PT  - JOURNAL ARTICLE
AU  - Jeong, Jae Seok
AU  - Lee, Kyung Bae
AU  - Kim, So Ri
AU  - Kim, Dong Im
AU  - Park, Hae Jin
AU  - Lee, Hern-Ku
AU  - Kim, Hyung Jin
AU  - Cho, Seong Ho
AU  - Kolliputi, Narasaiah
AU  - Kim, Soon Ha
AU  - Lee, Yong Chul
TI  - Airway epithelial phosphoinositide 3-kinase-δ contributes to the modulation of fungi-induced innate immune response
AID  - 10.1136/thoraxjnl-2017-210326
DP  - 2018 Aug 01
TA  - Thorax
PG  - 758--768
VI  - 73
IP  - 8
4099  - http://thorax.bmj.com/content/73/8/758.short
4100  - http://thorax.bmj.com/content/73/8/758.full
SO  - Thorax2018 Aug 01; 73
AB  - 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.