Immune‐pineal axis – acute inflammatory responses coordinate melatonin synthesis by pinealocytes and phagocytes

Abstract

Melatonin is well known for its circadian production by the pineal gland, and there is a growing body of data showing that it is also produced by many other cells and organs, including immune cells. The chronobiotic role of pineal melatonin, as well as its protective effects in vitro and in vivo, have been extensively explored. However, the interaction between the chronobiotic and defence functions of endogenous melatonin has been little investigated. This review details the current knowledge regarding the coordinated shift in melatonin synthesis from the pineal gland (circadian and monitoring roles) to the regulation of acute immune responses via immune cell production and autocrine effects, producing systemic interactions termed the immune-pineal axis. An acute inflammatory response drives the transcription factor, NFκB, to switch melatonin synthesis from pinealocytes to macrophages/microglia and, upon acute inflammatory resolution, back to pinealocytes. The potential pathophysiological relevance of immune-pineal axis dysregulation is highlighted, with both research and clinical implications, across several medical conditions, including host/parasite interaction, neurodegenerative diseases and cancer.

STAT1‐NFκB crosstalk triggered by interferon gamma regulates noradrenaline‐induced pineal hormonal production

“…Moreover, considering the relevance of temporal variations of pineal melatonin production during immunological responses, the present data depict a functional crosstalk among STAT1 and NFκB transcriptional factors, exposing the multiplicity of the mechanisms associated with pineal integration of immune signals. Microglia and astrocytes play pivotal roles in regulating pineal response to immune signals.…”

“…The immune‐pineal axis concept elaborated by Markus et al synthesizes this integration and highlights the role of melatonin in several immune‐related functions, such as the rolling and adhesion of leukocytes to endothelial cells and immunocompetent cell activation . Additionally, characterization of the mechanisms controlling melatonin synthesis by the pineal gland is pivotal for understanding the interactions between the gland and immune signals in the assembly of defense responses …”

“…Extensive vascularization of this circumventricular organ enables the gland to detect and respond to circulating immunological signals. Moreover, fine‐tuned regulation of melatonin production by the pineal gland coordinates the appropriate timing of healthy and pathophysiologic processes in mammals . In the immunologic context, pathogen‐ and danger‐associated molecular patterns (PAMPs and DAMPs) modulate nocturnal melatonin synthesis in rodents and humans during inflammatory processes.…”

The Underrated Circadian System and Its Contribution to Neurodegeneration in Mood Disorders

“…Insofar, it is not surprising that polymorphisms of genes involved in melatonin synthesis and signaling were also reported to be associated with depressive disorders 46,51 . Decreases in melatonin levels also occur in response to epigenetic changes or other pathology-induced effects on the pineal gland 52 and, thus, can be independent of genetic deficiencies. Nevertheless, the polymorphisms are well in accordance with decreased melatonin levels observed in patients with depressive disorders, as recently summarized 4 .…”

Recent developments in research of melatonin and its potential therapeutic applications

“…On the basis of a portfolio of endocrine, paracrine and autocrine actions for melatonin, Markus et al (2018) explain how melatonin could affect processes as diverse as: migration of leukocytes through the vascular endothelium; macrophage and microglia phenotype; the life cycle of infective parasitic organisms; tumour growth and neurodegeneration. Markus et al (2018) propose that synthesis and release of melatonin switches between the pineal gland and immune competent cells, and back again, and that this process is a component of the fine control of the inflammatory response. A clear stream of evidence, throughout this review, is that the NF-κB pathway has a fundamental role in co-ordinating the 'switch' and could help explain why inflammatory responses have a circadian rhythm.…”