Nucleotide-binding oligomerization domain 2 (NOD2) belongs to the family of intracellular NOD-like receptors, which are present in various cell types (Bertin et al., 1999
; Inohara et al., 2001
). NOD2 has a C-terminal leucine-rich repeat region for sensing microbial products, a central nucleotide-binding domain (NACHT), and an N-terminal CARD (caspase activation and recruitment domain). NOD2 detects muramyl dipeptide (MDP), a molecule which is produced during the synthesis and degradation of peptidoglycan, a cell wall component of most bacteria (Inohara and Nunez, 2003
). Stimulation of NOD2 induces recruitment of Rip2 (also called RICK) at the N-terminal CARD domain. Activation of Rip2 leads to subsequent steps that ultimately result in activation and nuclear translocation of NF-κB and transcription of its target genes.
NOD2 has been studied in human Crohn's disease and in mouse models for inflammatory bowel disease. Single nucleotide polymorphisms (SNPs) near, or within, the NOD2 leucine-rich repeat region (G908R, L1007insC, and R702W) constitute genetic risk factors for the development of Crohn's disease (Hugot et al., 2001
; Ogura et al., 2001
). Mutations in the NACHT region of NOD2 are linked to other inflammatory diseases such as Blau syndrome (Miceli-Richard et al., 2001
) and early onset sarcoidosis (Kanazawa et al., 2005
). Several groups have investigated the role of NOD2 in experimental models for intestinal inflammation, which has led to the development of three hypotheses regarding the function of NOD2. Kobayashi et al. (2005)
found greater susceptibility to enteral infection with Listeria monocytogenes
and reduced expression of α defensins, antibacterial peptides produced by intestinal Paneth cells, in NOD2−/−
mice. Watanabe et al. (2004
) demonstrated increased sensitivity to experimental colitis in NOD2−/−
mice, which was driven by T helper type 1 cells and increased IL-12 release. Maeda et al. (2005)
created a knockout/knockin transgenic NOD2 mouse using the mouse equivalent to a human mutation (L1007insC) and found abundant IL-1β production in response to MDP. Collectively, these experimental data do not allow for one unified conclusion regarding the mechanism of NOD2-mediated regulation of inflammatory diseases.
Recently, SNPs in the NOD2 gene locus have been linked to graft-versus-host disease (GVHD), which is the major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). GVHD is a systemic inflammatory disease caused by alloreactive donor T cells and characterized by tissue damage in gut, liver, and skin. Holler et al. (2004
) found an association between SNPs (alleles 8, 12, and 13) of the NOD2 gene in the donor or host and a higher incidence of GVHD, as well as increased transplant-related mortality. Interestingly, these findings were only partially confirmed by Elmaagacli et al. (2006)
, who also found an increased incidence of GVHD when NOD2 SNPs were present in both the donor and recipient but reduced incidence of GVHD when the NOD2 SNPs were present in the donor only. In addition, Mayor et al. (2007)
connected NOD2 SNPs with an increased leukemia relapse rate after allo-HSCT, which could not be confirmed by other investigators (Holler et al., 2008
). Collectively, it appears that NOD2 SNPs of allo-HSCT recipients influence posttransplant immunity; however, the underlying mechanism is unclear. In the present study, we aim to clarify the underlying role of NOD2 in mouse models for allogenic BM transplantation (allo-BMT), colitis, and tumors.