Dataset Information

Interactions between ?-adrenergic vasodilation and cervical sympathetic nerves are mediated by ?2-adrenoceptors in the rat masseter muscle.

ABSTRACT: Neural and humoral autonomic mechanisms may be important in the maintenance of blood flow in the masseter muscle (MBF). However, their interactions remain unclear. In this study, we examined interactions between neural and humoral regulation of MBF and investigated the mechanisms mediating these interactions in urethane-anesthetized rats. Stimulation of the adrenal nerve (AN) projecting to the adrenal medulla increased MBF, and this increase was mediated by ?-adrenoceptors. Sectioning of the superior cervical sympathetic trunk (CST) significantly inhibited increases in MBF induced by AN stimulation during high activity in the CST, but not during low activity. AN stimulation with clonidine after CST sectioning induced a significant increased in MBF, however phenylephrine had no observable effect. Pretreatment with yohimbine or propranolol significantly inhibited the increase in the MBF. Our results suggest an interaction between ?-adrenergic vasodilation evoked by circulating adrenaline and the cervical sympathetic nerves that is mediated by ?2-adrenoceptors in the masseter muscle.

SUBMITTER: Ishii H

PROVIDER: S-EPMC5910521 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Interactions between β-adrenergic vasodilation and cervical sympathetic nerves are mediated by α<sub>2</sub>-adrenoceptors in the rat masseter muscle.

Ishii Hisayoshi H Sato Toshiya T

The journal of physiological sciences : JPS 20161108 6

Neural and humoral autonomic mechanisms may be important in the maintenance of blood flow in the masseter muscle (MBF). However, their interactions remain unclear. In this study, we examined interactions between neural and humoral regulation of MBF and investigated the mechanisms mediating these interactions in urethane-anesthetized rats. Stimulation of the adrenal nerve (AN) projecting to the adrenal medulla increased MBF, and this increase was mediated by β-adrenoceptors. Sectioning of the sup ...[more]

PMID: 27826897

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Project description:CD8+ T cells are essential components of the body’s immune reaction against viral infections and tumors, capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion. Exhausted CD8+ T cells are characterized by expression of multiple inhibitory receptors, like PD-1 and TIM3 and reduced capacity to secrete cytokines, and are commonly found in chronic viral infections, like HIV and HBV, as well as in immunosuppressive tumor microenvironments (TME). Cancer and chronic infection also place considerable stress on tissue architecture and function, and while it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a previously undescribed link between the stress-associated catecholamines adrenaline and noradrenaline and the development of T cell exhaustion through the β1-adrenergic receptor, ADRB1. We identify that exhausted CD8+ T cells express higher levels of ADRB1, and exposure of ADRB1-expressing T cells to catecholamines suppresses cytokine production and impairs T cell proliferation. Genetic or pharmacological ablation of β-adrenergic signaling via ADRB1 reduces development of T cell exhaustion in a chronic infection model and improves cytotoxic functions in tumor-infiltrating lymphocytes (TILs) when combined with immune checkpoint blockade (ICB) therapy in a melanoma model. Extending these findings to an ICB-resistant tumor model of murine pancreatic cancer, we show that beta-blockers and ICB synergize to enhance and reprogram T cell responses. Given that malignant disease is associated with increased systemic catecholamine levels in patients and therapeutic stress reduction improves survival in cancer patients, our results demonstrate a potential link between systemic stress, tumor innervation and immune responses. Our findings show that β-adrenergic signaling constitutes a novel targetable immune checkpoint in CD8+ T cells to rejuvenate antitumor functions. More broadly, our results support further clinical investigation into the application of beta-blockers, which are clinically safe and widely prescribed, as an immunomodulating agent for cancer immunotherapy.

Dataset Information

Interactions between ?-adrenergic vasodilation and cervical sympathetic nerves are mediated by ?2-adrenoceptors in the rat masseter muscle.

Publications

Interactions between β-adrenergic vasodilation and cervical sympathetic nerves are mediated by α<sub>2</sub>-adrenoceptors in the rat masseter muscle.

Similar Datasets

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