Response to injury or infection involves a proinflammatory phase and an antiinflammatory or resolution phase. Ariel et al. used mice deficient for the chemokine receptor CCR5, which binds chemokines CCL3, CCL4, and CCL5, to show that CCR5 contributes to the clearance of these chemokines during mouse peritonitis. Peritoneal exudates from ccr5−/− mice with peritonitis had higher concentrations of CCL3 and CCL5 and exhibited decreased abundance of polymorphonuclear neutrophils (PMNs) and an increased percentage of macrophage-PMN conjugates than did exudates from wild-type mice with peritonitis. Cultured human PMNs spontaneously undergo apoptosis in the absence of added survival factors, and late apoptotic cells exhibited increased CCR5 abundance at the cell surface compared with freshly isolated cells; this increase was blocked by caspase inhibitors that also blocked apoptosis. Exposure of the cells to lipid mediators that contribute to inflammation resolution also stimulated CCR5 abundance at the cell surface without altering the percentage of apoptotic cells, suggesting that these lipids stimulate trafficking of CCR5 to the surface of apoptotic cells. T cells are also cleared by macrophages and, using either isolated human T cells or Jurkat T cell lines, the authors showed that stimuli that trigger apoptosis also increased the percentage of cells on which CCR5 could be detected. However, this increase was noted only for cells in the late stages of apoptosis, not live cells or cells in the early stages of apoptosis, in which abundance of CCR5 was low. The up-regulated CCR5 appeared to have a higher affinity for CCL4 than that of CCR5 on live cells, and CCL4 appeared to bind in clusters on the surface of the apoptotic cells. The increase in CCR5 at the surface of the T cells was also blocked by caspase inhibition, suggesting that the apoptotic cascade contributes to this process. The authors propose that PMNs and T cells initially attracted to the site of inflammation by chemokines eventually undergo apoptosis, resulting in increased cell surface CCR5, which binds the inflammatory chemokines. As these apoptotic cells are engulfed by the macrophages, the inflammatory chemokines are removed from the site of injury, allowing healing to occur.
A. Ariel, G. Fredman, Y.-P. Sun, A. Kantarci, T. E. Van Dyke, A. D. Luster, C. N. Serhan, Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression. Nat. Immunol. 7, 1209-1216 (2006). [PubMed]