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

Jyotirmoi Aich, Ulaganathan Mabalirajan, Tanveer Ahmad, Anurag Agrawal and Balaram Ghosh ()
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Jyotirmoi Aich: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology
Ulaganathan Mabalirajan: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology
Tanveer Ahmad: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology
Anurag Agrawal: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology
Balaram Ghosh: Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: Abstract 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.

Date: 2012
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DOI: 10.1038/ncomms1880

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