MDP-Induced selective tolerance to TLR4 ligands: impairment in NOD2 mutant Crohn's disease patients
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Published on: April 21, 2015
Elisabet Cantó1, Esther Moga, Elena Ricart
1Department of Immunology, Institut Rec & Hospital Sant Pau, Barcelona, Spain.
Background:
Pathogen infection is a complex process in which several pathogen-recognition receptor (PRR) pathways are activated to induce proinflammatory mediators. The activation of multiple PRRs suggests an interaction between Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptor (NOD) signaling pathways.
Methods:
To understand the modulation induced by NOD2 signals on successive responses to pathogen-associated molecular patterns (PAMPs), we examined how muramyl dipeptide (MDP) pretreatment reprograms the MDP+LPS (lipopolysaccharide) response of monocytes from human peripheral blood.
Results:
Preexposure to bacterial MDP components induced selective tolerance to a subsequent NOD2+TLR4 stimulation. MDP pretreatment inhibited the production of tumor necrosis factor alpha (TNFalpha) and interleuken 10 (IL10), whereas IL6 and IL8 remained unaffected. MDP-induced tolerance was independent of receptor downregulation but was associated with reduced levels of phosphorylated TAK1 and abrogated phosphorylation of the downstream MAPK.Since Nod2 mutations have been associated with susceptibility to develop Crohn's disease (CD), we compared the MDP-induced tolerance in healthy donors and CD patients with compound heterozygous Nod2 mutations (Mut-Nod2) expressing variant NOD2 proteins. MDP-induced tolerance in Mut-Nod2 patients reduced IL10 but not TNFalpha production. In contrast with healthy donors, a p38-independent TNFalpha production was observed during the kinetics of the MDP+LPS response in Mut-Nod2 patients.
Conclusions:
Our findings suggest that the selective tolerance induced by MDP in healthy donors was related to the modulation of a convergent nub of NOD2 and TLR4 signaling pathways. This MDP-induced tolerance was impaired in Mut-Nod2 CD patients, resulting in a p38-independent TNFalpha production and an imbalance between pro- and antiinflammatory cytokines that could be partly responsible for the pathogenesis of CD.
Insights
Bacterial muramyl dipeptide (MDP) pretreatment induces selective tolerance to subsequent pathogen stimulation in healthy individuals. This tolerance is impaired in Crohn's disease patients with NOD2 mutations, affecting cytokine production and potentially contributing to disease pathogenesis.
Area of Science:
- Immunology
- Molecular Biology
- Gastroenterology
Background:
- Pathogen infection activates multiple pathogen-recognition receptor (PRR) pathways, including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NODs).
- Interactions between TLR and NOD signaling pathways are crucial in innate immune responses to pathogens.
Purpose of the Study:
- To investigate how NOD2 signaling modulates subsequent responses to pathogen-associated molecular patterns (PAMPs).
- To examine the reprogramming of monocyte responses to muramyl dipeptide (MDP) and lipopolysaccharide (LPS) following MDP pretreatment.
Main Methods:
- Monocytes from healthy donors and Crohn's disease (CD) patients with NOD2 mutations were pretreated with MDP.
- Subsequent responses to MDP+LPS stimulation were analyzed, focusing on cytokine production (TNFα, IL-6, IL-8, IL-10) and signaling pathway activation (MAPK, TAK1).
Main Results:
- MDP pretreatment induced selective tolerance to subsequent NOD2+TLR4 stimulation in healthy donors, inhibiting TNFα and IL-10 production.
- This tolerance was linked to reduced phosphorylated TAK1 and abrogated MAPK phosphorylation, independent of receptor downregulation.
- In CD patients with NOD2 mutations (Mut-Nod2), MDP-induced tolerance was impaired, with reduced IL-10 but unaffected TNFα production. A p38-independent TNFα production pathway was observed in Mut-Nod2 patients.
Conclusions:
- Selective tolerance induced by MDP in healthy individuals involves modulation of convergent NOD2 and TLR4 signaling pathways.
- Impaired MDP-induced tolerance in Mut-Nod2 CD patients leads to altered cytokine profiles and potentially contributes to CD pathogenesis.
- The findings highlight a link between NOD2 signaling, immune tolerance, and the inflammatory processes in Crohn's disease.
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