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High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling

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E. P. C. van der Vorst, K. Theodorou, Y. Wu, M. A. Hoeksema, P. Goossens, C. A. Bursill, T. Aliyev, L. F. A. Huitema, S. W. Tas, I. M. J. Wolfs, M. J. E. Kuijpers, M. J. Gijbels, C. G. Schalkwijk, D. P. Y. Koonen, S. Abdollahi-Roodsaz, K. McDaniels, C. C. Wang, M. Leitges, T. Lawrence, J. Plat & 6 more M. Van Eck, K. A. Rye, L. Touqui, M. P. J. de Winther, E. A. L. Biessen, M. M. P.C Donners

Original languageEnglish
Pages (from-to)197-207
Number of pages11
JournalCELL METABOLISM
Volume25
Issue number1
DOIs
Accepted/In press20 Oct 2016
Published10 Jan 2017

King's Authors

Abstract

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.

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