The Circadian Clock Drives Mast Cell Functions in Allergic Reactions [23.07.18]
Although the cellular mechanisms of circadian rhythms are still under investigation, the team of Axel Lorentz togehter with their partner from Rehovot (Hebrew University, Israel) summarizes the evidence on the importance of the biological clock in allergic syndromes and conclude that targeting mast cell clock can be considered a valuable target of chronotherapy.
Figure 1. The mast cell clock in type I allergic reaction (Christ et al 2018)
Original Mini Review
Christ, P., Sowa, A.S., Froy, O., Lorentz, A. (2018) The circadian clock drives mast cell functions in allergic reactions Frontiers in Immunology, 9(JUL), Front. Immunol., 06 July 2018 | doi.org/10.3389/fimmu.2018.01526
- Institute for Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
- Food Science and Nutrition, the Robert H. Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry, The Hebrew University, Rehovot, Israel
Abstract
Allergic diseases are known to vary in the severity of their symptoms throughout the day/night cycle. This rhythmicity is also observed in mast cell function and responsiveness. Mast cells are key effector cells of allergic reactions and release cytokines, chemokines, and important inflammatory mediators such as histamine, which have been shown to display diurnal variation. Recent research clarified that mast cells are controlled by their internal clock—which is regulated by a specific set of clock genes—as well as external factors such as light sensed by the suprachiasmatic nuclei, hormonal status, or diet. Here, we give an overview of the connections between circadian clock, mast cells, and allergic disease. Further work aimed at studying the role of chronotherapy/chronomedicine should take into account this rhythmic nature of not only mast cells but also the immune responses generated by mast cell signaling.
Figure 1 further explanantion: Allergens are taken up by antigen-presenting cells such as dendritic cells (DC), which present them to naïve CD4+ T cells via major histocompatibility complex class II. In the presence of IL-4, naïve CD4+ T cells differentiate into Th2 cells. Secretion of IL-4 or IL-13 by Th2 cells causes an isotype switch to IgE in B cells. Allergen-specific IgE engages to FcεRI on mast cells. If allergens bind to specific IgE, FcεRI is cross-linked, followed by the release of mast cell mediators such as histamine and tryptase and induction of allergic symptoms. The circadian clock consists of the central oscillator, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and peripheral oscillators present in virtually all cell types. Light activates photoreceptors and via retinohypothalamic tract (RHT) the central SCN clock. Peripheral circadian clocks are synchronized and entrained by autonomic innervation and humoral factors. Clocks in peripheral tissues use the same molecular components like present in SCN, as the core molecular clock consists of interlocked transcriptional and translational feedback loops. Core clock proteins BMAL1 and CLOCK form a heterodimer and, by binding to E-box-motifs, induce the expression of other clock components. Among them are BMAL1 positively regulatory proteins like RORα as well as negatively regulatory proteins like REV-ERBs, PERs, and CRYs, thus concurrently attenuate their own transcription and initiate a new transcription cycle. DBP and NFIL3 form another loop that regulates transcription of genes containing D-box sequences, including those for PERs, and thus cooperate with the core clock to establish robust 24-h rhythms. The mast cell clock may temporally gate expression of FcεRI, ST2, OCT3, etc., via CLOCK and E-box elements, thereby generating a marked circadian variation in IgE/mast cell-mediated allergic reactions.
