Melatonin and inflammation-Story of a double-edged blade

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Abstract

Melatonin is an immune modulator that displays both pro- and anti-inflammatory properties. Proinflammatory actions, which are well documented by many studies in isolated cells or leukocyte-derived cell lines, can be assumed to enhance the resistance against pathogens. However, they can be detrimental in autoimmune diseases. Anti-inflammatory actions are of particular medicinal interest, because they are observed in high-grade inflammation such as sepsis, ischemia/reperfusion, and brain injury, and also in low-grade inflammation during aging and in neurodegenerative diseases. The mechanisms contributing to anti-inflammatory effects are manifold and comprise various pathways of secondary signaling. These include numerous antioxidant effects, downregulation of inducible and inhibition of neuronal NO synthases, downregulation of cyclooxygenase-2, inhibition of high-mobility group box-1 signaling and toll-like receptor-4 activation, prevention of inflammasome NLRP3 activation, inhibition of NF-κB activation and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). These effects are also reflected by downregulation of proinflammatory and upregulation of anti-inflammatory cytokines. Proinflammatory actions of amyloid-β peptides are reduced by enhancing α-secretase and inhibition of β- and γ-secretases. A particular role in melatonin's actions seems to be associated with the upregulation of sirtuin-1 (SIRT1), which shares various effects known from melatonin and additionally interferes with the signaling by the mechanistic target of rapamycin (mTOR) and Notch, and reduces the expression of the proinflammatory lncRNA-CCL2. The conclusion on a partial mediation by SIRT1 is supported by repeatedly observed inhibitions of melatonin effects by sirtuin inhibitors or knockdown.

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Inflammaging and 'Garb-aging'.

Claudio Franceschi, Paolo Garagnani, Giovanni Vitale … (2017)

'Inflammaging' refers to the chronic, low-grade inflammation that characterizes aging. Inflammaging is macrophage centered, involves several tissues and organs, including the gut microbiota, and is characterized by a complex balance between pro- and anti-inflammatory responses. Based on literature data, we argue that the major source of inflammatory stimuli is represented by endogenous/self, misplaced, or altered molecules resulting from damaged and/or dead cells and organelles (cell debris), recognized by receptors of the innate immune system. While their production is physiological and increases with age, their disposal by the proteasome via autophagy and/or mitophagy progressively declines. This 'autoreactive/autoimmune' process fuels the onset or progression of chronic diseases that can accelerate and propagate the aging process locally and systemically. Consequently, inflammaging can be considered a major target for antiaging strategies.

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SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging.

Hung-Chun Chang, Leonard Guarente (2013)

SIRT1 is a NAD(+)-dependent protein deacetylase that governs many physiological pathways, including circadian rhythm in peripheral tissues. Here, we show that SIRT1 in the brain governs central circadian control by activating the transcription of the two major circadian regulators, BMAL1 and CLOCK. This activation comprises an amplifying circadian loop involving SIRT1, PGC-1α, and Nampt. In aged wild-type mice, SIRT1 levels in the suprachiasmatic nucleus are decreased, as are those of BMAL1 and PER2, giving rise to a longer intrinsic period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain SIRT1 phenocopy these aging-dependent circadian changes, whereas mice that overexpress SIRT1 in the brain are protected from the effects of aging. Our findings indicate that SIRT1 activates the central pacemaker to maintain robust circadian control in young animals, and a decay in this activity may play an important role in aging. Copyright © 2013 Elsevier Inc. All rights reserved.

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Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.

Valeriya Lyssenko, Cecilia L F Nagorny, Michael R Erdos … (2009)

Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.