Year: 2023
Type: preprint
Abstract: Chronic low-grade inflammation, also called metaflammation, is associated with prevalent non-communicable diseases, such as atherosclerosis. Anti-inflammatory therapy provides a clinical benefit in patients, but the triggers that incite metaflammation remain largely unknown. To uncover non-genetic inflammatory factors influencing atherosclerosis severity, we performed an unbiased in vivo screen measuring thousands of host- and microbe-derived molecules in a mouse model of atherosclerosis. Machine learning-supported analyses identified, next to known pro- and anti-atherogenic factors, the medium fatty acid-chain sphingomyelin d18:1/14:0 (S14) as highly positively associated with atherogenesis. S14 activated macrophage innate immune signalling, immune-metabolic reprogramming and pro-inflammatory gene transcription. The inflammatory activity of S14 was TLR4- and MD-2-dependent, consistent with biochemical and molecular dynamics simulation analyses showing that S14 promoted the formation of active TLR4/MD-2 dimers. Human interventional and observational trials demonstrated that dietary changes altered concentrations of S14 and that increased circulating S14 was associated with carotid plaque development in obese individuals. Collectively, these findings identify an inducible endogenous ligand for TLR4 that drives metaflammation, providing the rationale for preventative approaches and pharmacological interventions that may curb detrimental inflammation secondary to Western-type lifestyle habits.
Source: Research Square
Authors: Eicke Latz, Friederike Gorki, Lenka Dohnalová, Christoph Thaiss, Jelena Zurkovic, Anette Christ, Umeharu Ohto, Jan Marzinek, Peter J. Bond, Eike Geißmar, Santu Singha, Arslan Hamid, Mohamed Yaghmour, Kyra de Goede, Maximilian Rothe, Katarzyna Placek, Amin Polzin, Philipp Wollnitzke, Bodo Levkau, Michael Fitzgerald, Joost Rutten, Mihai Netea, Niels Riksen, Christoph Thiele, Andreas Pfeiffer, Peter Düwell, Jan Van den Bossche
Institutions: University of Bonn, University of Pennsylvania, The University of Tokyo, Agency for Science, Technology and Research, Bioinformatics Institute, Massachusetts General Hospital, Center for Computational and Integrative Biology, Massachusetts General Hospital, Amsterdam UMC Location Vrije Universiteit Amsterdam, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, Harvard University, Radboud University Medical Center, Charité – Universitätsmedizin Berlin
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1285364889, SFB 1454: Metaflammation und Zelluläre Programmierung, G192932977, G1959237123, G2011482319, G218868216, A high-dimensional approach for unwinding immune-metabolic causes of cardiovascular disease-depression multimorbidities, TRR 237: NukleinsäureImmunität, G3207356259, G3726397627, G434337789, G4549622993, G4788092711, G5006260125, The regulation and function of 2-hydroxyglutarate as a newfound immunometabolite in macrophages, SFB 1403: Zelltod in Immunität, Entzündungen und Erkrankungen, GRK 2168: Myeloide antigenpräsentierende Zellen und Induktion adaptiver Immunität, G7048621333, G7673790519, EXC 2151: ImmunoSensation2 the immune sensory system, G896728979
OpenAlex ID: W4366998533