Monocyte Chemoattractant Protein-1 Contributes to Gut Homeostasis and Intestinal Inflammation by Composition of IL-10-Producing Regulatory Macrophage Subset

Lamina propria macrophages (LPM phi s) 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, LPM phi s produced large amounts of MCP-1, even in a steady state. MCP-1 deficiency caused impaired IL-10 production by LPM phi s and led to exacerbation of dextran sulfate sodium-induced acute colitis. As an explanation of this impaired IL-10 production by LPM phi s, we found that LPM phi s could be separated into two subsets with distinct side-scattered properties, namely LPM phi 1 (CD11b(+)F4/80(+)CD11c(-)SSC(hi)) and LPM phi 2 (CD11b(+)F4/80(+)CD11c(-)SSC(hi)). Unlike LPM phi 1, the LPM phi 2 subset migrated in response to MCP-1 and produced larger amount of IL-10 in response to commensal bacteria. LPM phi s isolated from MCP-1-deficient mice produced less IL-10 as consequence of the lack of the MCP-1-dependent LPM phi 2 population. This imbalanced composition in LPM phi 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 phi subsets in the intestine. Moreover, MCP-1-dependent LPM phi 2 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. The Journal of Immunology, 2010, 184: 2671-2676.