Apolipoprotein E is a concentration-dependent pulmonary danger signal that activates the NLRP3 inflammasome and IL-1? secretion by bronchoalveolar fluid macrophages from asthmatic subjects - 05/08/19
Abstract |
Background |
House dust mite (HDM)–challenged Apoe−/− mice display enhanced airway hyperreactivity and mucous cell metaplasia.
Objective |
We 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.
Methods |
Macrophages were isolated from asthmatic BALF and derived from THP-1 cells and human monocytes.
Results |
HDM-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.
Conclusion |
APOE 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.
El texto completo de este artículo está disponible en PDF.Key words : Asthma, apolipoprotein E, house dust mite, IL-1β, macrophages, NLRP3 inflammasome
Abbreviations used : APOE, ASC, BALF, ELF, HDM, HMDM, M-CSF, NF-κB, NHLBI, NLRC, NLRP, PAR, PMA, poly(I:C), P2RX7, TLR
Esquema
| This research was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 144 - N° 2
P. 426 - août 2019 Regresar al número
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