Aldh2 Attenuates Stem Cell Factor/Kit-Dependent Signaling and Activation in Mast Cells
Open Access
- 10 December 2019
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 20 (24), 6216
- https://doi.org/10.3390/ijms20246216
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.Funding Information
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (AI001206)
This publication has 39 references indexed in Scilit:
- Mitochondrial aldehyde dehydrogenase prevents ROS-induced vascular contraction in angiotensin-II hypertensive miceJournal of the American Society of Hypertension, 2011
- Over-expression of aldehyde dehydrogenase-2 protects against H2O2-induced oxidative damage and apoptosis in peripheral blood mononuclear cellsActa Pharmacologica Sinica, 2011
- Measuring Mast Cell Mediator ReleaseCurrent Protocols in Immunology, 2010
- Aldehyde Dehydrogenase Activation Prevents Reperfusion Arrhythmias by Inhibiting Local Renin Release From Cardiac Mast CellsCirculation, 2010
- SHP-1 Deficient Mast Cells Are Hyperresponsive to Stimulation and Critical in Initiating Allergic Inflammation in the LungThe Journal of Immunology, 2009
- Mitochondrial Uncoupling Protein 2 Inhibits Mast Cell Activation and Reduces Histamine ContentThe Journal of Immunology, 2009
- The tyrosine kinase network regulating mast cell activationImmunological Reviews, 2009
- New developments in mast cell biologyNature Immunology, 2008
- Mast cells and mastocytosisBlood, 2008
- Acetaldehyde Induces Histamine Release from Human Airway Mast Cells to Cause BronchoconstrictionInternational Archives of Allergy and Immunology, 2004