title: CX3CR1 regulates intestinal macrophage  homeostasis, bacterial translocation,  and colitogenic Th17 responses in mice.
abstract: The two most common forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, affect approximately 1 million people in the United States. Uncontrolled APC reactivity toward commensal bacteria is implicated in the pathogenesis of the disease. A number of functionally distinct APC populations exist in the mucosal lamina propria (LP) below the intestinal epithelium, but their relative contributions to inflammation remain unclear. Here, we demonstrate in mice important roles for the chemokine receptor CX3CR1 in maintaining LP macrophage populations, preventing translocation of commensal bacteria to mesenteric lymph nodes (mLNs), and limiting colitogenic Th17 responses. CX3CR1 was found to be expressed in resident LP macrophages (defined as CD11b(+)F4/80(+)) but not DCs (defined as CD11c(+)CD103(+)). LP macrophage frequency and number were decreased in two strains of CX3CR1-knockout mice and in mice deficient in the CX3CR1 ligand CX3CL1. All these knockout strains displayed markedly increased translocation of commensal bacteria to mLNs. Additionally, the severity of DSS-induced colitis was dramatically enhanced in the knockout mice as compared with controls. Disease severity could be limited by either administration of neutralizing IL-17A antibodies or transfer of CX3CR1-sufficient macrophages. Our data thus suggest key roles for the CX3CR1/CX3CL1 axis in the intestinal mucosa; further clarification of CX3CR1 function will likely direct efforts toward therapeutic intervention for mucosal inflammatory disorders such as IBD.
authors: Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
authors: Oscar
authors: O
authors: Medina-Contreras
authors: Duke
authors: D
authors: Geem
authors: Oskar
authors: O
authors: Laur
authors: Ifor R
authors: IR
authors: Williams
authors: Sergio A
authors: SA
authors: Lira
authors: Asma
authors: A
authors: Nusrat
authors: Charles A
authors: CA
authors: Parkos
authors: Timothy L
authors: TL
authors: Denning
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018988:Bacterial Translocation / Q000502:physiology*; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D003106:Colon / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000032:analysis; D006706:Homeostasis; D020381:Interleukin-17 / Q000502:physiology*; D007421:Intestine, Small / Q000382:microbiology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000145:classification / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000276:immunology; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015728:Receptors, HIV / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D000073883:CX3C Chemokine Receptor 1; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D018121:Receptors, Cytokine; D015728:Receptors, HIV