Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages
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 define...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1130162/full |
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| author | Martina B. Lorey Martina B. Lorey Amer Youssef Lauri Äikäs Matthew Borrelli Martin Hermansson Julia M. Assini Julia M. Assini Aapeli Kemppainen Hanna Ruhanen Hanna Ruhanen Maija Ruuth Sampsa Matikainen Petri T. Kovanen Reijo Käkelä Reijo Käkelä Michael B. Boffa Michael B. Boffa Marlys L. Koschinsky Marlys L. Koschinsky Katariina Öörni Katariina Öörni |
| author_facet | Martina B. Lorey Martina B. Lorey Amer Youssef Lauri Äikäs Matthew Borrelli Martin Hermansson Julia M. Assini Julia M. Assini Aapeli Kemppainen Hanna Ruhanen Hanna Ruhanen Maija Ruuth Sampsa Matikainen Petri T. Kovanen Reijo Käkelä Reijo Käkelä Michael B. Boffa Michael B. Boffa Marlys L. Koschinsky Marlys L. Koschinsky Katariina Öörni Katariina Öörni |
| author_sort | Martina B. Lorey |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T09:54:05Z |
| format | Article |
| id | doaj.art-e718ebe0203e44b68e68438c5b4d9562 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-03-13T09:54:05Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-e718ebe0203e44b68e68438c5b4d95622023-05-24T04:39:35ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-05-011010.3389/fcvm.2023.11301621130162Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophagesMartina B. Lorey0Martina B. Lorey1Amer Youssef2Lauri Äikäs3Matthew Borrelli4Martin Hermansson5Julia M. Assini6Julia M. Assini7Aapeli Kemppainen8Hanna Ruhanen9Hanna Ruhanen10Maija Ruuth11Sampsa Matikainen12Petri T. Kovanen13Reijo Käkelä14Reijo Käkelä15Michael B. Boffa16Michael B. Boffa17Marlys L. Koschinsky18Marlys L. Koschinsky19Katariina Öörni20Katariina Öörni21Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, FinlandMolecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, FinlandRobarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, CanadaAtherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, FinlandDepartment of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, CanadaAtherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, FinlandRobarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, CanadaDepartment of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, CanadaAtherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, FinlandMolecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, FinlandHelsinki University Lipidomics Unit (HiLIPID), Helsinki Institute of Life Science (HiLIFE) and Biocenter Finland, Helsinki, FinlandAtherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, FinlandHelsinki Rheumatic Disease and Inflammation Research Group, University of Helsinki and Helsinki University Hospital, Helsinki, FinlandAtherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, FinlandMolecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, FinlandHelsinki University Lipidomics Unit (HiLIPID), Helsinki Institute of Life Science (HiLIFE) and Biocenter Finland, Helsinki, FinlandRobarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, CanadaDepartment of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, CanadaRobarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, CanadaDepartment of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, CanadaAtherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, FinlandMolecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, FinlandIntroductionLipoprotein(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.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1130162/fullinflammationlipoprotein(a)apolipoproteinsatherosclerotic cardiovascular diseaseatherosclerosiscaspase-1 |
| spellingShingle | Martina B. Lorey Martina B. Lorey Amer Youssef Lauri Äikäs Matthew Borrelli Martin Hermansson Julia M. Assini Julia M. Assini Aapeli Kemppainen Hanna Ruhanen Hanna Ruhanen Maija Ruuth Sampsa Matikainen Petri T. Kovanen Reijo Käkelä Reijo Käkelä Michael B. Boffa Michael B. Boffa Marlys L. Koschinsky Marlys L. Koschinsky Katariina Öörni Katariina Öörni Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages Frontiers in Cardiovascular Medicine inflammation lipoprotein(a) apolipoproteins atherosclerotic cardiovascular disease atherosclerosis caspase-1 |
| title | Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages |
| title_full | Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages |
| title_fullStr | Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages |
| title_full_unstemmed | Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages |
| title_short | Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages |
| title_sort | lipoprotein a induces caspase 1 activation and il 1 signaling in human macrophages |
| topic | inflammation lipoprotein(a) apolipoproteins atherosclerotic cardiovascular disease atherosclerosis caspase-1 |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1130162/full |
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