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Norepinephrine inhibits macrophage migration by decreasing CCR2 expression.

ABSTRACT: Increased incidences of infectious and septic complications during post-burn courses represent the main contributor to burn injury mortality. Sustained increases in catecholamine levels, especially norepinephrine (NE), contribute to immune disturbances in severely burned patients. The precise mechanisms underlying NE-mediated immunoregulation are not fully understood. Here we hypothesize that persistently elevated NE levels are associated with immunodysfunctions. We examined the effects of NE on the phenotype and functions of bone marrow-derived macrophages (BMMs). Whole mouse bone marrow cells were treated in vitro with 40 ng/mL of M-CSF and with 1 x 10(-6) M or 1 x 10(-8) M of NE or without NE for 7 days; cells were collected and stained with antibodies for CD11b, F4/80, MHC II and the inflammatory CC chemokine receptor 2 (CCR2). We found 1 x 10(-6) M of NE inhibited MHC II and CCR2 expression on CD11b(+)/F4/80(+) BMM cells. It also inhibited BMM proliferation by inhibiting CSF-1R expression. On the contrary, 1 x 10(-8) M of NE slightly increased both MHC II and CCR2 expression on CD11b(+)/F4/80(+) BMM cells but inhibited CD11b(+)/F4/80(+) BMM proliferation. MCP-1 based migration assay showed that the migration of 1 x 10(-6) M of NE-treated BMM toward MCP-1 was significantly decreased compared to BMM without NE treatment. Both 1 x 10(-8) M and 1 x 10(-6) M of NE enhanced TNF-? production and phagocytosis of FITC-Dextran. Intracellular staining of transcriptional factor MafB showed that 1 x 10(-6) M of NE treatment enhanced its expression, whereas 1 x 10(-8) M of NE decreased expression. Stimulation with LPS in the last 24-hours of BMM culture further decreased CCR2 and MHC II expression of these BMM, suggesting the synergistic effect of LPS and NE on macrophage. Our results demonstrate that NE regulates macrophage differentiation, proliferation and function, and may play a critical role in the dysfunctional immune response post-burn.

SUBMITTER: Xiu F

PROVIDER: S-EPMC3699643 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Norepinephrine inhibits macrophage migration by decreasing CCR2 expression.

Xiu Fangming F Stanojcic Mile M Jeschke Marc G MG

PloS one 20130702 7

Increased incidences of infectious and septic complications during post-burn courses represent the main contributor to burn injury mortality. Sustained increases in catecholamine levels, especially norepinephrine (NE), contribute to immune disturbances in severely burned patients. The precise mechanisms underlying NE-mediated immunoregulation are not fully understood. Here we hypothesize that persistently elevated NE levels are associated with immunodysfunctions. We examined the effects of NE on ...[more]

PMID: 23844252

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Project description:BackgroundGlioma cells are characterized by high migration ability, resulting in aggressive growth of the tumors and poor prognosis of patients. It has been reported that the stress-induced hormone norepinephrine (NE) contributes to tumor progression through mediating a number of important biological processes in various cancers. However, the role of NE in the regulation of glioma migration is still unclear. Epithelial-to-mesenchymal transition (EMT) is one of the most important steps for tumor migration and metastasis. Twist1, as a key regulator of EMT, has been found to be elevated during glioma migration. But it is still unknown whether Twist1 is involved in the effect of NE on the migration of glioma cells.MethodsWound healing assay and transwell assay were conducted to evaluate the migration of glioma cells upon different treatments. The mesenchymal-like phenotype and the expression of Twist1 after NE treatment were assessed by cell diameters, real-time PCR, western blot and immunofluorescence staining. The gain-and loss-of-function experiments were carried out to investigate the biological function of Twist1 in the migration induced by NE. Finally, the clinical significance of Twist1 was explored among three public glioma datasets.ResultsIn this study, our finding revealed a facilitative effect of NE on glioma cell migration in a β-adrenergic receptor (ADRB)-dependent way. Mechanistically, NE induced mesenchymal-like phenotype and the expression of Twist1. Twist1 overexpression promoted glioma cells migration, while knockdown of Twist1 abolished the discrepancy in the migration ability between NE treated glioma cells and control cells. In addition, the clinical analysis demonstrated that Twist1 was up-regulated in malignant gliomas and recurrent gliomas, and predicted a poor prognosis of glioma patients.ConclusionsNE enhanced the migration ability of glioma cells through elevating the expression of Twist1. Our finding may provide potential therapeutic target for protecting patients with glioma from the detrimental effects of stress biology on the tumor progression.

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Norepinephrine inhibits macrophage migration by decreasing CCR2 expression.

Publications

Norepinephrine inhibits macrophage migration by decreasing CCR2 expression.

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