Abstract
Polyethyleneimine (PEI) induced immune responses were investigated in human bronchial epithelial (hBE) cells and mice. PEI rapidly induced ATP release from hBE cells and pretreatment with glutathione (GSH) blocked the response. PEI activated two conductive pathways, VDAC-1 and pannexin 1, which completely accounted for ATP efflux across the plasma membrane. Moreover, PEI increased intracellular Ca2+ concentration ([Ca2+]i), which was reduced by the pannexin 1 inhibitor, 10Panx (50 μM), the VDAC-1 inhibitor, DIDS (100 μM), and was nearly abolished by pretreatment with GSH (5 mM). The increase in [Ca2+]i involved Ca2+ uptake through two pathways, one blocked by oxidized ATP (oATP, 300 μM) and another that was blocked by the TRPV-1 antagonist A784168 (100 nM). PEI stimulation also increased IL-33 mRNA expression and protein secretion. In vivo experiments showed that acute (4.5 h) PEI exposure stimulated secretion of Th2 cytokines (IL-5 and IL-13) into bronchoalveolar lavage (BAL) fluid. Conjugation of PEI with ovalbumin also induced eosinophil recruitment and secretion of IL-5 and IL-13 into BAL fluid, which was inhibited in IL-33 receptor (ST2) deficient mice. In conclusion, PEI-induced oxidative stress stimulated type 2 immune responses by activating ATP-dependent Ca2+ uptake leading to IL-33 secretion, similar to allergens derived from Alternaria.
Highlights
The commercial production of engineered nanomaterials (ENMs) is a steadily growing industry with increasing potential to impact human health as exposure to consumer products containing ENMs becomes more prevalent [1,2,3,4,5]
Previous studies showed that human bronchial epithelial (HBE) cells exhibit a rapid and sustained release of ATP following exposure to Alternaria [26]
Initial rates of ATP release were determined from linear regression analysis of the ATP kinetic data (Figure 1A) between 0.5–2.0 min for PEI (6.58 ± 0.43), GSH + PEI (1.79 * ± 0.16) and DIDS + PEI (1.48 * ± 0.30) (Figure 1B)
Summary
The commercial production of engineered nanomaterials (ENMs) is a steadily growing industry with increasing potential to impact human health as exposure to consumer products containing ENMs becomes more prevalent [1,2,3,4,5]. PEI possesses a large number of positively charged amine groups, which enables electrostatic condensation with negatively charged molecules such as nucleic acids [14,18]. When PEI is used in excess during complexation and condensation reactions, PEI-nucleic acid polyplexes are formed that possess a net positive charge This positive zeta potential enables electrostatic interactions with specific negatively charged constituents within the plasma membrane, including heparin sulfate and proteoglycans, which facilitates uptake across the cell membrane by endocytic, pinocytotic or phagocytic mechanisms [16]. Cytotoxicity appears to be associated with the positive charge of PEI polyplexes
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