Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4

Autor: Pablo Pelegrín, Helios Martínez-Banaclocha, Panagiotis Tourlomousis, Monique Gangloff, Caroline Lonez, Alberto Baroja-Mazo, Jean Marie Ruysschaert, Malvina Pizzuto, Clare E. Bryant
Přispěvatelé: Pizzuto, Malvina [0000-0001-6330-6937], Apollo - University of Cambridge Repository
Rok vydání: 2019
Předmět:
Lipopolysaccharides
Lipopolysaccharide Receptors
Pharmacologie
Monocytes
Toll-like receptor (TLR)
Mice
chemistry.chemical_compound
0302 clinical medicine
Anti-Infective Agents
Cardiolipin
Inflammation resolution
Receptor
0303 health sciences
Toll-like receptor
NF-kappa B
Inflammasome
Transfection
3. Good health
Cell biology
Molecular Medicine
Original Article
lipids (amino acids
peptides
and proteins)
Sciences cognitives
Protein Binding
Signal Transduction
medicine.drug
Cardiolipins
Cell Survival
Lymphocyte Antigen 96
Vaccine adjuvant
Binding
Competitive
Peripheral blood mononuclear cell
03 medical and health sciences
Cellular and Molecular Neuroscience
TLR4-antagonist
NLR Family
Pyrin Domain-Containing 3 Protein
medicine
Animals
Humans
Secretion
Molecular Biology
030304 developmental biology
Pharmacology
Tumor Necrosis Factor-alpha
Macrophages
Biologie moléculaire
TLR4-agonist
Cell Biology
Chemokine CXCL10
Toll-Like Receptor 4
HEK293 Cells
chemistry
TLR4
Biologie cellulaire
Barth syndrome
Anti-inflammatory
030215 immunology
Zdroj: Cellular and molecular life sciences
ISSN: 1420-9071
1420-682X
DOI: 10.1007/s00018-019-03113-5
Popis: 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-κB activation, TNF-α and IP-10 secretion in human and murine macrophages, as well as LPS-induced TNF-α and IL-1β 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-α 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.
SCOPUS: ar.j
info:eu-repo/semantics/published
Databáze: OpenAIRE
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