Physiologic TLR9-CpG-DNA Interaction Is Essential for the Homeostasis of the Intestinal Immune System


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Abstract

Background:Cytosine-guanosine dinucleotide (CpG) motifs are immunostimulatory components of bacterial DNA and activators of innate immunity through Toll-like receptor 9 (TLR9). Administration of CpG oligodeoxynucleotides before the onset of experimental colitis prevents intestinal inflammation by enforcement of regulatory mechanisms. It was investigated whether physiologic CpG/TLR9 interactions are critical for the homeostasis of the intestinal immune system.Methods:Mesenteric lymph node cell and lamina propria mononuclear cell (LPMC) populations from BALB/c wild-type (wt) or TLR9−/− mice were assessed by flow cytometry and proteome profiling. Cytokine secretion was determined and nuclear extracts were analyzed for nuclear factor kappa B (NF-κB) and cAMP response-element binding protein activity. To assess the colitogenic potential of intestinal T cells, CD4+-enriched cells from LPMC of wt or TLR9−/− donor mice were injected intraperitoneally in recipient CB-17 SCID mice.Results:TLR9 deficiency was accompanied by slight changes in cellular composition and phosphorylation of signaling proteins of mesenteric lymph node cell and LPMC. LPMC from TLR9−/− mice displayed an increased proinflammatory phenotype compared with wt LPMC. NF-κB activity in cells from TLR9−/− mice was enhanced, whereas cAMP response-element binding activity was reduced compared with wt. Transfer of lamina propria CD4+-enriched T cells from TLR9−/− mice induced severe colitis, whereas wt lamina propria CD4+-enriched T cells displayed an attenuated phenotype.Conclusions:Lack of physiologic CpG/TLR9 interaction impairs the function of the intestinal immune system indicated by enhanced proinflammatory properties. Thus, physiologic CpG/TLR interaction is essential for homeostasis of the intestinal immune system as it is required for the induction of counterregulating anti-inflammatory mechanisms.

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