Airway exposure to polyethyleneimine nanoparticles induces type 2 immunity by a mechanism involving oxidative stress and atp release

Yotesawee Srisomboon, Noriyuki Ohkura, Koji Iijima, Takao Kobayashi, Peter J. Maniak, Hirohito Kita, Scott M. O’grady

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8 Scopus citations


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,10 Panx (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.

Original languageEnglish (US)
Article number9071
JournalInternational journal of molecular sciences
Issue number16
StatePublished - Aug 2 2021

Bibliographical note

Funding Information:
Funding: This research was supported by a grant from the National Institutes of Health (AI128729) to HK and SMO and by a grant from the Minnesota Agriculture Research Station (16-096 USDA/AES-CRIS) to SMO.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Allergic inflammation
  • IL-33
  • Intracellular Ca
  • Purinergic signaling
  • Th2 cytokines


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