• Elizabeth M Gordon, Xianglan Yao, Haitao Xu, William Karkowsky, Maryann Kaler, Or Kalchiem-Dekel, Amisha V Barochia, Meixia Gao, Karen J Keeran, Kenneth R Jeffries, and Stewart J Levine.
• Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
• J. Allergy Clin. Immunol. 2019 Aug 1; 144 (2): 426-441.e3.

BackgroundHouse dust mite (HDM)-challenged Apoe-/- mice display enhanced airway hyperreactivity and mucous cell metaplasia.ObjectiveWe sought to characterize the pathways that induce apolipoprotein E (APOE) expression by bronchoalveolar lavage fluid (BALF) macrophages from asthmatic subjects and identify how APOE regulates IL-1β secretion.MethodsMacrophages were isolated from asthmatic BALF and derived from THP-1 cells and human monocytes.ResultsHDM-derived cysteine and serine proteases induced APOE secretion from BALF macrophages through protease-activated receptor 2. APOE at concentrations of less than 2.5 nmol/L, which are similar to levels found in epithelial lining fluid from healthy adults, did not induce IL-1β release from BALF macrophages. In contrast, APOE at concentrations of 25 nmol/L or greater induced nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein (NLRP) 3 and pro-IL-1β expression by BALF macrophages, as well as the caspase-1-mediated generation of mature IL-1β secreted from cells. HDM acted synergistically with APOE to both prime and activate the NLRP3 inflammasome. In a murine model of neutrophilic airway inflammation induced by HDM and polyinosinic-polycytidylic acid, APOE reached a concentration of 32 nmol/L in epithelial lining fluid, with associated increases in BALF IL-1β levels. APOE-dependent NLRP3 inflammasome activation in macrophages was primarily mediated through a potassium efflux-dependent mechanism.ConclusionAPOE can function as an endogenous, concentration-dependent pulmonary danger signal that primes and activates the NLPR3 inflammasome in BALF macrophages from asthmatic subjects to secrete IL-1β. This might represent a mechanism through which APOE amplifies pulmonary inflammatory responses when concentrations in the lung are increased to greater than normal levels, which can occur during viral exacerbations of HDM-induced asthma characterized by neutrophilic airway inflammation.Published by Elsevier Inc.

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