Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation.
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.
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.
Jyotirmoi
J
Aich
Ulaganathan
U
Mabalirajan
Tanveer
T
Ahmad
Anurag
A
Agrawal
Balaram
B
Ghosh
D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction
D034741:RNA, Small Interfering; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; D002154:Calpain