The interplay between mast cells, pineal gland, and circadian rhythm: Links between histamine, melatonin, and inflammatory mediators

Abstract

Our daily rhythmicity is controlled by a circadian clock with a specific set of genes located in the suprachiasmatic nucleus in the hypothalamus. Mast cells (MCs) are major effector cells that play a protective role against pathogens and inflammation. MC distribution and activation are associated with the circadian rhythm via two major pathways, IgE/FcεRI- and IL-33/ST2-mediated signaling. Furthermore, there is a robust oscillation between clock genes and MC-specific genes. Melatonin is a hormone derived from the amino acid tryptophan and is produced primarily in the pineal gland near the center of the brain, and histamine is a biologically active amine synthesized from the decarboxylation of the amino acid histidine by the L-histidine decarboxylase enzyme. Melatonin and histamine are previously reported to modulate circadian rhythms by pathways incorporating various modulators in which the nuclear factor-binding near the κ light-chain gene in B cells, NF-κB, is the common key factor. NF-κB interacts with the core clock genes and disrupts the production of pro-inflammatory cytokine mediators such as IL-6, IL-13, and TNF-α. Currently, there has been no study evaluating the interdependence between melatonin and histamine with respect to circadian oscillations in MCs. Accumulating evidence suggests that restoring circadian rhythms in MCs by targeting melatonin and histamine via NF-κB may be promising therapeutic strategy for MC-mediated inflammatory diseases. This review summarizes recent findings for circadian-mediated MC functional roles and activation paradigms, as well as the therapeutic potentials of targeting circadian-mediated melatonin and histamine signaling in MC-dependent inflammatory diseases.

Keywords: circadian rhythm; clock genes; histamine; inflammation; mast cells; melatonin.

FIGURE 1

IgE/FcεRI- and IL33/ST2-mediated MC activation pathways. There is a robust oscillation between the circadian clock genes (Per1/2, Clock, and Bmal1) and MC-specific genes (Mcpt-5/7, c-Kit, FcεRI, and Tryptase). IgE/FcεRI- and IL-33/ST2-mediated MC activations are the two major pathways underlying the modulation of the circadian clock and MC functions. The promoter of β subunit of the Fc receptor for IgE (FcεRIβ) and IL-33 receptor (ST2) bind CLOCK with high affinity leading to a circadian rhythm-dependent MC activation. Upon the respective binding of IgE and IL-33 to FcεRI and ST2 in MCs, the expression level of the nuclear factor NF-κB is significantly elevated leading to the increase in the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-5/6/8/13, and MCP-1. IL-33 exhibits dualistic effect in MCs with ability to both inducing and suppressing NF-κB activity. More studies are required to decipher this dichotomous effect to avoid putative false therapeutic drugs targeting the IL-33/ST2 axis in MCs.

FIGURE 2

Therapeutic potentials targeting circadian MC-mediated melatonin. Melatonin is a hormone produced primarily in the pineal gland which helps maintain circadian rhythm and regulate reproductive hormones. Daily expressions of melatonin-forming enzymes (Aanat and Asmt) and melatonin receptors (MT1 and MT2) are in synchronized rhythmic oscillation with expression of clock genes (Clock, Bmal1, Per1/2, Cry1/2, and Rev-erbα). Melatonin is also a key mediator which recognizes potential damages and risk status in MCs via NF-κB and STAT1 pathways. Binding of melatonin to MT1 and MT2 leads to the inhibition of NF-κB activation, which in turn down-regulates MC activation, proliferation, and differentiation. Based on these findings, many compounds have been extensively investigated to impose various regulatory effects on NF-κB and melatonin in MCs and play a role as potential therapeutic drugs in MC-mediated inflammatory reactions.