β-Adrenoceptors Trigger Melatonin Synthesis in Phagocytes.

Marco Pires-Lapa,Erika Cecon,Pedro Fernandes,Regina Markus,Claudia Carvalho-Sousa

doi:10.3390/ijms19082182

Marco Pires-Lapa, Erika Cecon + Show 3 more

Open Access

https://doi.org/10.3390/ijms19082182

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Abstract

Melatonin (5-methoxy-N-acetylserotonin), the pineal hormone, is also synthesized by immune-competent cells. The pineal hormone signals darkness, while melatonin synthesized on demand by activated macrophages at any hour of the day acts locally, favoring regulatory/tolerant phenotypes. Activation of β-adrenoceptors in pinealocytes is the main route for triggering melatonin synthesis. However, despite the well-known role of β-adrenoceptors in the resolution macrophage phenotype (M2), and the relevance of macrophage synthesized melatonin in facilitating phagocytic activity, there is no information regarding whether activation of β-adrenoceptors would induce melatonin synthesis by monocytes. Here we show that catecholamines stimulate melatonin synthesis in bone marrow-derived dendritic cells and RAW 264.7 macrophages. Activation of β-adrenoceptors promotes the synthesis of melatonin by stimulating cyclic AMP/protein kinase A (PKA) pathway and by activating the nuclear translocation of NF-κB. Considering the great number of macrophages around sympathetic nerve terminals, and the relevance of this system for maintaining macrophages in stages compatible to low-grade inflammation, our data open the possibility that extra-pineal melatonin acts as an autocrine/paracrine signal in macrophages under resolution or tolerant phenotypes.

Highlights

Melatonin acts as a buffer of the immune system, stimulating immune responses under immunosuppressed conditions, and repressing innate and adaptive immune responses in physiological conditions [1]
The incubation of human colostrum monocytes with Escherichia coli induces melatonin synthesis which stops after all bacteria are killed, whereas in the same cell type the melatonin synthesis induced by the PAMP derived from the fungi membrane, zymosan, lasts throughout the experimental observation [7,8]
To further characterize the system, we evaluated the signaling pathways involved in catecholamine-induced melatonin synthesis in macrophages

Summary

Introduction

Melatonin acts as a buffer of the immune system, stimulating immune responses under immunosuppressed conditions, and repressing innate and adaptive immune responses in physiological conditions [1]. The incubation of human colostrum monocytes with Escherichia coli induces melatonin synthesis which stops after all bacteria are killed, whereas in the same cell type the melatonin synthesis induced by the PAMP derived from the fungi membrane, zymosan, lasts throughout the experimental observation [7,8] Both exogenous melatonin [9,10,11,12] and melatonin synthesized by activated immunocompetent cells regulate the inflammatory response [13,14,15,16,17,18]. In resolution macrophages (M2), melatonin induces the synthesis of membrane proteins, such as dectin-1 [6] which increases phagocytosis [5,6], and arginase I which deviates arginine conversion from nitric oxide into ornithine and urea [19] These are transient changes, and the return to basal conditions results in the restoration of daily pineal melatonin rhythm and reduction of melatonin synthesis by macrophages. Such switching of melatonin sources, from pineal-to-immune-back-to-pineal, was defined as the immune-pineal axis, which provides a theoretical basis for the chronobiotic and protective functions of melatonin [3]

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