Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis.

The objective of this study was to determine whether endogenous nitric oxide (NO) inhibits leukocyte adhesion to vascular endothelium. This was accomplished by superfusing a cat mesenteric preparation with inhibitors of NO production, NG-monomethyl-L-arginine (L-NMMA) or NG_ nitro-L-arginine methyl ester (L-NAME), and observing single (30-,um diameter) venules by intravital video microscopy. Thirty minutes into the superfusion period the number of adherent and emigrated leukocytes, the erythrocyte velocity, and the venular diameter were measured; venular blood flow and shear rate were calculated from the measured parameters. The contribution of the leukocyte adhesion glycoprotein CD11/CD18 was determined using the CD18-specific monoclonal antibody IB4. Both inhibitors of NO production increased leukocyte adherence more than 15-fold. Leukocyte emigration was also enhanced, whereas venular shear rate was reduced by nearly half. Antibody IB4 abolished the leukocyte adhesion induced by L-NMMA and L-NAME. Incubation of isolated cat neutrophils with L-NMMA, but not L-NAME, resulted in direct upregulation of CD11/CD18 as assessed by flow cytometry. Decrements in venular shear rate induced by partial occlusion of the superior mesenteric artery in untreated animals revealed that only a minor component of L-NAMEinduced leukocyte adhesion was shear rate-dependent. The L-NAME-induced adhesion was inhibited by L-argimnie but not D-arginine. These data suggest that endothelium-derived NO may be an important endogenous modulator of leukocyte adherence and that impairment of NO production results in a pattern of leukocyte adhesion and emigration that is characteristic of acute inflammation. ation (2). The observation that SOD does not affect the adhesion of PMNs to biologically inert surfaces (glass or plastic) suggests that superoxide-mediated PMN adhesion is an endothelium-dependent process (2, 3).The mechanism by which superoxide mediates endothelium-dependent leukocyte adhesion has not been defined; however, one possibility is that superoxide may interact with an endothelial cell-derived antiadhesive substance and render it inactive. Nitric oxide (NO) is a biologically active compound produced by vascular endothelium and is rapidly inactivated by superoxide (4, 5). There is circumstantial evidence in the literature that NO may interfere with the ability of PMNs to adhere to microvascular endothelium. It is well established that NO prevents the adhesion of platelets to endothelial monolayers (6). Additionally, NO inhibits neutrophil aggregation in vitro, an effect that is potentiated by SOD (7). The primary objective of this study was to test the hypothesis that endogenous production of NO plays an important role in the modulation of PMN adhesion to endothelial cells in postcapillary venules. This was accomplished by quantifying leukocyte adhesion in cat mesenteric venules that were superfused with NG monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME), analogues of L-arginine that inhibit NO ...