Abstract
Mitochondrial aldehyde dehydrogenase (ALDH2) metabolizes endogenous and exogenous aldehydes and protects cells against oxidative injury. Inactivating genetic polymorphisms in humans are common and associate with alcohol flush reactions. However, whether mast cell Aldh2 activity impacts normal mast cell responses is unknown. Using bone marrow-derived mast cells from Aldh2 knockout mice, we found evidence for a role of mast cell Aldh2 in Kit-mediated responses. Aldh2-deficient mast cells showed enhanced Kit tyrosine kinase phosphorylation and activity after stimulation with its ligand (stem cell factor) and augmentation of downstream signaling pathways, including Stat4, MAPKs, and Akt. The activity of the phosphatase Shp-1, which attenuates Kit activity, was reduced in Aldh2−/− mast cells, along with an increase in reactive oxygen species, known to regulate Shp-1. Reduced Shp-1 activity concomitant with sustained Kit signaling resulted in greater proliferation following Kit engagement, and increased mediator and cytokine release when Aldh2−/− mast cells were co-stimulated via Kit and FcεRI. However, FcεRI-mediated signaling and responses were unaffected. Therefore, our findings reveal a functional role for mast cell intrinsic Aldh2 in the control of Kit activation and Kit-mediated responses, which may lead to a better understanding of mast cell reactivity in conditions related to ALDH2 polymorphisms.
Highlights
Aldehyde dehydrogenase 2 (Aldh2) is a mitochondrial enzyme that protects cells from biogenic aldehydes accumulated through metabolism, and the most efficient isoenzyme within the family of ALDH enzymes to remove toxic acetaldehyde derived from the metabolism of alcohol [1]
Flushing has been linked to the activation of mast cells [6,7] and in alcohol flushing mast cell involvement is suggested by reports showing that the metabolite of alcohol acetaldehyde causes mast cell degranulation and increases histamine release [8,9,10], and by the improvement of alcohol flushing by antihistamine treatment [11]
When 5-week-old mature bone marrow-derived mast cells (BMMCs) were plated at the same density, Aldh2−/− cells continued to increase in number at a higher rate than Aldh2+/+ BMMCs (Figure 1C)
Summary
Aldehyde dehydrogenase 2 (Aldh2) is a mitochondrial enzyme that protects cells from biogenic aldehydes accumulated through metabolism, and the most efficient isoenzyme within the family of ALDH enzymes to remove toxic acetaldehyde derived from the metabolism of alcohol [1]. A genetic polymorphism (rs671) in ALDH2 (ALDH2*2) is the most common single point mutation in humans, present in approximately 40% of Eastern Asian populations [1,4] This polymorphism causes a severe reduction in ALDH2 activity, even in heterozygous individuals, through a dominant negative effect and is associated with conditions such as alcohol flush syndrome [5], manifested by facial flushing, headaches, nausea, dizziness, and cardiac palpitations after the consumption of alcoholic beverages [1]. FcεRI stimulation in tissues occurs in the context of signals derived from Kit, the receptor for the stem cell factor (SCF) which is produced in tissues and enhances mast cell responses to IgE/Ag and other mast cell stimulants. Understanding the factors that impact Kit signaling in mast cells is important for understanding mast cell responsiveness
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