed elevated EGFP expression throughout the colon of bacteria-associated IL-10−/−;NF-κBEGFP mice. Confocal microscopy analysis revealed EGFP-positive enterocytes during the early phase of bacterial colonization (1 wk) in both IL-10wt/wt and IL-10−/− mice, while the signal shifted toward lamina propria T cells, dendritic cells, neutrophils, and macrophages in IL-10−/− mice during colitis (7 wk). The NF-κB inhibitor BAY 11-7085 attenuated E. faecalis/E. coli-induced EGFP expression and development of colitis. Additionally, E. faecalis/E. coli-induced NF-κB signaling and IL-23 gene expression were blocked in bone marrow-derived dendritic cells derived from IL-10−/−;MyD88−/− mice. We conclude that bacteria-induced experimental colitis involves the activation of TLR-induced NF-κB signaling derived mostly from mucosal immune cells. Blocking TLR-induced NF-κB activity may represent an attractive strategy to treat immune-mediated intestinal inflammation.

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Section: Discussionmentioning

confidence: 99%

Gnotobiotic IL-10−/−;NF-κBEGFP Mice Reveal the Critical Role of TLR/NF-κB Signaling in Commensal Bacteria-Induced Colitis

Karrasch

Kim

Mühlbauer

et al. 2007

The Journal of Immunology

109

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“…These hypotheses have now been tested to some extent for the gut where microbial encounter is permanent and strong [4,[10][11][12][13]. However, only limited information is available for the situation in the upper airways.…”

Section: Introductionmentioning

confidence: 99%

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

et al. 2008

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The upper airways are prone to contact with pathogenic as well as non-pathogenic microbes, therefore immune recognition principles have to be tightly controlled. Here we show that human BEAS-2B bronchial epithelial cells inhibited secretion of the proinflammatory cytokines TNF-a and IL-12 by monocytes, macrophages and dendritic cells. This inhibitory effect could be transferred by supernatant of resting BEAS-2B cells and was also observed when primary murine tracheal epithelial cells were prepared. In contrast to inhibition of pro-inflammatory cytokine secretion epithelial cell-conditioned dendritic cells showed increased expression of IL-10 and arginase-1, thus displaying properties of alternative activation. Accordingly, Toll-like receptor-mediated up-regulation of CD40, CD86 and PD-L2 (CD273) on murine dendritic cells was reduced in the presence of bronchial epithelial cell supernatant. However, expression of negative regulatory PD-L1 (CD274) was increased and dendritic cell induced proliferation of T lymphocytes was diminished. Epithelial cells also showed a direct inhibitory effect on T lymphocyte proliferation and this was due to the constitutive secretion of TGF-b by bronchial epithelial cells. Moreover, epithelial cell-conditioned T lymphocytes showed increased differentiation towards IL-10-producing Tr1 cells. The results indicate that bronchial epithelial cells induce a noninflammatory microenvironment that regulates local immune homeostasis.

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“…For instance, although fetal intestinal cells are known to be responsive to LPS, postnatal endotoxin hyporesponsiveness of enterocytes has been observed, and recently shown to be due to a decrease in the expression of the TLR4 signaling intermediate, IRAK1 (198).…”

Section: Peaceful Coexistence: Mechanisms Allowing Epithelial Cells Tmentioning

confidence: 99%

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

Gribar

Richardson

Sodhi

et al. 2008

Mol Med

142

109

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Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. It is well accepted that a breakdown of the normally impermeant epithelial barrier of the intestine, the lung, and the kidney is associated with the development of inflammatory disease in these organs, yet significant controversy exists as to how this breakdown actually occurs, and how such a breakdown may lead to inflammation. In this regard, much work has focused upon the role of the epithelium as an "innocent bystander," a target of a leukocyte-mediated inflammatory cascade that leads to its destruction in the mucosal inflammatory process. However, recent evidence from a variety of laboratories indicates that the epithelium is not merely a passive component in the steps that lead to mucosal inflammation, but is a central participant in the process. In addressing this controversy, we and others have determined that epithelial cells express Toll-like receptors (TLRs) of the innate immune system, and that activation of TLRs by endogenous and exogenous ligands may play a central role in determining the balance between a state of "mucosal homeostasis," as is required for optimal organ function, and "mucosal injury," leading to mucosal inflammation and barrier breakdown. In particular, activation of TLRs within intestinal epithelial cells leads to the development of cellular injury and impairment in mucosal repair in the pathogenesis of intestinal inflammation, while activation of TLRs in the lung and kidney may participate in the development of pneumonitis and nephritis respectively. Recent work in support of these concepts is extensively reviewed, while essential areas of further study that are required to determine the significance of epithelial TLR signaling during states of health and disease are outlined.

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Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells

Cited by 137 publications

References 10 publications

Gnotobiotic IL-10−/−;NF-κBEGFP Mice Reveal the Critical Role of TLR/NF-κB Signaling in Commensal Bacteria-Induced Colitis

Gnotobiotic IL-10−/−;NF-κBEGFP Mice Reveal the Critical Role of TLR/NF-κB Signaling in Commensal Bacteria-Induced Colitis

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

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