In:
Thorax, BMJ, Vol. 73, No. 8 ( 2018-08), p. 758-768
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0040-6376
,
1468-3296
DOI:
10.1136/thoraxjnl-2017-210326
DOI:
10.1136/thoraxjnl-2017-210326.supp13
DOI:
10.1136/thoraxjnl-2017-210326.supp1
DOI:
10.1136/thoraxjnl-2017-210326.supp2
DOI:
10.1136/thoraxjnl-2017-210326.supp3
DOI:
10.1136/thoraxjnl-2017-210326.supp4
DOI:
10.1136/thoraxjnl-2017-210326.supp5
DOI:
10.1136/thoraxjnl-2017-210326.supp6
DOI:
10.1136/thoraxjnl-2017-210326.supp7
DOI:
10.1136/thoraxjnl-2017-210326.supp8
DOI:
10.1136/thoraxjnl-2017-210326.supp9
DOI:
10.1136/thoraxjnl-2017-210326.supp10
DOI:
10.1136/thoraxjnl-2017-210326.supp11
DOI:
10.1136/thoraxjnl-2017-210326.supp12
Language:
English
Publisher:
BMJ
Publication Date:
2018
detail.hit.zdb_id:
1481491-2
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