Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 76, Issue 18, Pages 3667-3678Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-019-03113-5
Keywords
Cardiolipin; Toll-like receptor (TLR); TLR4-antagonist; TLR4-agonist; Inflammation resolution; Barth syndrome; Vaccine adjuvant; Anti-inflammatory
Categories
Funding
- FRIA-FNRS [F3/5/5-MCF/XH/FC-17514]
- Wiener-Anspach Foundation
- Wallonie-Bruxelles International
- Wellcome Trust [WT100321/z/12/Z, 108045/Z/15/Z]
- Medical Research Council [RG87390]
- Wiener Anspach Foundation
- Marie Curie Actions [TLR4-CAT PIEF-GA-2012-326481]
- European Research Council [ERC-2013-CoG 614578]
- MRC [MR/S002340/1] Funding Source: UKRI
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Cardiolipins (CLs) are tetra-acylated diphosphatidylglycerols found in bacteria, yeast, plants, and animals. In healthy mammals, CLs are unsaturated, whereas saturated CLs are found in blood cells from Barth syndrome patients and in some Gram-positive bacteria. Here, we show that unsaturated but not saturated CLs block LPS-induced NF-kappa B activation, TNF-alpha and IP-10 secretion in human and murine macrophages, as well as LPS-induced TNF-alpha and IL-1 beta release in human blood mononuclear cells. Using HEK293 cells transfected with Toll-like receptor 4 (TLR4) and its co-receptor Myeloid Differentiation 2 (MD2), we demonstrate that unsaturated CLs compete with LPS for binding TLR4/MD2 preventing its activation, whereas saturated CLs are TLR4/MD2 agonists. As a consequence, saturated CLs induce a pro-inflammatory response in macrophages characterized by TNF-alpha and IP-10 secretion, and activate the alternative NLRP3 inflammasome pathway in human blood-derived monocytes. Thus, we identify that double bonds discriminate between anti- and pro-inflammatory properties of tetra-acylated molecules, providing a rationale for the development of TLR4 activators and inhibitors for use as vaccine adjuvants or in the treatment of TLR4-related diseases.
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