In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes

Abstract

The resolution of acute inflammation requires bulk clearance of extravasated inflammatory cells in an ordered manner. Neutrophils undergo apoptosis and are ingested by macrophages (M psi) via a novel recognition mechanism that fails to provoke proinflammatory responses. Thereafter, the fate of inflammatory M psi themselves remains unclear. We investigated this in vivo, developing a semiallogeneic adoptive transfer system to track the fate of inflammatory M psi in a murine model of resolving peritonitis. Fluorescently labeled M psi from H-2k/d mice were transferred into the peritoneal cavity of H-2k mice at the same stage of resolving inflammation as the donor mice. Dual color flow cytometry permitted discrimination among donor cells, recipient cells, and donor cells that had been phagocytosed by recipient M psi. Despite the absence of significant local phagocytosis, the number of transferred M psi free in the peritoneum of recipient mice declined rapidly, being undetectable by 96 h. These data suggest that inflammatory M psi normally emigrate rapidly from the peritoneal cavity during the resolution of inflammation, contrasting with resident M psi, which persist in the noninflamed peritoneum for weeks. Accordingly, labeled nonphagocytosed cells were detected in the draining lymph nodes, but not in a variety of other tissues. Thus, unlike the polymorphonuclear leukocyte, which dies by apoptosis and is ingested by M psi, the inflammatory M psi itself does not die locally. Having performed its acute inflammatory and scavenging roles, it emigrates in a nonrandom fashion to the draining lymph node, where it may play an important part in the presentation of Ags from the inflamed site.