Monocyte Trafficking, Inflammation, and Atherosclerosis

Macrophages are central to the progression of atherosclerosis. An increased number of macrophages in plaque are associated with larger, more stenotic lesions. Furthermore, activated plaque macrophages promote rupture, the most significant clinical event affecting mortality. Plaque macrophages derive from monocytes that are recruited from blood. We have thus focused our efforts on understanding the mechanisms that regulate plaque macrophages, with emphasis on how macrophage-burden might be reduced to lower disease risk. We have developed techniques to discern whether macrophage contraction in plaques is due to emigration out of the plaque environment. Although this idea was our leading hypothesis, data obtained in a model of regression carried out in apoE^-/- mice indicates that emigration of macrophages does not occur during regression. The idea was based on previous literature that monocyte-derived cells might be removed from sites of acute inflammation by emigrating to local lymph nodes. After finding that emigration of macrophages from resolving plaque in apoE^-/- mice was poor, we revisited models of acute inflammation; in particular, thioglycollate-induced peritonitis, where emigration had been claimed to account for macrophage removal. New methodology to improve the quantification of macrophage loss from the peritoneum indicated that, like atherosclerosis, emigration of macrophages was a minor contributor to the contraction of macrophages associated with resolution. Instead, in both settings, macrophage loss was associated with a strong suppression of monocyte recruitment, coupled with ongoing macrophage apoptosis. These data strongly suggest that methods to block monocyte recruitment may provide a viable approach to reversing atherosclerosis. Current efforts focus on integrating the role of monocyte recruitment with local proliferation of macrophages in plaques, investigating macrophage motility in plaques during different disease states, and evaluating contraction of macrophages from plaques using other models of disease regression.