Schematic illustration of the fate of aged neutrophils in homeostasis and inflammation. In the steady state, nonaged neutrophils are released from the bone marrow into the circulation before these immune cells age during intravascular margination in peripheral organs. Ultimately, aged neutrophils are cleared in bone marrow, liver, and spleen (via SDF-1α/CXCL12 and CXCR4). Upon onset of inflammation, however, aged neutrophils cease returning to the bone marrow and immediately infiltrate inflamed tissues in a TLR-4- and Mac-1/CD11b-dependent manner, thereby being in the first line of defense in the acute inflammatory response.