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

Hofmann, Claudia PhD*; Dunger, Nadja*; Doser, Kristina PhD; Lippert, Elisabeth MD*; Siller, Sebastian*; Edinger, Matthias MD; Falk, Werner PhD*; Obermeier, Florian MD*

doi: 10.1097/01.MIB.0000436276.19755.c1
Original Basic Science Articles

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.

Article first published online 15 November 2013

*Departments of Internal Medicine I, and

Internal Medicine III, Regensburg University Medical Center, Regensburg, Germany.

Reprints: Claudia Hofmann, PhD, Department of Internal Medicine I, University of Regensburg, 93042 Regensburg, Germany (e-mail: claudia.hofmann@klinik.uni-regensburg.de).

The authors have no conflicts of interest to disclose.

Supported by a DFG grant to F. Obermeier (OB 135/10-2).

Received September 24, 2013

Accepted September 24, 2013

© Crohn's & Colitis Foundation of America, Inc.
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