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A critical role for ABC transporters in persistent lung inflammation in the development of emphysema after smoke exposure
Author(s) -
Sonett Jarrod,
Goldklang Monica,
Sklepkiewicz Piotr,
Gerber Adam,
Trischler Jordis,
Zelonina Tina,
Westerterp Marit,
Lemaître Vincent,
Okada Yasunori,
Armiento Jeanine D’
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201701381
Subject(s) - abca1 , inflammation , liver x receptor , abcg1 , tlr4 , cholesterol , chemistry , pharmacology , immunology , medicine , transporter , biochemistry , nuclear receptor , transcription factor , gene
ABSTRACT Macrophage infiltration is common to both emphysema and atherosclerosis, and cigarette smoke down‐regulates the macrophage cholesterol efflux transporter ATP binding cassette (ABC)A1. This decreased cholesterol efflux results in lipid‐laden macrophages. We hypothesize that cigarette smoke adversely affects cholesterol transport via an ABCA1‐dependent mechanism in macrophages, enhancing TLR4/myeloid differentiation primary response gene 88 (Myd88) signaling and resulting in matrix metalloproteinase (MMP) up‐regulation and exacerbation of pulmonary inflammation. ABCA1 is significantly down‐regulated in the lung upon smoke exposure conditions. Macrophages exposed to cigarette smoke in vivo and in vitro exhibit impaired cholesterol efflux correlating with significantly decreased ABCA1 expression, up‐regulation of the TLR4/Myd88 pathway, and downstream MMP‐9 and MMP‐13 expression. Treatment with liver X receptor (LXR) agonist restores ABCA1 expression after short‐term smoke exposure and attenuates the inflammatory response; after long‐term smoke exposure, there is also attenuated physiologic and morphologic changes of emphysema. In vitro , treatment with LXR agonist decreases macrophage inflammatory activation in wild‐type but not ABCA1 knockout mice, suggesting an ABCA1‐dependent mechanism of action. These studies demonstrate an important association between cigarette smoke exposure and cholesterol‐mediated pathways in the macrophage inflammatory response. Modulation of these pathways through manipulation of ABCA1 activity effectively blocks cigarette smoke–induced inflammation and provides a potential novel therapeutic approach for the treatment of chronic obstructive pulmonary disease.—Sonett, J., Goldklang, M., Sklepkiewicz, P., Gerber, A., Trischler, J., Zelonina, T., Westerterp, M., Lemaître, V., Okada, V., D’Armiento, J. A critical role for ABC transporters in persistent lung inflammation in the development of emphysema after smoke exposure. FASEB J. 32, 6724–6736 (2018). www.fasebj.org