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TNF? promotes mucosal wound repair through enhanced platelet activating factor receptor signaling in the epithelium.

ABSTRACT: Pathobiology of several chronic inflammatory disorders, including ulcerative colitis and Crohn's disease is related to intermittent, spontaneous injury/ulceration of mucosal surfaces. Disease morbidity has been associated with pathologic release of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF?). In this report, we show that TNF? promotes intestinal mucosal repair through upregulation of the GPCR platelet activating factor receptor (PAFR) in the intestinal epithelium. Platelet activating factor (PAF) was increased in healing mucosal wounds and its engagement with epithelial PAFR leads to activation of epidermal growth factor receptor, Src and Rac1 signaling to promote wound closure. Consistent with these findings, delayed colonic mucosal repair was observed after administration of a neutralizing TNF? antibody and in mice lacking PAFR. These findings suggest that in the injured mucosa, the pro-inflammatory milieu containing TNF? and PAF sets the stage for reparative events mediated by PAFR signaling.

SUBMITTER: Birkl D

PROVIDER: S-EPMC6599476 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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TNFα promotes mucosal wound repair through enhanced platelet activating factor receptor signaling in the epithelium.

Birkl Dorothee D Quiros Miguel M García-Hernández Vicky V Zhou Dennis W DW Brazil Jennifer C JC Hilgarth Roland R Keeney Justin J Yulis Mark M Bruewer Matthias M García Andrés J AJ O Leary Monique N MN Parkos Charles A CA Nusrat Asma A

Mucosal immunology 20190410 4

Pathobiology of several chronic inflammatory disorders, including ulcerative colitis and Crohn's disease is related to intermittent, spontaneous injury/ulceration of mucosal surfaces. Disease morbidity has been associated with pathologic release of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). In this report, we show that TNFα promotes intestinal mucosal repair through upregulation of the GPCR platelet activating factor receptor (PAFR) in the intestinal epithelium. Platelet a ...[more]

PMID: 30971752

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Project description:This data series contains spotted oligo microarray data from 10 different experiments using Agilent Rat v2 microarrays. This data is being made public in support of Fillon S et al. Journal of Immunology, (2006). Proinflammatory bacterial components are at least partially responsible for causing the clinical features of sepsis, a syndrome that causes >100,000 deaths each year in the US (1). In the case of Gram positive infection, a key bacterial element recognized by the innate immune system is the cell wall, a complex network of peptidoglycan covalently linked to teichoic acids, proteins and lipoproteins. The current model of innate immune recognition of Gram positive bacteria suggests bacterial cell wall interacts with host recognition proteins, such as toll-like receptors (TLR) and Nod proteins. We describe an additional recognition system mediated by the platelet activating factor receptor (PAFr) and directed to the pathogen associated molecular pattern (PAMP) phosphorylcholine that results in uptake of bacterial components into host cells. Intravascular choline-containing cell walls bound to endothelial cells and caused rapid lethality in wild type, Tlr2-/- and Nod2-/- mice, but not in Pafr-/- mice. Cell wall exited the vasculature into the heart and brain, accumulating within endothelial cells, cardiomyocytes and neurons in a PAFr-dependent way. Physiological consequences of the cell wall/PAFr interaction were cell specific, being noninflammatory in endothelial cells and neurons, but causing rapid loss of cardiomyocyte contractility that contributed to death. Thus, PAFr shepherds phosphorylcholine-containing bacterial components such as cell wall into host cells from where the response ranges from quiescence to severe pathophysiology. Keywords: Competitive hybridizations The ten experiments in this series comprise of four distinct experiments, two of which were performed as biological triplicates and two as biological duplicates. The table below describes the overall design in detail: File Name Experiment 16011868017643v41_GEO_format.txt RBCEC Replicate 1 16011868017644v41_GEO_format.txt RBCEC Replicate 2 251186821865v41_GEO_format.txt Neuron Replicate 1 16011868021377v41_GEO_format.txt Neuron Replicate 2 251186821690v41_GEO_format.txt CW/Lyt44 Replicate 1 251186821691v41_GEO_format.txt CW/Lyt44 Replicate 2 251186821692v41_GEO_format.txt CW/Lyt44 Replicate 1 251186821693v41_GEO_format.txt CW+TNF/Lyt44+TNF Replicate 1 251186821694v41_GEO_format.txt CW+TNF/Lyt44+TNF Replicate 2 251186829677v41_GEO_format.txt CW+TNF/Lyt44+TNF Replicate 3

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TNF? promotes mucosal wound repair through enhanced platelet activating factor receptor signaling in the epithelium.

Publications

TNFα promotes mucosal wound repair through enhanced platelet activating factor receptor signaling in the epithelium.

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