Neutrophils, monocytes and macrophages are closely related phagocytic cells that cooperate during the onset, progression and resolution of inflammation. This Review highlights the mechanisms involved in the intimate partnership of phagocytes during each progressive phase of the inflammatory response. We describe how tissue-resident macrophages recognize tissue damage to promote the recruitment of neutrophils and the mechanisms by which infiltrating neutrophils can then promote monocyte recruitment. Furthermore, we discuss the phagocyte-derived signals that abrogate neutrophil recruitment and how the uptake of apoptotic neutrophils by macrophages leads to termination of the inflammatory response. Finally, we highlight the potential therapeutic relevance of these interactions.

Increased vascular permeability is a key feature of inflammatory conditions. In severe infections, leakage of plasma from the vasculature induces a life-threatening hypotension. Streptococcus pyogenes, a major human bacterial pathogen, causes a toxic shock syndrome (STSS) characterized by excessive plasma leakage and multi-organ failure. Here we find that M protein, released from the streptococcal surface, forms complexes with fibrinogen, which by binding to beta2 integrins of neutrophils, activate these cells. As a result, neutrophils release heparin binding protein, an inflammatory mediator inducing vascular leakage. In mice, injection of M protein or subcutaneous infection with S. pyogenes causes severe pulmonary damage characterized by leakage of plasma and blood cells. These lesions were prevented by treatment with a beta2 integrin antagonist. In addition, M protein/fibrinogen complexes were identified in tissue biopsies from a patient with necrotizing fasciitis and STSS, further underlining the pathogenic significance of such complexes in severe streptococcal infections.

The leukocyte response in inflammation is characterized by an initial recruitment of polymorphonuclear leukocytes (PMN) preceding a second wave of monocytes to the site of injury or infection. In the mouse, 2 populations of monocytes have been identified, Gr1 ؊ CCR2 ؊ CX3CR1 hi resident monocytes and Gr1 ؉ CCR2 ؉ CX3CR1 lo inflammatory monocytes. Here, intravital microscopy of the musculus cremaster and a subcutaneous air pouch model were used to investigate a possible link between PMN extravasation and the subsequent emigration of inflammatory monocytes in response to local stimulation with PAF. In mice that were made neutropenic by injection of a PMNdepleting antibody, the extravasation of inflammatory monocytes, but not resident monocytes, was markedly reduced compared with mice with intact white blood cell IntroductionPolymorphonuclear leukocytes (PMN) dominate the initial leukocyte influx to sites of acute infection and inflammation. 1 This first wave of PMN extravasation precedes a second wave of monocyte extravasation. Recruited PMN are thought to trigger this cellular switch by releasing soluble factors that initiate monocyte recruitment, 2-4 much of which may be mediated by ready-made PMN granule proteins deposited at the site of inflammation. 5,6 Indeed, supernatants of activated PMN from patients with specific granule deficiency lacking proteins in their primary, secondary, and tertiary granules show a reduced capacity to attract monocytes despite normal monocyte chemotaxis in vitro to other stimuli. 7 After this initial observation, several PMN-derived granule proteins with monocyte-chemotactic activity were identified, among them LL-37, cathepsin G, human neutrophil peptide 1-3 (HNP1-3, ␣-defensins), and heparin-binding protein (HBP, also known as CAP37 and azurocidin). [8][9][10][11] Their action was found to be pertussis toxin (PTx)-sensitive and several receptors were suggested to mediate the chemotactic effect. [11][12][13] Peripheral blood monocytes constitute a heterogeneous population of circulating leukocytes in both humans 14 and mice. 15 In the murine blood, 2 monocyte subsets can be distinguished based on their expression of CX3CR1, CCR2, and Gr1. Whereas resident monocytes (Gr1 Ϫ CCR2 Ϫ CX3CR1 hi ) home to noninflamed tissues, inflammatory monocytes (Gr1 ϩ CCR2 ϩ CX3CR1 lo ) are predominantly recruited to sites of inflammation by mechanisms involving CCR2. 15 These inflammatory monocytes were recently shown to be of critical importance in diverse inflammatory and infectious diseases. [16][17][18][19] In this study, we investigated the significance of the initial PMN efflux for the subsequent extravasation of monocytes. Our results demonstrate that PMN seed granule proteins in the tissue which contribute to mobilization specifically of inflammatory monocytes. Functionally, the PMN-dependent invasion of inflammatory monocytes results in a more vigorous immune response as shown by enhanced cytokine release and bacterial clearance at the site of inflammation. Methods AnimalsWild-type C57BL/...

Polymorphonuclear leukocyte infiltration into tissues in host defense and inflammatory disease causes increased vascular permeability and edema formation through unknown mechanisms. Here, we report the involvement of a paracrine mechanism in neutrophil-evoked alteration in endothelial barrier function. We show that upon neutrophil adhesion to the endothelial lining, leukocytic beta2 integrin signaling triggers the release of neutrophil-borne heparin-binding protein (HBP), also known as CAP37/azurocidin, a member of the serprocidin family of neutrophil cationic proteins. HBP induced Ca++-dependent cytoskeletal rearrangement and intercellular gap formation in endothelial-cell monolayers in vitro, and increased macromolecular efflux in microvessels in vivo. Moreover, selective inactivation of HBP prevented the neutrophils from inducing endothelial hyperpermeability. Our data suggest a fundamental role of neutrophil-derived HBP in the vascular response to neutrophil trafficking in inflammation. Targeting this molecule in inflammatory disease conditions offers a new strategy for prevention of endothelial barrier dysfunction caused by misdirected leukocyte activation.

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