Forskningsbeskrivning
The focus in my research is to identify connections between inflammatory mediators and unstable atherosclerotic plaques. My projects have contributed in identifying several responses in the process where hypercholesterolemia elicits vascular inflammation in atherosclerosis. The set-up is to look for primary findings in our carotid plaque biobank (see below), and then verify and challenge the data by conducting studies in in vitro studies or experimental mouse models.1-10
In patients with severe atherosclerosis that are going through removal of carotid plaques we have identified a pathway linking innate immune response to improved outcome. Our recent finding show that expression of Pattern recognition receptor, Toll-like receptor 7 (TLR7), in the removed atherosclerotic tissue correlate to improved outcome for the patient.2 Our follow up study in a mouse model showed that treatment with synthetic TLR7 ligand could reduce atherosclerosis and can lead to plaque healing.1 In the periphery TLR7 activation in hypercholesterolemic mice helped to expand specific lymphocyte populations, like Marginal Zone B cells and Treg. Taken together, our studies show that TLR7 may be a strong candidate in balancing inflammation and promoting healing in atherosclerosis.1, 2
To be able to study mechanisms within atherosclerotic tissue on a molecular level the prospective study BiKE–Biobank of Karolinska Carotid Endarterectomies was started 2001 in collaboration with myself, Göran Hansson and professor Ulf Hedin and clinical colleagues on Vascular surgery on Karolinska Hospital. The BiKE biobank is central for my research projects and it has also become a resource in several important collaborations with groups outside the steering team 11-18.
References:
1. Karadimou G, Gisterå A, Gallina AL, Caravaca AS, Centa M, Salagianni M, Andreakos E, Hansson GK, Malin S, Olofsson PS and Paulsson-Berne G. Treatment with a Toll-like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice. J Intern Med. 2020;288:321-334. DOI: 10.1111/joim.13085
2. Karadimou G, Folkersen L, Berg M, Perisic L, Discacciati A, Roy J, Hansson GK, Persson J and Paulsson-Berne G. Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events. Cardiovasc Res. 2017;113:30-39. PMCID: PMC5220676
3. Folkersen L, Persson J, Ekstrand J, Agardh HE, Hansson GK, Gabrielsen A, Hedin U and Paulsson-Berne G. Prediction of ischemic events on the basis of transcriptomic and genomic profiling in patients undergoing carotid endarterectomy. Mol Med. 2012;18:669-75. PMCID: PMC3388132
4. Persson J, Folkersen L, Ekstrand J, Helleberg J, Gabrielsen A, Lundman P, Hedin U and Paulsson-Berne G. High plasma adiponectin concentration is associated with all-cause mortality in patients with carotid atherosclerosis. Atherosclerosis. 2012;225:491-6. DOI: 10.1016/j.atherosclerosis.2012.09.036
5. Persson J, Lindberg K, Gustafsson TP, Eriksson P, Paulsson-Berne G and Lundman P. Low plasma adiponectin concentration is associated with myocardial infarction in young individuals. J Intern Med. 2010;268:194-205. DOI: 10.1111/j.1365-2796.2010.02247.x
6. Agardh HE, Folkersen L, Ekstrand J, Marcus D, Swedenborg J, Hedin U, Gabrielsen A and Paulsson-Berne G. Expression of fatty acid–binding protein 4/aP2 is correlated with plaque instability in carotid atherosclerosis. Journal of Internal Medicine. 2011;269:200-210. DOI: 10.1111/j.1365-2796.2010.02304.x
7. Folkersen L, Kurtovic S, Razuvaev A, Agardh HE, Gabrielsen A and Paulsson-Berne G. Endogenous control genes in complex vascular tissue samples. BMC Genomics. 2009;10:516. PMCID: PMC2779820
8. Tupin E, Nicoletti A, Elhage R, Rudling M, Ljunggren HG, Hansson GK and Paulsson Berne G. CD1d-dependent activation of NKT cells aggravates atherosclerosis. J Exp Med. 2004;199:417-22. PMCID: PMC2211791
9. Nicoletti A, Paulsson G, Caligiuri G, Zhou X and Hansson GK. Induction of neonatal tolerance to oxidized lipoprotein reduces atherosclerosis in ApoE knockout mice. Mol Med. 2000;6:283-90. PMCID: PMC1949951
10. Paulsson G, Zhou X, Tornquist E and Hansson GK. Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2000;20:10-7. DOI: 10.1161/01.atv.20.1.10
11. Tomas L, Edsfeldt A, Mollet IG, Perisic Matic L, Prehn C, Adamski J, Paulsson-Berne G, Hedin U, Nilsson J, Bengtsson E, Goncalves I and Bjorkbacka H. Altered metabolism distinguishes high-risk from stable carotid atherosclerotic plaques. Eur Heart J. 2018;39:2301-2310. PMCID: PMC6012762
12. van der Laan SW, Siemelink MA, Haitjema S, Foroughi Asl H, Perisic L, Mokry M, van Setten J, Malik R, Dichgans M, Worrall BB, Consortium MCotISG, Samani NJ, Schunkert H, Erdmann J, Hedin U, Paulsson-Berne G, Bjorkegrenn JLM, de Borst GJ, Asselbergs FW, den Ruijter FW, de Bakker PIW and Pasterkamp G. Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques. Circ Genom Precis Med. 2018;11:e002115. PMCID: PMC7664607
13. Joly AL, Seitz C, Liu S, Kuznetsov NV, Gertow K, Westerberg LS, Paulsson-Berne G, Hansson GK and Andersson J. Alternative Splicing of FOXP3 Controls Regulatory T Cell Effector Functions and Is Associated With Human Atherosclerotic Plaque Stability. Circ Res. 2018;122:1385-1394. DOI: 10.1161/CIRCRESAHA.117.312340
14. Laguna-Fernandez A, Checa A, Carracedo M, Artiach G, Petri MH, Baumgartner R, Forteza MJ, Jiang X, Andonova T, Walker ME, Dalli J, Arnardottir H, Gistera A, Thul S, Wheelock CE, Paulsson-Berne G, Ketelhuth DFJ, Hansson GK and Back M. ERV1/ChemR23 Signaling Protects Against Atherosclerosis by Modifying Oxidized Low-Density Lipoprotein Uptake and Phagocytosis in Macrophages. Circulation. 2018;138:1693-1705. PMCID: PMC6200387
15. Seijkens TTP, Poels K, Meiler S, van Tiel CM, Kusters PJH, Reiche M, Atzler D, Winkels H, Tjwa M, Poelman H, Slutter B, Kuiper J, Gijbels M, Kuivenhoven JA, Matic LP, Paulsson-Berne G, Hedin U, Hansson GK, Nicolaes GAF, Daemen M, Weber C, Gerdes N, de Winther MPJ and Lutgens E. Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8+ T cell-mediated macrophage death. Eur Heart J. 2019;40:372-382. PMCID: PMC6340101
16. Matic LP, Jesus Iglesias M, Vesterlund M, Lengquist M, Hong MG, Saieed S, Sanchez-Rivera L, Berg M, Razuvaev A, Kronqvist M, Lund K, Caidahl K, Gillgren P, Ponten F, Uhlen M, Schwenk JM, Hansson GK, Paulsson-Berne G, Fagman E, Roy J, Hultgren R, Bergstrom G, Lehtio J, Odeberg J and Hedin U. Novel Multiomics Profiling of Human Carotid Atherosclerotic Plaques and Plasma Reveals Biliverdin Reductase B as a Marker of Intraplaque Hemorrhage. JACC Basic Transl Sci. 2018;3:464-480. PMCID: PMC6115646
17. Eken SM, Jin H, Chernogubova E, Li Y, Simon N, Sun C, Korzunowicz G, Busch A, Backlund A, Osterholm C, Razuvaev A, Renne T, Eckstein HH, Pelisek J, Eriksson P, Gonzalez Diez M, Perisic Matic L, Schellinger IN, Raaz U, Leeper NJ, Hansson GK, Paulsson-Berne G, Hedin U and Maegdefessel L. MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions. Circ Res. 2017;120:633-644. DOI: 10.1161/CIRCRESAHA.116.309318
18. Perisic L, Aldi S, Sun Y, Folkersen L, Razuvaev A, Roy J, Lengquist M, Åkesson S, Wheelock CE, Maegdefessel L, Gabrielsen A, Odeberg J, Hansson GK, Paulsson-Berne G and Hedin U. Gene expression signatures, pathways and networks in carotid atherosclerosis. Journal of Internal Medicine. 2016;279:293-308. DOI: 10.1111/joim.12448