Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110 007, India.
Nat Commun. 2012 Jun 6;3:877. doi: 10.1038/ncomms1880.
Inositol polyphosphate phosphatases regulate the magnitude of phosphoinositide-3 kinase signalling output. Although inositol polyphosphate-4-phosphatase is known to regulate phosphoinositide-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 of asthma. Allergic airway inflammation in mice led to calpain-mediated degradation of inositol polyphosphate-4-phosphatase. In allergic airway inflammation models, preventing inositol polyphosphate-4-phosphatase degradation by inhibiting calpain activity, or overexpression of inositol polyphosphate-4-phosphatase in mouse lungs, led to attenuation of the asthma phenotype. Conversely, knockdown of inositol polyphosphate-4-phosphatase severely aggravated the allergic airway inflammation and the asthma phenotype. Interestingly, inositol polyphosphate-4-phosphatase knockdown in lungs of naive mice led to spontaneous airway hyper-responsiveness, suggesting that inositol polyphosphate-4-phosphatase could be vital in maintaining the lung homeostasis. We suggest that inositol polyphosphate-4-phosphatase has an important role in modulating inflammatory response in asthma, and thus, uncover a new understanding of the complex interplay between inositol signalling and asthma, which could provide alternative strategies in asthma management.
肌醇多磷酸磷酸酶调节磷酸肌醇-3 激酶信号输出的幅度。虽然已知肌醇多磷酸-4-磷酸酶可调节磷酸肌醇-3 激酶信号，但对其在哮喘发病机制中的作用知之甚少。在这里，我们表明肌醇多磷酸-4-磷酸酶的调节可改变哮喘的严重程度。在小鼠中，过敏气道炎症导致钙蛋白酶介导的肌醇多磷酸-4-磷酸酶降解。在过敏气道炎症模型中，通过抑制钙蛋白酶活性或在小鼠肺部过表达肌醇多磷酸-4-磷酸酶来防止肌醇多磷酸-4-磷酸酶降解，可减轻哮喘表型。相反，肌醇多磷酸-4-磷酸酶的敲低严重加重了过敏气道炎症和哮喘表型。有趣的是，在无敏小鼠的肺部敲低肌醇多磷酸-4-磷酸酶会导致自发性气道高反应性，这表明肌醇多磷酸-4-磷酸酶在维持肺稳态方面可能至关重要。我们认为肌醇多磷酸-4-磷酸酶在调节哮喘中的炎症反应中具有重要作用，从而为肌醇信号与哮喘之间的复杂相互作用提供了新的认识，这可能为哮喘管理提供替代策略。
