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© Research
Publication : Cell metabolism

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Cell metabolism - 17 Nov 2017

van der Vorst EP, Theodorou K, Wu Y, Hoeksema MA, Goossens P, Bursill CA, Aliyev T, Huitema LF, Tas SW, Wolfs IM, Kuijpers MJ, Gijbels MJ, Schalkwijk CG, Koonen DP, Abdollahi-Roodsaz S, McDaniels K, Wang CC, Leitges M, Lawrence T, Plat J, Van Eck M, Rye KA, Touqui L, de Winther MP, Biessen EA, Donners MM

Link to Pubmed [PMID] – 27866837

Cell Metab. 2017 Jan;25(1):197-207

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.

https://www.ncbi.nlm.nih.gov/pubmed/27866837