Melatonin and inflammation—Story of a double‐edged blade

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.

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

“…Melatonin is a modulator of the inflammatory mechanism and a valuable tool in treating neuroinflammation . Neuroinflammation drives neuronal death and affects neurobehaviors.…”

Melatonin in macrophage biology: Current understanding and future perspectives

“…Despite the multiplicity of NF‐κB subforms, the inhibitory action of melatonin toward this signaling pathway seems to reflect a general property observed in many different cell types. NF‐κB activation can be inhibited by interference with various upstream regulators, most often demonstrated for TLR4, but corresponding effects were also reported for TLR2 and TLR9 . In addition to the inhibition of TLR4 activity, a concomitant reduction of TRIF activity or expression level by melatonin was also described .…”

“…With regard to the above‐mentioned presence of melatonin receptors in these cells, melatonin appears to have an autocrine function, which does not exclude effects of macrophage‐derived melatonin on other cells. Interestingly, macrophage AANAT expression was found to be induced by NF‐κB, a transcriptional regulator that is usually suppressed by melatonin . Concerning external regulation, RAW 264.7 cells were recently shown to upregulate melatonin formation upon β‐adrenergic stimulation …”

“…However, exosomes derived from hepatocellular carcinoma cells treated with 0.1 mmol/L melatonin could attenuate the high expression of IL‐10 and decreased STAT‐3 activation in TAM, suggesting that melatonin inhibits the function of M2 macrophages in tumors . Differences in melatonin's actions toward tumor and nontumor cells are not uncommon and concern apoptosis, ROS production, the circadian system, and SIRT1 expression …”

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…Absorbance was determined at 570 nm. The relative cell viability was recorded as a ratio to that in the control group …”