An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation.
Macrophages (Mphis) in the large intestine are crucial effectors of inflammatory bowel disease, but are also essential for homeostasis. It is unclear if these reflect separate populations of Ms or if resident Ms change during inflammation. In this study, we identify two subsets of colonic Ms in mice, whose proportions differ in healthy and inflamed intestine. Under resting conditions, most F4/80+ Ms are TLR- CCR2- CX3CR1hi and do not produce TNF-alpha 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+ CX3CR1int Ly6Chi Gr-1+, TNF-alpha-producing Ms come to dominate, and some of these are also present in the normal colon. The TLR2+ and TLR2- 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 proinflammatory 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-alpha-producing Ms. The balance between proinflammatory and resident Ms in the colon is controlled by CCR2-dependent recruitment mechanisms, which could prove useful as targets for therapy in inflammatory bowel disease.
Platt
Andrew M
AM
Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom.
Bain
Calum C
CC
Bordon
Yvonne
Y
Sester
David P
DP
Mowat
Allan McI
AM
D000818:Animals; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003092:Colitis / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D054390:Receptors, CCR2 / Q000096:biosynthesis / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000096:biosynthesis / Q000276:immunology*
C515335:Ccr2 protein, mouse; D016207:Cytokines; D012333:RNA, Messenger; D054390:Receptors, CCR2; D051193:Toll-Like Receptors