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-α 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.

β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury

“…CCR2 is highly expressed on proinflammatory monocyte populations and, although β2AR has been shown to modulate chemotaxis, our findings are novel in that they directly link decreased hematopoietic cell β2AR expression with a corresponding reduction in CCR2 levels and CCL2-dependent migration. Previous studies have shown either no effect of sympathetic nervous system (SNS) stimulation on CCR2 expression in peripheral blood mononuclear cells (28) or decreased CCR2 expression in BM with SNS stimulation (29). These differences may be due to the lack of specificity of norepinephrine and epinephrine treatment and activation of multiple adrenergic receptor subtypes.…”

Palmitate differentially regulates the polarization of differentiating and differentiated macrophages

“…All animal procedures were Murine bone marrow isolation was conducted as previously described. 17 Briefly, for experiments carried out in differentiating macrophages, total bone marrow cells were treated with various doses of glucose (7Á5, 10 and 12Á5 mM) or various doses of palmitate (0Á1, 0Á2 and 0Á4 mM) or in combination (10 mM glucose plus 0Á2 mM palmitate) during the differentiation period. Macrophages were then harvested on day 7.…”

“…17 Internalization ability was evaluated at the percentage or mean fluorescence intensity of FITC-positive cells gated on the CD11b + F4/80 + BMM or gated on THP-1 cells.…”

Effects of cold stress andSalmonellaHeidelberg infection on bacterial load and immunity of chickens

“…One possible explanation for this finding includes NOR. Recently, Xiu et al (2013) examined the effects of NOR on the phenotype and functions of bone marrow-derived macrophages. They found that low NOR doses (<10 6 M) inhibited MHCII and CCR2 (chemokine receptor type II) expression and bone marrow-derived macrophage proliferation.…”