Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset.
Lamina propria macrophages (LPMs) spontaneously produce large amounts of anti-inflammatory IL-10 and play a central role in regulation of immune responses against commensal bacteria. MCP-1 is a chemokine that plays an important role in recruitment of monocytes and macrophages to inflamed tissues. We demonstrated that, in addition to IL-10, LPMs produced large amounts of MCP-1, even in a steady state. MCP-1 deficiency caused impaired IL-10 production by LPMs and led to exacerbation of dextran sulfate sodium-induced acute colitis. As an explanation of this impaired IL-10 production by LPMs, we found that LPMs could be separated into two subsets with distinct side-scattered properties, namely LPM1 (CD11b(+)F4/80(+)CD11c(-)SSC(hi)) and LPM2 (CD11b(+)F4/80(+)CD11c(-)SSC(lo)). Unlike LPM1, the LPM2 subset migrated in response to MCP-1 and produced a larger amount of IL-10 in response to commensal bacteria. LPMs isolated from MCP-1-deficient mice produced less IL-10 as a consequence of the lack of the MCP-1-dependent LPM2 population. This imbalanced composition in LPM population may be involved in the susceptibility to DSS-induced colitis in MCP-1-deficient mice. Our results suggest that endogenous MCP-1 contributes to the composition of resident LPM subsets in the intestine. Moreover, MCP-1-dependent LPM2 subset may play an important role in maintenance of gut homeostasis in the steady state, and in the termination of excess inflammatory responses in the intestine, by producing IL-10.
Takada
Yasuhiro
Y
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
Hisamatsu
Tadakazu
T
Kamada
Nobuhiko
N
Kitazume
Mina T
MT
Honda
Haruki
H
Oshima
Yosuke
Y
Saito
Riko
R
Takayama
Tetsuro
T
Kobayashi
Taku
T
Chinen
Hiroshi
H
Mikami
Yohei
Y
Kanai
Takanori
T
Okamoto
Susumu
S
Hibi
Toshifumi
T
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate; D013293:Enterococcus faecalis / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006706:Homeostasis; D007249:Inflammation / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000942:Antigens, Bacterial; D039481:CD11b Antigen; D018932:Chemokine CCL2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016264:Dextran Sulfate