Secretory inositol polyphosphate 4-phosphatase protects against airway inflammation and remodeling

Kritika Khanna, Rituparna Chaudhuri, Jyotirmoi Aich, Bijay Pattnaik, Lipsa Panda, Y. S. Prakash, Ulaganathan Mabalirajan, Balaram Ghosh, Anurag Agrawal

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The asthma candidate gene inositol polyphosphate 4-phosphatase type I A (INPP4A) is a lipid phosphatase that negatively regulates the PI3K/Akt pathway.Destabilizing genetic variants ofINPP4Aincrease the risk of asthma, and lung-specific INPP4A knockdown induces asthma-like features.INPP4A is known to localize intracellularly, and its extracellular presence has not been reported yet. Here we show for the first time that INPP4A is secreted by airway epithelial cells and that extracellularINPP4A critically inhibits airway inflammation and remodeling. INPP4A was present in blood and BAL fluid, and this extracellular INPP4A was reduced in patients with asthma and mice with allergic airway inflammation. In both naive mice and mice with allergic airway inflammation, antibody-mediated neutralization of extracellular INPP4A potentiated PI3K/Akt signaling and induced airway hyperresponsiveness, with prominent airway remodeling, subepithelial fibroblast proliferation, and collagen deposition. The link between extracellular INPP4A and fibroblasts was investigated in vitro. Cultured airway epithelial cells secreted enzymatically active INPP4A in extracellular vesicles and in a free form. Extracellular vesicle-mediated transfer of labeled INPP4A, from epithelial cells to fibroblasts, was observed. Inhibition of such transfer by anti-INPP4A antibody increased fibroblast proliferation. We propose that secretory INPP4A is a novel "paracrine" layer of the intricate regulation of lung homeostasis, by which airway epithelium dampens PI3K/Akt signaling in inflammatory cells or local fibroblasts, thereby limiting inflammation and remodeling.

Original languageEnglish (US)
Pages (from-to)399-412
Number of pages14
JournalAmerican journal of respiratory cell and molecular biology
Volume60
Issue number4
DOIs
StatePublished - Apr 2019

Keywords

  • Airway remodeling asthma
  • Exosomes
  • INPP4A
  • Microvesicles
  • PI3K/Akt signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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