Abstract
BackgroundSensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants.Methodology/Principal FindingsBy mapping the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IκB kinase α/β (IKKα/β), the initial step in the nuclear factor κB (NFκB) pathway, whereas activation of mitogen-activated protein (MAP)-kinases was unaffected. MDP additionally stimulates the inflammasome which is of importance for processing of cytokines. The inflammasome was constitutively activated in CD, but unresponsive to MDP both in CD and control monocytes.Conclusions/SignificanceThese results suggest that inhibited MDP-dependent pathways in CD patients not carrying the disease-associated CARD15 variants might be of importance for the pathogenesis of CD. The results reveal a dysfunctional immune response in CD patients, not able to sense relevant stimuli on the one hand, and on the other hand possessing constitutively active cytokine processing.
Highlights
There is growing evidence of an impaired innate inflammatory response playing a key role in the pathogenesis of Crohn’s disease (CD) [1]
Effect of muramyl dipeptide (MDP) on Cytokine Expression Levels To determine whether CARD15 stimulation resulted in expression of typical nuclear factor kB (NFkB) dependent pro-inflammatory cytokines, the mRNA expression levels of tumour necrosis factor-a (TNF-a) and IL-1b were measured in monocytes from controls and from CD patients without disease linked CARD15 mutations
The dysfunctional response is in accordance with the increasing evidence of an impaired innate immune function in CD, and in particular monocytes isolated from CD patients [1,23,24]
Summary
There is growing evidence of an impaired innate inflammatory response playing a key role in the pathogenesis of Crohn’s disease (CD) [1]. Three common variants of the NLR gene caspase activation and recruitment domain 15 (CARD15, known as nucleotide binding and oligomerisation domain 2 (NOD2)) has been associated with CD: SNP 8, 12 and 13 [3,4]. Interaction between MDP and CARD15 leads to activation of the nuclear factor kB (NFkB) by binding of the adaptor protein RIP2 to CARD15 via caspase recruitment domains (CARDs) on both proteins [5,6]. Sensing of muramyl dipeptide (MDP) is impaired in Crohn’s disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. The aim of this study was to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants
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