Local apoptosis mediates clearance of macrophages from resolving inflammation in mice

Abstract

Key Points• Macrophage migration to lymph nodes during acute inflammation is quantitatively minor.• Macrophages are cleared from acute inflammation by local death.Chronic inflammatory diseases such as atherosclerosis are characterized by an accumulation of macrophages. To design therapies that would reduce macrophage burden during disease, understanding the cellular and molecular mechanisms that regulate macrophage removal from sites of resolving inflammation is critical. Although past studies have considered the local death of macrophages or the possibility that they emigrate out of inflammatory foci, methods to quantify death or emigration have never been employed.Here, we applied quantitative competition approaches and other methods to study resolution of thioglycollate-induced peritonitis, the model in which earlier work indicated that emigration to lymph nodes accounted for macrophage removal. We show that migration to lymph nodes occurred in a CC chemokine receptor 7-independent manner but, overall, had a quantitatively minor role in the removal of macrophages. Blocking migration did not significantly delay resolution. However, when macrophages resistant to death were competed against control macrophages, contraction of the macrophage pool was delayed in the apoptosis-resistant cells. These data refute the concept that macrophages are dominantly cleared through emigration and indicate that local death controls macrophage removal. This finding alters the emphasis on which cellular processes merit targeting in chronic diseases associated with accumulation of macrophages. (Blood. 2013;122(15):2714-2722

Specific Contributions of CSF-1 and GM-CSF to the Dynamics of the Mononuclear Phagocyte System

“…The same phenotyping strategy as earlier indicated that at day 4 the PECs were mainly CD115 hi inflammatory macrophages and CD115 int SSc hi eosinophils (Supplemental Fig. 4A) with only a few neutrophils (data not shown) (45). As in Gautier et al (45), and unlike the AIP CD11c 2 MHCII + macrophages (Fig.…”

“…4A) with only a few neutrophils (data not shown) (45). As in Gautier et al (45), and unlike the AIP CD11c 2 MHCII + macrophages (Fig. 3A), the thioglycolate-elicited macrophages were mainly CD11c 2 MHCII 2 (Supplemental Fig.…”

“…4A). Even given the CD11c expression in a small proportion of CD115 + cells, a macrophage phenotype in this model has been supported by transcriptomic analysis (45 Fig. 4A).…”

“…In support of this proposal, resident tissue macrophages have been proposed to participate in the initiation of an inflammatory reaction via their ability to sense and produce proinflammatory cytokines and chemokines (76), and the depletion of perivascular macrophages impairs the recruitment of blood-derived inflammatory cells in a Staphylococcus aureus skin infection model (77). Alternatively, CSF-1 neutralization during an inflammatory reaction, as suggested earlier for the unstimulated peritoneal cavity, may lead to enhanced inflammatory The Journal of Immunologymacrophage apoptosis and/or migration out of the inflamed cavity leading to a faster resolution of the reaction; both mechanisms formulated for macrophages during the normal resolution of thioglycolate-induced peritonitis (45,78).…”

Mouse Macrophages Completely Lacking Rho Subfamily GTPases (RhoA, RhoB, and RhoC) Have Severe Lamellipodial Retraction Defects, but Robust Chemotactic Navigation and Altered Motility

“…This finding indicates that the Rho subfamily is not required for monocytes to egress through a continuous endothelium, at least in the peritoneum. Gautier et al (48) showed that the clearance of macrophages from thioglycollate-induced peritonitis is mediated principally via macrophage apoptosis rather than emigration to lymph nodes, as previously thought (49). Thus, we would expect that the clearance of macrophages during the resolution phase of peritoneal inflammation, in which emigration to draining lymph nodes plays a minor role, would not be significantly affected in myeloid-restricted RhoA/RhoB dKO mice.…”