Abstract
Sirt1, a key regulator of metabolism and longevity, has recently been implicated in the regulation of allergic reactions, although the underlying mechanism remains unclear. Here we show that Sirt1 negatively regulates FcεRI-stimulated mast cell activation and anaphylaxis through two mutually regulated pathways involving AMP-activated protein kinase (AMPK) and protein tyrosine phosphatase 1B (PTP1B). Mast cell-specific knockout of Sirt1 dampened AMPK-dependent suppression of FcεRI signaling, thereby augmenting mast cell activation both in vitro and in vivo. Sirt1 inhibition of FcεRI signaling also involved an alternative component, PTP1B, which attenuated the inhibitory AMPK pathway and conversely enhanced the stimulatory Syk pathway, uncovering a novel role of this phosphatase. Moreover, a Sirt1 activator resveratrol stimulated the inhibitory AMPK axis, with reciprocal suppression of the stimulatory PTP1B/Syk axis, thus potently inhibiting anaphylaxis. Overall, our results provide a molecular explanation for the beneficial role of Sirt1 in allergy and underscore a potential application of Sirt1 activators as a new class of anti-allergic agents.
Highlights
Sirt[1], a key regulator of metabolism and longevity, has recently been implicated in the regulation of allergic reactions, the underlying mechanism remains unclear
Given that Sirt[1] lies upstream of AMPK34, 36, we investigated the effect of resveratrol, a Sirt[1] activator, on IgE/Ag-stimulated mast cell activation in the context of AMPK signaling
To determine the proper concentration of resveratrol for Sirt[1] activation, mouse bone marrow-derived mast cells (BMMCs) sensitized with anti-dinitrophenyl (DNP) IgE were treated with various concentrations (1–100 μM) of resveratrol for 1 h prior to stimulation with DNP-human serum albumin (HSA) as an Ag
Summary
Sirt[1], a key regulator of metabolism and longevity, has recently been implicated in the regulation of allergic reactions, the underlying mechanism remains unclear. Crosslinking of FcεRI-bound IgE with antigen (Ag) on mast cells induces the activation of proximal FcεRI-associated Src kinases (Lyn and Fyn) and Syk, which in turn activate multiple signaling pathways including phospholipase Cγ (PLCγ), mitogen-activated protein kinases, Akt and NF-κB, leading to release of preformed mediators by degranulation and de novo synthesis of lipid mediators and cytokines[1, 2] Besides these positive signaling pathways, understanding of the negative regulatory mechanisms that turn off positive signals is of importance to gain comprehensive insights into FcεRI signaling and thereby a novel strategy for treatment of allergic diseases. It can be speculated that Sirt[1] may have a negative regulatory role in mast cell activation through interaction with AMPK, experimental evidence for this hypothesis has currently been lacking
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