Fungal allergen‐induced IL‐33 secretion involves cholesterol‐dependent, VDAC‐1‐mediated ATP release from the airway epithelium

Abstract

Alternaria 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. r 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. r 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. r Pretreatment with simvastatin for 24 h also inhibited the increase in tight junction macromolecule permeability that occurs following Alternaria exposure. r 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.

International consensus statement on allergy and rhinology: rhinosinusitis 2021

“…IL‐33 is a key epithelial cell derived cytokine and driver of the Type 2 immune response. Sinonasal epithelial cells increase IL‐33 expression and production when challenged with fungi 626,627 . This increase in IL‐33 is in part associated with a fungal serine protease activated receptor 2 (PAR2) 628 .…”

“…In AFRS, PAR2 expression is increased on SNECs 628,629 . In addition, fungi can also drive an increased intracellular uptake of calcium via P2X 7 receptor activation that also leads to increase in IL‐33 secretion 627 . These 2 pathways describe how fungi can initiate the Type 2 immune response of CRSwNP via IL‐33.…”

Treating fungus‐induced allergic asthma: Do VDACs have the answer!

“…Nevertheless, the studies by Srisomboon et al . (2020) establish VDAC‐1 as a pathway involved in fungal allergen‐induced ATP release and IL‐33 production and suggest a therapeutic use for cholesterol lowering compounds with respect to reducing fungus‐stimulated allergic inflammation. However, additional studies in animal models of allergic airway disease are needed to evaluate the therapeutic potential of these findings.…”

“…In this issue of The Journal of Physiology , Srisomboon et al . (2020) extend their previous work and report the novel finding that allergens from Alternaria release IL‐33 via the extracellular ATP‐dependent pathway involving P2X7 receptors and increased Ca 2+ uptake across the plasma membrane. More importantly, they demonstrate that ATP was released upon exposure to Alternaria allergens (AA) following activation of voltage‐dependent anion channel‐1 (VDAC‐1), which is located in the plasma membrane of airway epithelial cells.…”

“…The additional cholesterol lowering property for VDAC inhibition, as shown in the study by Srisomboon et al . (2020), makes the case for the repurposing of statins much stronger and their use through inhalation is an option worthy of exploration. However, such use of statins may have its limitations and the benefits and risks need to be considered carefully.…”