This information is current as Mice Deficient − acrophages and Colitis in IL-10 2 Signaling Promotes Hyperresponsive M Nucleotide-Binding Oligomerization Domain Parkinson and

IL-10 contributes to the maintenance of intestinal homeostasis via the regulation of inflammatory responses to enteric bacteria. Loss of IL-10 signaling results in spontaneous colitis in mice and early onset enterocolitis in humans. Nucleotide-binding oligomerization domain (NOD) 2 is an intracellular receptor of bacterial peptidoglycan products, and, although NOD2 mutations are associated with Crohn's disease, the precise role of NOD2 in the development of intestinal inflammation remains undefined. To determine the role of NOD2 in the development of colitis on the clinically relevant genetic background of IL-10–deficient signaling, we generated mice lacking IL-10 and NOD2 (IL-10 2/2 NOD2 2/2). Loss of NOD2 in IL-10 2/2 mice resulted in significant amelioration of chronic colitis, indicating that NOD2 signaling promotes the development of intestinal inflammation in IL-10 2/2 mice. Contrary to previous reports investigating immune function in NOD2 2/2 mice, T cell proliferative capacity and IL-2 production were not impaired, and immune polarization toward type 1 immunity was not affected. However, loss of NOD2 in IL-10–deficient macro-phages reduced IL-6, TNF-a, and IL-12p40 production in response to bacterial stimulation. Further analysis of the intrinsic macrophage response before the onset of inflammation revealed that, in the absence of IL-10, synergistic signaling between various TLRs and NOD2 resulted in hyperresponsive, proinflammatory macrophages, thus providing the appropriate immune environment for the development of colitis. Data presented in this study demonstrate that NOD2 signaling contributes to intestinal inflammation that arises through loss of IL-10 and provides mechanistic insight into the development of colitis in inflammatory bowel disease patients with impaired IL-10 signaling. I nflammatory bowel disease (IBD) is a relapsing remitting disease of the intestinal tract that encompasses two clinically defined forms, ulcerative colitis (UC) and Crohn's disease (CD). The condition is heterogeneous in nature, and the exact causes are as yet unknown. However, one widely accepted theory is that IBD arises due to inappropriate responses to commensal bacteria in genetically susceptible hosts (1). Nucleotide-binding oligomerization domain (NOD) 2 belongs to a family of NOD-like receptors that function as intracellular pattern recognition receptors (PRR), sensing bacterial products and contributing to innate immunity (2). NOD2 was originally described as an intracellular receptor for muramyl dipeptide (MDP), a conserved motif present in peptidoglycan from Gram-positive and Gram-negative bacteria (3). Detection of MDP by NOD2 results in the potentiation of the innate inflammatory response to various TLR agonists, resulting in enhanced proinflammatory cytokine production from murine and human cells (4–11). …