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Fungal allergen‐induced IL‐33 secretion involves cholesterol‐dependent, VDAC‐1‐mediated ATP release from the airway epithelium
Author(s) -
Srisomboon Yotesawee,
Squillace Diane L.,
Maniak Peter J.,
Kita Hirohito,
O'Grady Scott M.
Publication year - 2020
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp279379
Subject(s) - voltage dependent anion channel , secretion , chemistry , intracellular , respiratory epithelium , microbiology and biotechnology , cytosol , biochemistry , biology , epithelium , enzyme , bacterial outer membrane , genetics , escherichia coli , gene
Key pointsAlternaria aeroallergens induce the release of ATP from human bronchial epithelial (HBE) cells by activating a conductive pathway involving voltage‐dependent anion channel‐1 (VDAC‐1) and by exocytosis of ATP localized within membrane vesicles. Inhibition of VDAC‐1 blocked Alternaria ‐evoked Ca 2+ uptake across the plasma membrane of HBE cells and interleukin (IL)‐33 release into the extracellular media. Reducing cholesterol content with a cholesterol scavenger (β‐methylcyclodextrin) or statin compound (simvastatin) blocked ATP and IL‐33 release by lowering the expression of VDAC‐1 in the plasma membrane. Pretreatment with simvastatin for 24 h also inhibited the increase in tight junction macromolecule permeability that occurs following Alternaria exposure. These results establish a novel role for VDAC‐1 as a mechanism underlying ATP release induced by fungal allergens and suggests a possible therapeutic use for cholesterol lowering compounds in reducing Alternaria ‐stimulated allergic inflammation.Abstract Human bronchial epithelial (HBE) cells exposed to allergens derived from the common saprophytic fungus, Alternaria alternata release ATP, which in turn stimulates P2X 7 receptor‐mediated Ca 2+ uptake across the plasma membrane. The subsequent increase in intracellular calcium concentration induces proteolytic processing and secretion of interleukin (IL)‐33, a critical cytokine involved in the initiation of allergic airway inflammation. A major objective of the present study was to identify the mechanism responsible for conductive ATP release. The results show that pretreatment of HBE cells with inhibitors of the voltage‐dependent anion channel‐1 (VDAC‐1) or treatment with a VDAC‐1 selective blocking antibody or silencing mRNA expression of the channel by RNA interference, inhibit Alternaria ‐evoked ATP release. Moreover, inhibition of VDAC‐1 channel activity or reducing protein expression blocked the secretion of IL‐33. Similarly, reducing the cholesterol content of HBE cells with simvastatin or the cholesterol scavenger β‐methylcyclodextrin also blocked ATP release and IL‐33 secretion by decreasing the level of VDAC‐1 expression in the plasma membrane. In addition, simvastatin inhibited the increase in tight junction macromolecule permeability that was previously observed after Alternaria exposure. These results demonstrate a novel function for VDAC‐1 as the conductive mechanism responsible for Alternaria ‐induced ATP release, an essential early step in the processing, mobilization and secretion of IL‐33 by the airway epithelium. Furthermore, the simvastatin‐evoked reduction of VDAC‐1 expression in the plasma membrane, suggests the possibility that cholesterol lowering compounds may be beneficial in alleviating allergic airway inflammation induced by fungal allergens.