Secretory Inositol Polyphosphate 4-Phosphatase Protects Against Airway Inflammation and Remodeling.

The asthma candidate gene, inositol polyphosphate 4-phosphatase (INPP4A) is a lipid phosphatase that negatively regulates the phosphoinositide-3-kinase (PI3K)/Akt pathway. Destabilizing genetic variants of INPP4A increase asthma risk and lung-specific INPP4A knockdown induces asthma-like features. INPP4A is known to localise 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 extracellular INPP4A critically inhibits airway inflammation and remodeling. INPP4A was present in blood and broncho-alveolar lavage fluid and this extracellular INPP4A was reduced in asthma patients and mice with allergic airway inflammation (AAI). In mice with AAI as well as naïve mice, antibody-mediated neutralization of extracellular INPP4A potentiated PI3K/Akt signaling and induced airway hyperresponsiveness, with prominent airway remodeling, sub-epithelial 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 (EV) and in a free form. EV mediated transfer of labelled 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.