Abstract 526: Macrophage Clearance from Resolving Inflammation Depends on Apoptosis Rather than Migration to Lymph Nodes
Resolution of acute inflammation is a key step in the return to homeostasis after initiation of tissue injury, and its failure ultimately leads to a state of chronic inflammation known to favor the initiation and/or the progression of numerous diseases such as atherosclerosis. However, the cellular mechanisms governing inflammatory macrophages (iMf) clearance during the process of resolution are not completely understood. To better investigate iMf clearance in acute inflammation, we for the first time compared the importance of emigration through lymphatics to that of local death using a classical model of acute resolving peritonitis induced by thioglycollate. Of note, Ly-6Chi monocyte-derived iMf that accumulated in the peritoneum became CD11c+ cells, but gene expression profiling revealed these cells as macrophages, not dendritic cells. Although these iMf migrate to draining lymph nodes, this appeared in a kinetic and a quantity that doesn’t fit with the onset and extend of macrophage contraction during resolution. We found that migration out of the peritoneal cavity surprisingly did not rely on CCR7 but was partially dependent on CCR2. Moreover, blocking migration using a Gαi signaling inhibitors (that block all chemokine-dependent migrations and others) minimally impact on iMf clearance. By contrast, competition assays between WT and CD68-Bcl2 transgenic or Bim-/- iMf revealed that macrophage protected from apoptosis were much less susceptible to be cleared from the cavity during resolution. Thus, we conclude that in a model previously claimed to remove macrophages via emigration, local death of macrophages is quantitatively the main mode of clearance. As we recently reported that iMf removal from regressing atherosclerotic plaques is an emigration-independent process, we are now completing experiments to study the role of apoptosis in this phenomenon. Overall, removal by local death and control of new recruitment may be universally dominant mechanisms for macrophage clearance.
- © 2012 by American Heart Association, Inc.