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Respiratory research
Original article
Airway epithelial phosphoinositide 3-kinase-δ contributes to the modulation of fungi-induced innate immune response
  1. Jae Seok Jeong1,
  2. Kyung Bae Lee1,
  3. So Ri Kim1,2,
  4. Dong Im Kim1,
  5. Hae Jin Park1,
  6. Hern-Ku Lee3,
  7. Hyung Jin Kim2,4,
  8. Seong Ho Cho5,
  9. Narasaiah Kolliputi5,
  10. Soon Ha Kim6,
  11. Yong Chul Lee1,2
  1. 1 Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea
  2. 2 Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea
  3. 3 Department of Immunology, Chonbuk National University Medical School, Jeonju, South Korea
  4. 4 Department of Urology, Chonbuk National University Medical School, Jeonju, South Korea
  5. 5 Division of Allergy and Immunology, Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
  6. 6 Department of Product Strategy and Development, LG Life Sciences Ltd, Seoul, South Korea
  1. Correspondence to Professor Yong Chul Lee, Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju 561-180, South Korea; leeyc{at}jbnu.ac.kr

Abstract

Background Respiratory fungal exposure is known to be associated with severe allergic lung inflammation. Airway epithelium is an essential controller of allergic inflammation. An innate immune recognition receptor, nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome, and phosphoinositide 3 kinase (PI3K)-δ in airway epithelium are involved in various inflammatory processes.

Objectives We investigated the role of NLRP3 inflammasome in fungi-induced allergic lung inflammation and examined the regulatory mechanism of NLRP3 inflammasome, focusing on PI3K-δ in airway epithelium.

Methods We used two in vivo models induced by exposure to Aspergillus fumigatus (Af) and Alternaria alternata (Aa), as well as an Af-exposed in vitro system. We also checked NLRP3 expression in lung tissues from patients with allergic bronchopulmonary aspergillosis (ABPA).

Results Assembly/activation of NLRP3 inflammasome was increased in the lung of Af-exposed mice. Elevation of NLRP3 inflammasome assembly/activation was observed in Af-stimulated murine and human epithelial cells. Similarly, pulmonary expression of NLRP3 in patients with ABPA was increased. Importantly, neutralisation of NLRP3 inflammasome derived IL-1β alleviated pathophysiological features of Af-induced allergic inflammation. Furthermore, PI3K-δ blockade improved Af-induced allergic inflammation through modulation of NLRP3 inflammasome, especially in epithelial cells. This modulatory role of PI3K-δ was mediated through the regulation of mitochondrial reactive oxygen species (mtROS) generation. NLRP3 inflammasome was also implicated in Aa-induced eosinophilic allergic inflammation, which was improved by PI3K-δ blockade.

Conclusion These findings demonstrate that fungi-induced assembly/activation of NLRP3 inflammasome in airway epithelium may be modulated by PI3K-δ, which is mediated partly through the regulation of mtROS generation. Inhibition of PI3K-δ may have potential for treating fungi-induced severe allergic lung inflammation.

  • airway epithelium
  • allergic lung disease
  • innate immunity
  • aspergillus lung disease
  • asthma mechanisms
  • oxidative stress

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/thoraxjnl-2017-210326

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    Footnotes

    • JSJ, KBL and SRK contributed equally.

    • Contributors JSJ interpreted data and wrote the manuscript. KBL, DIK and HJP conducted experiments and performed analysis. H-KL, HJK, SHC, NK and SHK reviewed and edited the manuscript. SRK and YCL designed research, interpreted data, and edited the manuscript.

    • Funding This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2014R1A2A1A01002823; Y.C.L.).

    • Competing interests None declared.

    • Ethics approval Institutional Review Board of the Biomedical Research Institute of Chonbuk National University Hospital (IRB file No. 2013-11-007-001).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Presented at Some of our data have been previously presented in the form of an abstract at an international scientific meeting (the 22nd congress of the Asia Pacific Society of Respirology, 2017).