TY - JOUR
T1 - High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling
AU - van der Vorst, Emiel P. C.
AU - Theodorou, Kosta
AU - Wu, Yongzheng
AU - Hoeksema, Marten A.
AU - Goossens, Pieter
AU - Bursill, Christina A.
AU - Aliyev, Taghi
AU - Huitema, Leonie F. A.
AU - Tas, Sander W.
AU - Wolfs, Ine M. J.
AU - Kuijpers, Marijke J. E.
AU - Gijbels, Marion J.
AU - Schalkwijk, Casper G.
AU - Koonen, Debby P. Y.
AU - Abdollahi-Roodsaz, Shahla
AU - McDaniels, Kimberly
AU - Wang, Chih-Chieh
AU - Leitges, Michael
AU - Lawrence, Toby
AU - Plat, Jogchum
AU - van Eck, Miranda
AU - Rye, Kerry-Anne
AU - Touqui, Lhousseine
AU - de Winther, Menno P. J.
AU - Biessen, Erik A. L.
AU - Donners, Marjo M. P. C.
PY - 2017
Y1 - 2017
N2 - Membrane cholesterol modulates a variety of cell signaling pathways and functions. While cholesterol depletion by high-density lipoproteins (HDLs) has potent anti-inflammatory effects in various cell types, its effects on inflammatory responses in macrophages remain elusive. Here we show overt pro-inflammatory effects of HDL-mediated passive cholesterol depletion and lipid raft disruption in murine and human primary macrophages in vitro. These pro-inflammatory effects were confirmed in vivo in peritoneal macrophages from apoA-I transgenic mice, which have elevated HDL levels. In line with these findings, the innate immune responses required for clearance of P. aeruginosa bacterial infection in lung were compromised in mice with low HDL levels. Expression analysis, ChIP-PCR, and combinatorial pharmacological and genetic intervention studies unveiled that both native and reconstituted HDL enhance Toll-like-receptor-induced signaling by activating a PKC-NF-κB/STAT1-IRF1 axis, leading to increased inflammatory cytokine expression. HDL's pro-inflammatory activity supports proper functioning of macrophage immune responses
AB - Membrane cholesterol modulates a variety of cell signaling pathways and functions. While cholesterol depletion by high-density lipoproteins (HDLs) has potent anti-inflammatory effects in various cell types, its effects on inflammatory responses in macrophages remain elusive. Here we show overt pro-inflammatory effects of HDL-mediated passive cholesterol depletion and lipid raft disruption in murine and human primary macrophages in vitro. These pro-inflammatory effects were confirmed in vivo in peritoneal macrophages from apoA-I transgenic mice, which have elevated HDL levels. In line with these findings, the innate immune responses required for clearance of P. aeruginosa bacterial infection in lung were compromised in mice with low HDL levels. Expression analysis, ChIP-PCR, and combinatorial pharmacological and genetic intervention studies unveiled that both native and reconstituted HDL enhance Toll-like-receptor-induced signaling by activating a PKC-NF-κB/STAT1-IRF1 axis, leading to increased inflammatory cytokine expression. HDL's pro-inflammatory activity supports proper functioning of macrophage immune responses
U2 - https://doi.org/10.1016/j.cmet.2016.10.013
DO - https://doi.org/10.1016/j.cmet.2016.10.013
M3 - Article
C2 - 27866837
SN - 1550-4131
VL - 25
SP - 197
EP - 207
JO - Cell metabolism
JF - Cell metabolism
IS - 1
ER -