THE CX3CR1+ LAMINA PROPRIA DENDRITIC CELL: MASTER SENTINEL OF THE TERMINAL ILEUM

Abstract

The CX3CR1+ lamina propria dendritic cell (LPDC) of the terminal ileum provides a unique sentinel role, critical for intestinal health. Here, we demonstrate that three Crohn's disease associated single nucleotide polymorphisms within the muramyl dipeptide receptor (MDP), NOD2, appear to alter the physical phenotype and transcriptome of the LPDC within the small intestine. Among the alterations described here, is a LPDC that is unable to extend its defining trans-epithelial dendrites (TEDs) into the lumen of the bowel despite (1) increased expression of the CX3CR1 receptor, (2) the presence of increased bacteria adherent to the mucosal wall and (3) the increased expression of the stress fractalkine, CX3CL1, all of which are directly associated with TED extension. In addition, the mRNA and protein expression profiles of the LPDC are also significantly distorted, including under-expression of genes within the TLR, ICAM and MIF families. There is also over expression of some inflammatory cytokines, such as IFN-ã and TNF-á, when comparing NOD2 mutants to wild types. Finally, the NOD2 mutation within the CX3CR1+ LPDC appears to depress Wnt5a expression both in vivo and in response to ex vivo MDP stimulation. In vivo observation of the Wnt5a/disheveled-2 axis showed reduced activation within the epithelium when in communication with the NOD2 mutant LPDC. However, once removed from the lamina propria compartment, the epithelium responded to Wnt5a stimulation by augmenting the transcription of Tcf4, a Paneth cell dependent transcription factor involved directly in the expression of human alpha defensin 5. We propose that Wnt5a participates in a novel homeostatic circuit involving the LPDC, epithelium, and Paneth cell and that a mutation in the NOD2 receptor within this LPDC alters its ability to communicate with its immunologic epithelial counterparts allowing for bacterial infiltration of the mucosal niche.