Microarray and gene co-expression analysis reveals that melatonin attenuates immune responses and modulates actin rearrangement in macrophages

Abstract

Melatonin produced by the pineal gland suppresses inflammatory responses in innate immune cells. However, the mechanism of how melatonin affects inflammatory gene regulation remains unclear. Here we performed comprehensive microarray analysis combined with transcription factor binding site (TFBS) analysis using LPS-induced mouse macrophages to investigate the effect of melatonin treatment. The results showed that melatonin preferentially downregulated interferon regulatory factors (IRFs) and signal transducers and activators of transcription (STATs) related signaling. The results also showed that melatonin strongly suppressed virus infection related gene expression. Furthermore, TFBS analysis implicated that melatonin downregulated the binding activity of hypoxia inducible factors (HIFs), following destabilizing actin cytoskeleton which are indispensable for induction of the TRIF-dependent signaling pathway. Indeed, it was demonstrated that melatonin treatment caused impaired phagocytosis in macrophages. Thus, melatonin regulates inflammatory responses by inhibiting specific subsets of transcription factors (TFs) by disrupting actin dynamics in the macrophage.

Melatonin in macrophage biology: Current understanding and future perspectives

“…Moreover, a significant increase in nocturnal circulating melatonin levels and a rise in the phagocytic activity of peritoneal macrophages were observed in administration of l ‐tryptophan (the precursor of melatonin biosynthesis) to rats . Melatonin has also been shown to inhibit the expressions of various genes in lipopolysaccharide (LPS)‐treated RAW264.7 macrophages, such as interleukin (IL)‐1β and IL‐6 . Mechanistically, melatonin alters various transcription factors in macrophages, such as nuclear factor‐κ‐gene binding (NF‐κB), interferon regulatory factors (IRFs), and hypoxia inducible factor (HIF)‐1α .…”

“…63 Mechanistically, melatonin alters various transcription factors in macrophages, such as nuclear factor-κ-gene binding (NF-κB), interferon regulatory factors (IRFs), and hypoxia inducible factor (HIF)-1α. 63,64 Melatonin may also affect macrophages through miRNAs, exosomes, and cellular metabolism. For instance, inhibition of miR-155 expression in tumor-associated macrophages (TAM) led to an inhibition of proinflammatory cytokine production indicating a change in macrophage polarization.…”

Melatonin mediates mucosal immune cells, microbial metabolism, and rhythm crosstalk: A therapeutic target to reduce intestinal inflammation

“…Melatonin modulates the inflammatory response via suppressing certain TFs subsets. Thus, combined with TF binding site analysis, it should be possible to explain the pathway affected by melatonin . Some new findings also show that melatonin suppresses extensive inflammation outcomes and regulates multiple types of TFs, including NF‐κB and IRFs .…”

Interplay between circadian clock and viral infection

“…With the recent Ebola epidemic, melatonin was investigated as a potential treatment option, and Tan et al reported that melatonin reduced many of the pathological changes associated with Ebola infection, such as endothelial disruption and disseminated intravascular coagulation [ 40 ]. There have been limited studies addressing the mechanism of melatonin anti-viral activity; however, a recent study from Kadena and colleagues [ 41 ] reported that melatonin down-regulated LPS induced expression of interferon regulatory factors and STAT signalling in macrophages. The lack of toxicity and ease of administration makes melatonin an attractive candidate for further study.…”