Data from Stress-induced Norepinephrine Downregulates CCL2 in Macrophages to Suppress Tumor Growth in a Model of Malignant Melanoma

Abstract

<div>Abstract<p>Psychological stressors have been implicated in the progression of various tumor types. We investigated a role for stress in tumor immune cell chemotaxis in the B16F10 mouse model of malignant melanoma. We exposed female mice to 6-hour periods of restraint stress (RST) for 7 days, then implanted B16F10 malignant melanoma tumor cells and continued the RST paradigm for 14 additional days. We determined serum corticosterone and liver catecholamine concentrations in these mice. To evaluate the tumor microenvironment, we performed IHC and examined cytokine expression profiles using ELISA-based analysis of tumor homogenates. We found that tumors in mice subjected to RST grew significantly slower, had reduced tumor C-C motif ligand 2 (CCL2), and contained fewer F4/80-positive macrophages than tumors from unstressed mice. We observed a concomitant increase in norepinephrine among the RST mice. An <i>in vitro</i> assay confirmed that norepinephrine downregulates CCL2 production in both mouse and human macrophages, and that pretreatment with the pan-β-adrenergic receptor inhibitor nadolol rescues this activity. Furthermore, RST had no effect on tumor growth in transgenic CCL2-deficient mice. This study suggests that stress reduces malignant melanoma by reducing recruitment of tumor-promoting macrophages by CCL2.</p></div>

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis

“…CCL2 is a major chemoattractant implicated in the infiltration of myeloid cells, especially monocytes and neutrophils, into the brain during inflammation 89,90 . A relationship between NE and CCL2 has not been extensively examined in microglia, but a recent report demonstrated that NE reduces CCL2 production in mouse and human macrophages in a β-adrenergic receptor-dependent manner 91 . Additionally, recent work in astrocytes has revealed a complicated relationship between NE and CCL2 that may provide insight for the data in this study and others.…”