Abstract
The cell-autonomous circadian clock regulates IgE- and IL-33-mediated mast cell activation, both of which are key events in the development of allergic diseases. Accordingly, clock modifiers could be used to treat allergic diseases, as well as many other circadian-related diseases, such as sleep and metabolic disorders. The nuclear receptors REV-ERB-α and -β (REV-ERBs) are crucial components of the circadian clockwork. Efforts to pharmacologically target REV-ERBs using putatively specific synthetic agonists, particularly SR9009, have yielded beneficial effects on sleep and metabolism. Here, we sought to determine whether REV-ERBs are functional in the circadian clockwork in mast cells and, if so, whether SR9009 affects IgE- and IL-33-mediated mast cell activation. Bone marrow-derived mast cells (BMMCs) obtained from wild-type mice expressed REV-ERBs, and SR9009 or other synthetic REV-ERBs agonists affected the mast cell clockwork. SR9009 inhibited IgE- and IL-33-mediated mast cell activation in wild-type BMMCs in association with inhibition of Gab2/PI3K and NF-κB activation. Unexpectedly, these suppressive effects of SR9009 were observed in BMMCs following mutation of the core circadian gene Clock. These findings suggest that SR9009 inhibits IgE- and IL-33-mediated mast cell activation independently of the functional circadian clock activity. Thus, SR9009 or other synthetic REV-ERB agonists may have potential for anti-allergic agents.
Highlights
The circadian clock controls a large proportion of genes in a cyclic manner, thereby regulating the timing of cellular activities [1,2]
Our results revealed that REV-ERBs are functional in mast cells, and that SR9009 inhibits IgE- and IL-33-mediated mast cell activation
This inhibition was independent of functional clock activity. These findings suggest that SR9009 or other synthetic REV-ERB agonists may have therapeutic potential against allergic diseases
Summary
The circadian clock controls a large proportion of genes in a cyclic manner, thereby regulating the timing of cellular activities [1,2]. The PER and CRY proteins form oligomers and enter the nucleus, where they inhibit BMAL1/CLOCK activity This negative-feedback loop takes ~24 h to be completed, with several post-transcriptional regulation. REV-ERBs regulate the expression of genes involved in the control of circadian rhythm, metabolism, and inflammatory response [9,10,11]. Administration of SR9009 induces wakefulness and reduces rapid-eye-movement (REM) and slow-wave sleep in mice [13] It remains unclear whether mast cells express functional REV-ERBs, and if so, whether synthetic REV-ERB agonists such as SR9009 would have beneficial in these cells. Our results revealed that REV-ERBs are functional in mast cells, and that SR9009 inhibits IgE- and IL-33-mediated mast cell activation. These findings suggest that SR9009 or other synthetic REV-ERB agonists may have therapeutic potential against allergic diseases
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