Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages

Frontiers in Cardiovascular Medicine

Cardiovascular Medicine

Maija Ruuth¹  Lauri Äikäs¹  Petri T. Kovanen¹  Aapeli Kemppainen¹  Martin Hermansson¹  Martina B. Lorey²  Katariina Öörni²  Matthew Borrelli³  Sampsa Matikainen⁴  Hanna Ruhanen⁵  Reijo Käkelä⁵  Amer Youssef⁶  Michael B. Boffa⁷  Julia M. Assini⁷  Marlys L. Koschinsky⁸ 

[1] Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland;Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland;Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland;Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada;Helsinki Rheumatic Disease and Inflammation Research Group, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland;Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute of Life Science (HiLIFE) and Biocenter Finland, Helsinki, Finland;Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada;Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada;Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada;Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada;Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada;

关键词: inflammation;    lipoprotein(a);    apolipoproteins;    atherosclerotic cardiovascular disease;    atherosclerosis;    caspase-1;    interleukin-1 family;   

DOI  :  10.3389/fcvm.2023.1130162

 received in 2022-12-22, accepted in 2023-05-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionLipoprotein(a) (Lp(a)) is an LDL-like particle with an additional apolipoprotein (apo)(a) covalently attached. Elevated levels of circulating Lp(a) are a risk factor for atherosclerosis. A proinflammatory role for Lp(a) has been proposed, but its molecular details are incompletely defined.Methods and resultsTo explore the effect of Lp(a) on human macrophages we performed RNA sequencing on THP-1 macrophages treated with Lp(a) or recombinant apo(a), which showed that especially Lp(a) induces potent inflammatory responses. Thus, we stimulated THP-1 macrophages with serum containing various Lp(a) levels to investigate their correlations with cytokines highlighted by the RNAseq, showing significant correlations with caspase-1 activity and secretion of IL-1β and IL-18. We further isolated both Lp(a) and LDL particles from three donors and then compared their atheroinflammatory potentials together with recombinant apo(a) in primary and THP-1 derived macrophages. Compared with LDL, Lp(a) induced a robust and dose-dependent caspase-1 activation and release of IL-1β and IL-18 in both macrophage types. Recombinant apo(a) strongly induced caspase-1 activation and IL-1β release in THP-1 macrophages but yielded weak responses in primary macrophages. Structural analysis of these particles revealed that the Lp(a) proteome was enriched in proteins associated with complement activation and coagulation, and its lipidome was relatively deficient in polyunsaturated fatty acids and had a high n-6/n-3 ratio promoting inflammation.DiscussionOur data show that Lp(a) particles induce the expression of inflammatory genes, and Lp(a) and to a lesser extent apo(a) induce caspase-1 activation and IL-1 signaling. Major differences in the molecular profiles between Lp(a) and LDL contribute to Lp(a) being more atheroinflammatory.

【 授权许可】

Unknown   
© 2023 Lorey, Youssef, Äikäs, Borrelli, Hermansson, Assini, Kemppainen, Ruhanen, Ruuth, Matikainen, Kovanen, Käkelä, Boffa, Koschinsky and Öörni.