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. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.

Figure 1

The immune‐pineal axis ‐ backward and forward switch of melatonin synthesis from the pinealocytes to macrophages. Left panel: Homoeostatic condition ‐ the sympathetic output to the pineal gland is activated at night. β₁‐adrenoceptors‐mediated PKA activation promotes the phosphorylation of CREB. PCREB migrates to the nucleus and induces the transcription of Aanat. PKA also phosphorylates AANAT, protecting it from ubiquitination and proteasomal degradation. PAANAT converts 5HT to NAS, the direct precursor of melatonin. The activation of melatonin membrane receptors in endothelial cells impairs the expression of adhesion molecules, avoiding spurious migration of leukocytes. Central panel: Pro‐inflammatory phase ‐ resident monocytes detect microbes or lesioned tissue and releases cytokines. In pinealocytes, PAMPs and DAMPs interact with membrane receptors and induce the activation of NFκB. p50/p50 NFκB dimers translocate to the nucleus and bind to the Aanat promoter, reducing its transcriptional activity. In the presence of a high sympathetic output, when both α₁‐ and β₁‐adrenoceptors are activated, adrenal cortex hormone (corticosteroid/cortisol) blocks pineal melatonin synthesis. The impairment of melatonin production at night allows neutrophils migration thorough the endothelial layer. Activated neutrophils release pro‐inflammatory cytokines and cytotoxic mediators recruiting monocytes that differentiate in macrophages and initiate tissue clearing. Right panel: Resolution phase ‐ macrophages‐synthesized melatonin acts in an autocrine/paracrine manner inducing the expression of membrane molecules, such as dectin‐1, that potentiate phagocytosis. This synthesis of melatonin is mediated by the NFκB dimer cRel/RelA, which promotes the transcription of Aanat. In the pineal gland, as the sympathetic tonus is reduced, GR activation favours Aanat transcription and allows the recovery of the nocturnal melatonin output.

Figure 2

Microglia–pinealocyte interaction in the pineal gland. Left panel: Representative images showing the expression of TNFR1 (green) in rat pineal glands. Astrocytes (GFAP), microglia (ED1) and pinealocytes (non‐labelled cells) express TNFR1. Astrocytes are localized in the stalk, whilst microglia are dispersed along all the gland (Carvalho‐Sousa et al., 2011). Right panel: Microglia–pinealocyte interaction – besides TNFR1, pinealocytes and astrocytes, and microglia also express TLRs (da Silveira Cruz‐Machado et al., 2012). In pinealocytes, activation of TLR4 by a PAMP, as LPS, or a DAMP, as Aβ (amyloid β peptide), inhibits the synthesis of melatonin and induces the synthesis of TNFR1. In microglia, TLR4 leads to the synthesis of TNF, which acting on TNFR1 in the pinealocytes reinforces the synthesis of melatonin. These multiple effects are mediated by specific NFκB dimers, p50/p50 blocks, whereas p50/RelA promotes gene transcription. Figures adapted from Frontiers in Endocrinoly (A) and Plos One (B).