The deregulation of inflammatory response during sepsis seems to reflect the overproduction of mediators, which suppress leukocyte functions. We investigated the intracellular mechanisms underlying the inability of neutrophils from severe septic patients to migrate toward chemoattractants. Patients IntroductionSepsis is a complex clinical syndrome resulting from a damaging host response to infection. 1 In the United States, more than 700 000 patients per year develop sepsis, with mortality rates reported to vary between 30% and 70%, despite the best available supportive care. 2 Polymorphonuclear neutrophils (PMNs) play the first line in the host defense against microorganisms, being recruited to the inflammatory sites by chemoattractants such as leukotriene B 4 (LTB 4 ) and chemokines. 3,4 Once emigrated, these leukocytes are able to phagocytose and to generate large amounts of reactive oxygen and nitrogen species, such as hydrogen peroxide and nitric oxide, which are crucial products for the microbicidal activity of these cells. 5,6 As neutrophils appear to play a crucial role in the control of the infectious process, one can hypothesize that a deficient migratory ability of neutrophils may aggravate infections. Indeed, impairment of neutrophil migration has been reported in leukemia, 7 diabetes, 8 and AIDS, 9 diseases associated with high susceptibility to infection. Furthermore, previous studies from our group showed that failure of neutrophil migration is observed in severe sepsis induced by cecal ligation and puncture and Staphylococcus aureus administration. 10,11 In these lethal models, failure of neutrophil migration to the site of infection was accompanied by increased numbers of bacteria in the peritoneal fluid and blood. Conversely, in sublethal infection in which massive neutrophil migration was observed, bacterial infection was restricted to the peritoneal cavity, and the animals exhibited a low mortality rate. 10,11 More recently, we have also reported that blood neutrophils obtained from patients with sepsis failed to respond in vitro to the chemotactic stimuli FMLP and LTB 4 . This unresponsiveness was directly associated to a poor prognosis. 12 Evidence from literature suggests that the high levels of circulating cytokines/chemokines observed in severe sepsis may mediate the impairment of neutrophil migration, in addition to being involved in the deleterious physiopathologic findings of the disease, such as coagulation disorders, cardiovascular collapse, and organ failure. 13 The intravenous administration of tumor necrosis factor-␣ (TNF-␣) or interleukin-8 (IL-8) inhibited neutrophil migration to mouse peritoneal cavity and anti-TNF-␣ antibody partially prevented the inhibition of neutrophil migration in endotoxemia model. 14 However, the molecular mechanisms involved in the reduced ability of neutrophils to migrate during sepsis were not completely clarified.Independent of their chemical nature, most chemoattractants exert their action via binding to specific G protein-coupled receptors (GP...