Secretory Inositol Polyphosphate 4-Phosphatase Protects against Airway Inflammation and Remodeling

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 of INPP4A increase 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 extracellular INPP4A 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.

EVs from BALF—Mediators of Inflammation and Potential Biomarkers in Lung Diseases

“…Furthermore, it was shown in asthma that airway epithelial cells secrete the lipid phosphatase inositol polyphosphate 4-phosphatase type I A (INPP4A) in the form of extracellular vesicles, which negatively regulate the phosphatidylinositol 3-kinase/serine/threonine protein kinase B (PI3K/Akt) pathway and inhibit airway inflammation and remodeling. Antibody-mediated neutralization of this vesicular INPP4A induced airway hyperresponsiveness, with prominent airway remodeling, subepithelial fibroblast proliferation, and collagen deposition in a murine model of asthma [ 89 ]. The anti-inflammatory effects of BALF-EVs are listed in Table 2 .…”

Extracellular Vesicles and Asthma—More Than Just a Co-Existence

“…In vitro experiments using cell lines demonstrated that AECs were able to secrete enzymatically active inositol polyphosphate 4-phosphatase type I A (INPP4A) in EVs and as a soluble free form. INPP4A was then transferred to lung fibroblasts, and inhibition of such transfer resulted in increased fibroblast proliferation [ 65 ]. Moreover, in mice with or without AAI neutralization of extracellular INPP4A-induced AHR, with prominent airway remodeling, subepithelial fibroblast proliferation, and collagen deposition [ 65 ].…”

“…INPP4A was then transferred to lung fibroblasts, and inhibition of such transfer resulted in increased fibroblast proliferation [ 65 ]. Moreover, in mice with or without AAI neutralization of extracellular INPP4A-induced AHR, with prominent airway remodeling, subepithelial fibroblast proliferation, and collagen deposition [ 65 ]. EV-mediated interactions between major cellular players involved in asthma/AAI (reported in Section 5.1 , Section 5.2 , Section 5.3 , Section 5.4 and Section 5.5 ) are summarized in Figure 3 .…”

The Role of Non-Immune Cell-Derived Extracellular Vesicles in Allergy

“…Specifically, it has been shown that fibroblasts-derived EVs secreted by cells obtained from severe asthmatics increase proliferation of bronchial epithelial cells (HBECs) in comparison to those in healthy individuals, due to a decrease in the TGF-b2 content (178). Vice versa, vesicular transfer between epithelial cells and fibroblasts which includes inositol polyphosphate 4-phosphatase type I A (INPP4A) cargo, may regulate inflammation and airway remodeling (179). Further to that, Gupta et al have shown that sEV transfer between airway epithelial cells (AECs) and human tracheobronchial cells (HTBEs) promotes expression several proteins which may contribute to allergic inflammation and exacerbation of asthma symptoms, i.e.…”