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

Martina B Lorey; Amer Youssef; Lauri Äikäs; Matthew Borrelli; Martin Hermansson; Julia M Assini; Aapeli Kemppainen; Hanna Ruhanen; Maija Ruuth; Sampsa Matikainen; Petri T Kovanen; Reijo Käkelä; Michael B Boffa; Marlys L Koschinsky; Katariina Öörni

doi:10.3389/fcvm.2023.1130162

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

Front Cardiovasc Med. 2023 May 24:10:1130162. doi: 10.3389/fcvm.2023.1130162. eCollection 2023.

Authors

Martina B Lorey^{1

2}, Amer Youssef³, Lauri Äikäs¹, Matthew Borrelli⁴, Martin Hermansson¹, Julia M Assini^{3

5}, Aapeli Kemppainen¹, Hanna Ruhanen^{2

6}, Maija Ruuth¹, Sampsa Matikainen⁷, Petri T Kovanen¹, Reijo Käkelä^{2

6}, Michael B Boffa^{3

5}, Marlys L Koschinsky^{3

4}, Katariina Öörni^{1

2}

Affiliations

¹ Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland.
² Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
³ Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada.
⁴ Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada.
⁵ Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada.
⁶ Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute of Life Science (HiLIFE) and Biocenter Finland, Helsinki, Finland.
⁷ Helsinki Rheumatic Disease and Inflammation Research Group, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Abstract

Introduction: Lipoprotein(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 results: To 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.

Discussion: Our 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.

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

Grants and funding

Wihuri Research Institute is funded by Jenny and Antti Wihuri Foundation. The study was supported by grants from the Academy of Finland (#332564 to KÖ), Finnish Foundation for Cardiovascular Research (ML and KÖ), Aarne Koskelo Foundation (ML and KÖ), Sigrid Jusélius Foundation (to KÖ) and Novo Nordisk Fonden (NNF19OC005714 to KÖ). MK and MB were supported by a grant from the Heart and Stroke Foundation of Canada (#G-17-0018740). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.