IntroductionAcute inflammation is the host response to tissue injury or infection that is characterized by the production of inflammatory mediators, culminating in the initial but transient recruitment of polymorphonuclear leukocytes (PMNs) that is followed by a prolonged macrophage accumulation. 1 However, the underlying, multifactorial mechanisms that shape the extent and kinetics of PMN and macrophage recruitment, apoptosis, and clearance remain unclear. Chemokines are an important class of chemoattractant cytokines produced locally in tissues that provide the directional cues for the movement of blood-derived leukocytes in development, homeostasis, and inflammation. 2 These potent chemoattractants are classified according to the position and spacing of their N-terminal cysteine residues, with 46 human chemokines currently divided into 4 families: C, CC, CXC, and CX 3 C. 3 The initial phase of inflammation involves a subset of CXC chemokines, which rapidly attract PMNs. 4 These PMN chemoattractants contain a conserved Glu-Leu-Arg (ELR) motif proximal to the CXC sequence, which is critical in cognate receptor binding and activation, 5 as well as PMN chemotaxis. 6 In humans, there are 7 ELR ϩ CXC chemokines: CXCL1, -2, and -3, also known as growth-related oncogenes ␣, , and ␥, respectively; CXCL5/epithelial cell-derived neutrophil activating peptide-78 (ENA-78); CXCL6/granulocyte chemotactic protein-2 (GCP-2); CXCL7/neutrophil-activating peptide-2 (NAP-2); and CXCL8/interleukin-8 (IL-8).All bind the CXC-receptor (CXCR) 1; CXCL6 and -8 also signal through CXCR2. 7 Mice lack complete homologs of the 7 human ELR ϩ chemokines, having only 4: mCXCL1/ keratinocyte-derived chemokine (KC); mCXCL2/macrophage-inflammatory protein-2 (MIP-2); the more recently described mCXCL3/ dendritic cell inflammatory protein-1 (DCIP-1) 8 ; and mCXCL5/ lipopolysaccharide (LPS)-induced CXC chemokine (LIX). 9 All bind a single receptor that is homologous to human CXCR2. 10 After the initial PMN influx, the next stage of inflammation is directed in part by CC chemokines consisting of CCL2/monocyte chemoattractant protein (MCP)-1, CCL7/MCP-3, CCL8/MCP-2, and CCL13/MCP-4, which target multiple leukocyte subsets (monocytes, T lymphocytes, basophils, and eosinophils). 11 Monocytes can differentiate into macrophages whose role is to phagocytose and degrade microorganisms and foreign material and to present these antigens to initiate specific immune responses. In addition, macrophages ingest apoptotic PMNs from the inflamed site as a prelude to tissue resolution. 12 However, apoptosis alone cannot account for the entirety of the reduction in PMN numbers, because the potential for continued recruitment and replacement.Resident mast cells, macrophages, and epithelial cells have been proposed to produce the initial signals responsible for the accumulation of PMNs, eosinophils, and mononuclear cells in experimental models of inflammation by secretion of chemokines such as mCXCL1 and mCCL3. 13 Modulation of specific ELR ϩ chemokines by proteolytic ...