Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severityof allergic airway inflammation

摘要

Inositol polyphosphate phosphatases regulate the magnitude of phosphoinositide-3 kinasesignalling output. Although inositol polyphosphate-4-phosphatase is known to regulatephosphoinositide-3 kinase signalling, little is known regarding its role in asthma pathogenesis.Here we show that modulation of inositol polyphosphate-4-phosphatase alters the severity ofasthma. Allergic airway inflammation in mice led to calpain-mediated degradation of inositolpolyphosphate-4-phosphatase. In allergic airway inflammation models, preventing inositolpolyphosphate-4-phosphatase degradation by inhibiting calpain activity, or overexpressionof inositol polyphosphate-4-phosphatase in mouse lungs, led to attenuation of the asthmaphenotype. Conversely, knockdown of inositol polyphosphate-4-phosphatase severelyaggravated the allergic airway inflammation and the asthma phenotype. Interestingly, inositolpolyphosphate-4-phosphatase knockdown in lungs of naive mice led to spontaneous airwayhyper-responsiveness, suggesting that inositol polyphosphate-4-phosphatase could be vital inmaintaining the lung homeostasis. We suggest that inositol polyphosphate-4-phosphatase hasan important role in modulating inflammatory response in asthma, and thus, uncover a newunderstanding of the complex interplay between inositol signalling and asthma, which couldprovide alternative strategies in asthma management.