Colonic Inflammation CCR2-Dependent Macrophages Promotes An Independent Subset of TLR Expressing Sester and Allan McI. Mowat

Macrophages (Mfs) in the large intestine are crucial effectors of inflammatory bowel disease, but are also essential for homeo-stasis. It is unclear if these reflect separate populations of Mfs or if resident Mfs change during inflammation. In this study, we identify two subsets of colonic Mfs in mice, whose proportions differ in healthy and inflamed intestine. Under resting conditions, most F4/80 + Mfs are TLR 2 CCR2 2 CX3CR1 hi and do not produce TNF-a in response to stimulation. The lack of TLR expression is stable, affects all TLRs, and is determined both transcriptionally and posttranscriptionally. During experimental colitis, TLR2 + CCR2 + CX3CR1 int Ly6C hi Gr-1 + , TNF-a–producing Mfs come to dominate, and some of these are also present in the normal colon. The TLR2 + and TLR2 2 subsets are phenotypically distinct and have different turnover kinetics in vivo, and these properties are not influenced by the presence of inflammation. There is preferential CCR2-dependent recruitment of the proin-flammatory population during colitis, suggesting they are derived from independent myeloid precursors. CCR2 knockout mice show reduced susceptibility to colitis and lack the recruitment of TLR2 + CCR2 + Gr-1 + , TNF-a–producing Mfs. The balance between proinflammatory and resident Mfs in the colon is controlled by CCR2-dependent recruitment mechanisms, which could prove useful as targets for therapy in inflammatory bowel disease. T he two main forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, are chronic, relapsing inflammatory disorders that remain difficult to manage despite recent therapeutic advances such as anti–TNF-a (1). Therefore, it is important to understand the mechanisms of tissue damage, the cells involved, and the processes of cellular infiltration and inflammation. Macrophage (Mf) infiltration and activation are central features of IBD, participating in a chronic inflammatory response driven by recognition of commensal microbiota by proinflammatory CD4 + T cells (2). The subsequent production of TNF-a and other mediators by the activated Mf plays a crucial role in the tissue damage (3, 4), and these are important targets for therapy. If it could be shown that a distinct population of Mfs is responsible for these inflammatory effects, targeting these cells could prove an even more direct and effective means of disease modification. Mfs are also abundant in the normal intestine, especially the colon, where they sit in close proximity to the enormous population of commensal microbiota. Despite the resulting potential for Mf activation, inflammation …