Dynamic Changes in Macrophage Activation

Macrophages (Mws) 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 Mws in some tissues can result from the proliferation of resident Mws in situ. However, little is known about the proliferation and activation state of Mw subsets in the gut during the development and resolution of intestinal inflammation. We show that inflammatory Mws accumulate in the large intestine of mice during the local inflammatory response to infection with the gastrointestinal nematode parasite Trichuris muris. Classically activated Mws predominate initially (as the inflammation develops) and then, following worm expulsion (as the inflammation resolves), both the resident and inflammatory populations of Mws become alternatively activated. A small but significant increase in the proliferation of inflammatory Mws is seen but only during the resolution phase of the inflammatory response following both worm expulsion and the peak in Mw accumulation. In contrast to recent studies in the pleural and peritoneal cavities, the proliferation of resident and alternatively activated Mws does not increase during the inflammatory response. Furthermore, in CCR2 2/2 mice, monocyte recruitment to the gut is impeded, and the accumulation of alternatively activated Mws is greatly reduced. In conclusion, the recruitment of blood monocytes is the principle mechanism of Mw accumulation in the large intestine. This study provides a novel insight into the phenotype and behavior of intestinal Mw during infection-driven inflammation. M acrophages (Mws) are mononuclear phagocytes of the innate immune system and are involved in host-defense, metabolism, and the homeostatic regulation of healthy tissues. Playing diverse and contrasting roles, Mws can initiate, amplify, and regulate the adaptive immune system and both drive and resolve inflammatory responses. The gut is the largest reservoir of Mws in the body (1), and intestinal Mws play a key role in driving the pathogenesis of inflammatory bowel disease (2). Mws can assume several functionally different states of activation that are regulated by the prevailing cytokine milieu and other factors that are present at sites of inflammation. Mws respond to IFN-g, with or without LPS, to become classically activated (3, 4). Classically activated Mws (M1s) play a vital role in Th1-mediated immunity against intracellular pathogens and are characterized by the expression of inducible NO synthetase (iNOS) (3, 4). In contrast, IL-4 and IL-13 …