![]() ![]() Nonetheless, strong evidence has supported the involvement of the hypothalamic-pituitary-adrenal (HPA) axis. The molecular mechanisms involved in the delivery of mature neutrophils into the blood during physiological or stress conditions are complex and not completely understood. In agreement with this model, treatment with the CXCR4 antagonist plerixafor induces neutrophilia in humans and mice ( 10, 33). The resulting severe neutropenia detected in WHIM subjects reflects the retention of mature granulocytes together with augmented apoptosis in the bone marrow ( 1, 11, 23, 59). The relevance of the CXCR4-SDF-1α axis in neutrophil trafficking is evident in CXCR4-knockout mice ( 14) and individuals with WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) congenital syndrome, which is caused by persistent CXCR4 expression in bone marrow neutrophils. In the circulation, senescent neutrophils undergo progressive CXCR4 expression with increased responsiveness to bone marrow stromal-derived factor-1α (SDF-1α), which drives CXCR4 + senescent neutrophils back to the bone marrow to be cleared by local macrophages ( 19, 54). The mature pool of granulocytes in the bone marrow is CXCR4 high, which is decreased during the delivery process into the blood ( 19). In contrast, it is well established that expression of chemokine (C-X-C motif) receptor 4 (CXCR4) mediates the maintenance of mature granulocytes in the bone marrow as well as the homing of circulating senescent neutrophils back to the bone marrow. Although the role of CD62L, CD18, and CD49d expressed on neutrophils has been proposed in bone marrow/blood traffic, the data are controversial ( 2, 3, 8). ![]() ![]() The bone marrow blood trafficking of neutrophils is mediated by membrane adhesion molecule expression on neutrophils, sinusoids, and postcapillary venules. ![]() Although recent data have suggested that a specific population of neutrophils may circulate for longer periods of time ( 42), the majority of these cells circulate for 6–8 h, becoming senescent and migrating into different terminal tissues ( 19). A continuous delivery of mature granulocytes from the bone marrow yields about 10 11 and 10 7 neutrophils each day into the blood in humans and mice, respectively ( 19, 31). The traffic of neutrophils in body compartments is pivotal to homeostasis. Moreover, ACTH actions render circulating neutrophils to a phenotype with early reactivity, such as in vivo leukocyte-endothelial interactions, but with impaired locomotion and clearance. We conclude that alterations on HPA axis affect the pattern of membrane receptors in circulating neutrophils, which may lead to different neutrophil phenotypes in the blood. In an 18-h senescence protocol, neutrophils from WT ACTH-treated mice had a higher proportion of ANXAV low/CXCR4 low, and they were less phagocytosed by peritoneal macrophages. The membrane phenotype of neutrophils collected from WT ACTH-treated mice was paralleled by elevated fractions of rolling and adherent leukocytes to the cremaster postcapillary venules together with impaired neutrophil migration into inflamed air pouches in vivo and in vitro reduced formyl-methionyl-leucyl-phenylalanine (fMLP) or stromal-derived factor-1 (SDF-1α)-induced chemotaxis. Neutrophils from WT ACTH-treated mice presented higher expression of Ly6G +ANXA1 high, CD18 high, CD62L high, CD49 high, CXCR4 high, and formyl-peptide receptor 1 (FPR1 low) than those observed in RU-pretreated or ANXA1 −/− mice. ACTH injection (5 μg ip, 4 h) induced neutrophilia in wild-type (WT) mice and did not alter the elevated numbers of neutrophils in RU-38486 (RU)-pretreated or ANXA1 −/− mice injected with ACTH. Here, we investigated the dependence of glucocorticoid receptor activation and glucocorticoid-regulated protein annexin A1 (ANXA1) on ACTH-induced neutrophilia and the phenotype of blood neutrophil after ACTH injection, focusing on adhesion molecule expressions and locomotion properties. Elevated levels of adrenocorticotrophic hormone (ACTH) mobilize granulocytes from bone marrow into the blood, although these neutrophils are refractory to a full migratory response into inflamed tissues. ![]()
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