Chapter 9 : Pathogen-Initiated Inflammatory Response in Intestinal Epithelial Cells: Cross Talk with Neutrophils

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This chapter considers the interactions of bacteria and their metabolites with the intestinal epithelium, how neutrophil-mediated inflammation results, and how perturbing microbes are cleared and homeostasis is restored. The chapter limits its focus to bacterially mediated pathways of activation. In contrast to most other cell types, intestinal epithelial cells are relatively unresponsive, in terms of proinflammatory gene expression, to large quantities of commensal bacteria and their products. Using molecular, pharmacologic, and biochemical approaches, the authors have characterized the intestinal adenosine receptor to be of the A2b subtype in both model intestinal epithelial cells and native intestinal epithelium. They have recently shown that adenosine, acting via the activation of the A2b receptor, causes substantial and polarized IL-6 secretion into the luminal compartment of intestinal epithelial cells. In addition to its effect on intestinal epithelial cells, adenosine has also been shown to interact with neutrophil adenosine receptors to downregulate neutrophil activation, adherence, and neutrophil-mediated inflammation in endothelial cells. Furthermore, recent studies have demonstrated that lipoxins not only block activation of proinflammatory pathways but also actively aid in the resolution of inflammation by stimulating nonphlogistic phagocytosis of apoptotic neutrophils by macrophages. Further knowledge of the basic mechanisms that regulate the activation of this and other proinflammatory transcription factors will be essential for improved understanding and subsequent pharmacological manipulation of intestinal inflammation.

Citation: Gewirtz A, Sitaraman S, Merlin D, Madara J. 2003. Pathogen-Initiated Inflammatory Response in Intestinal Epithelial Cells: Cross Talk with Neutrophils, p 141-154. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch9

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Bacterial Proteins
Type III Secretion System
Innate Immune System
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Image of FIGURE 1

Mechanism of Salmonella-induced active intestinal inflammation. Serovar Typhimurium colonization of model epithelia results in translocation of the microbes' flagellin across the epithelium. Such flagellin can activate, via a Ca2+-dependent pathway, the transcription factor NF-B. This will result in an influx of polymorphonuclear leukocytes and their subsequent pathogen-elicited epithelial chemoattractant (PEEC)-driven migration across the epithelium, resulting in a crypt abscess. While such neutrophils clear the infection, they are also responsible for the clinical manifestations of pathogen-induced gastroenteritis.

Citation: Gewirtz A, Sitaraman S, Merlin D, Madara J. 2003. Pathogen-Initiated Inflammatory Response in Intestinal Epithelial Cells: Cross Talk with Neutrophils, p 141-154. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch9
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Image of FIGURE 2

Molecular mechanism of neutrophil-elicited epithelial chloride secretion. Lumenal neutrophils secrete 5'-AMP, which is converted to adenosine by an apical ectonucleotidase. Such adenosine activates the A2B receptor, leading to apical chloride secretion that provides the driving force for secretory diarrhea.

Citation: Gewirtz A, Sitaraman S, Merlin D, Madara J. 2003. Pathogen-Initiated Inflammatory Response in Intestinal Epithelial Cells: Cross Talk with Neutrophils, p 141-154. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch9
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Image of FIGURE 3

Neutrophil-epithelial positive feedback loop. Neutrophil-derived adenosine elicits epithelial secretion of IL-6, which will activate lumenal neutrophils to secrete oxidants and other antibacterial products.

Citation: Gewirtz A, Sitaraman S, Merlin D, Madara J. 2003. Pathogen-Initiated Inflammatory Response in Intestinal Epithelial Cells: Cross Talk with Neutrophils, p 141-154. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch9
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