Dynamic Changes in Macrophage Activation and Proliferation during the Development and Resolution of Intestinal Inflammation

Macrophages (M phi s) accumulate at sites of inflammation, and, because they can assume several functionally distinct states of activation, they can either drive or restrain inflammatory responses. Once believed to depend on the recruitment of blood monocytes, it is now clear that the accumulation of M phi s in some tissues can result from the proliferation of resident M phi s in situ. However, little is known about the proliferation and activation state of M phi subsets in the gut during the development and resolution of intestinal inflammation. We show that inflammatory M phi s accumulate in the large intestine of mice during the local inflammatory response to infection with the gastrointestinal nematode parasite Trichuris muris. Classically activated M phi s predominate initially (as the inflammation develops) and then, following worm expulsion (as the inflammation resolves), both the resident and inflammatory populations of M phi s become alternatively activated. A small but significant increase in the proliferation of inflammatory M phi s is seen but only during the resolution phase of the inflammatory response following both worm expulsion and the peak in M phi accumulation. In contrast to recent studies in the pleural and peritoneal cavities, the proliferation of resident and alternatively activated M phi s does not increase during the inflammatory response. Furthermore, in CCR2(-/-) mice, monocyte recruitment to the gut is impeded, and the accumulation of alternatively activated M phi s is greatly reduced. In conclusion, the recruitment of blood monocytes is the principle mechanism of M phi accumulation in the large intestine. This study provides a novel insight into the phenotype and behavior of intestinal M phi during infection-driven inflammation.