Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerotic Plaque Inflammation and Progression in Hyperlipidemic Mice
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animal Experiments
2.2. 18F-FDG PET-CT Imaging
2.3. Gamma Counting
2.4. Flow Cytometry
2.5. Histology
2.6. Confocal Microscopy
2.7. Statistics
3. Results
3.1. Antibody-Mediated Inhibition of CTLA4 Does Not Affect Monocyte/Macrophage-Driven Vascular Inflammation
3.2. Antibody-Mediated Inhibition of CTLA4 Induces an Activated T Cell Profile in Hyperlipidemic Mice
3.3. CTLA4 Inhibition Aggravates Endothelial Activation
3.4. Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerosis in the Aortic Arch
3.5. Inhibition of CTLA4 Aggravates Plaque Inflammation and Progression in the Aortic Root
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Gisterå, A.; Hansson, G.K. The immunology of atherosclerosis. Nat. Rev. Nephrol. 2017, 13, 368–380. [Google Scholar] [CrossRef]
- Seijkens, T.T.; Lutgens, E. Cardiovascular oncology: Exploring the effects of targeted cancer therapies on atherosclerosis. Curr. Opin. Lipidol. 2018, 29, 381–388. [Google Scholar] [CrossRef]
- Fernandez, D.M.; Rahman, A.H.; Fernandez, N.F.; Chudnovskiy, A.; Amir, E.-A.D.; Amadori, L.; Khan, N.S.; Wong, C.K.; Shamailova, R.; Hill, C.A.; et al. Single-cell immune landscape of human atherosclerotic plaques. Nat. Med. 2019, 25, 1576–1588. [Google Scholar] [CrossRef]
- Ahmadi, A.; Leipsic, J.; Blankstein, R.; Taylor, C.; Hecht, H.; Stone, G.W.; Narula, J. Do Plaques Rapidly Progress Prior to Myocardial Infarction? The Interplay Between Plaque Vulnerability and Progression. Circ. Res. 2015, 117, 99–104. [Google Scholar] [CrossRef] [Green Version]
- Hansson, G.K.; Robertson, A.-K.L.; Söderberg-Nauclér, C. Inflammation and atherosclerosis. Annu. Rev. Pathol. 2006, 1, 297–329. [Google Scholar] [CrossRef] [PubMed]
- Kusters, P.J.H.; Lutgens, E.; Seijkens, T.T.P. Exploring immune checkpoints as potential therapeutic targets in atherosclerosis. Cardiovasc. Res. 2017, 114, 368–377. [Google Scholar] [CrossRef]
- Kusters, P.J.H.; Lutgens, E. Cytokines and immune responses in murine atherosclerosis. In Methods in Mouse Atherosclerosis; Springer: New York, NY, USA, 2015; pp. 17–40. [Google Scholar]
- Walker, L.S.K.; Sansom, D. Confusing signals: Recent progress in CTLA-4 biology. Trends Immunol. 2015, 36, 63–70. [Google Scholar] [CrossRef] [Green Version]
- Blair, H.A.; Deeks, E.D. Abatacept: A Review in Rheumatoid Arthritis. Drugs 2017, 77, 1221–1233. [Google Scholar] [CrossRef]
- Hellmann, M.D.; Paz-Ares, L.; Caro, R.B.; Zurawski, B.; Kim, S.-W.; Costa, E.C.; Park, K.; Alexandru, A.; Lupinacci, L.; Jimenez, E.D.L.M.; et al. Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2019, 381, 2020–2031. [Google Scholar] [CrossRef]
- Larkin, J.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.-J.; Rutkowski, P.; Lao, C.D.; Cowey, C.L.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 2019, 381, 1535–1546. [Google Scholar] [CrossRef] [Green Version]
- Buono, C.; Pang, H.; Uchida, Y.; Libby, P.; Sharpe, A.H.; Lichtman, A.H. B7-1/B7-2 Costimulation Regulates Plaque Antigen–Specific T-Cell Responses and Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice. Circulation 2004, 109, 2009–2015. [Google Scholar] [CrossRef] [PubMed]
- Ewing, M.M.; Karper, J.C.; Abdul, S.; De Jong, R.C.M.; Peters, H.A.B.; De Vries, M.R.; Redeker, A.; Kuiper, J.; Toes, R.E.M.; Arens, R.; et al. T-cell co-stimulation by CD28–CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development. Int. J. Cardiol. 2013, 168, 1965–1974. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Seijkens, T.T.; Van Tiel, C.M.; Kusters, P.J.; Atzler, D.; Soehnlein, O.; Zarzycka, B.; Aarts, S.A.; Lameijer, M.; Gijbels, M.J.; Beckers, L.; et al. Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis. J. Am. Coll. Cardiol. 2018, 71, 527–542. [Google Scholar] [CrossRef]
- Beldman, T.J.; Malinova, T.S.; Desclos, E.; Grootemaat, A.E.; Misiak, A.L.S.; Van Der Velden, S.; Van Roomen, C.P.A.A.; Beckers, L.; Van Veen, H.A.; Krawczyk, P.M.; et al. Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy. ACS Nano 2019, 13, 13759–13774. [Google Scholar] [CrossRef] [PubMed]
- Ogawa, M.; Ishino, S.; Mukai, T.; Asano, D.; Teramoto, N.; Watabe, H.; Kudomi, N.; Shiomi, M.; Magata, Y.; Iida, H.; et al. (18)F-FDG accumulation in atherosclerotic plaques: Immunohistochemical and PET imaging study. J. Nucl. Med. 2004, 45, 1245–1250. [Google Scholar] [PubMed]
- Hag, A.M.F.; Pedersen, S.F.; Christoffersen, C.; Binderup, T.; Jensen, M.M.; Jørgensen, J.T.; Skovgaard, D.; Ripa, R.S.; Kjær, A. 18F-FDG PET Imaging of Murine Atherosclerosis: Association with Gene Expression of Key Molecular Markers. PLoS ONE 2012, 7, e50908. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Davignon, J.; Ganz, P. Role of Endothelial Dysfunction in Atherosclerosis. Circulation 2004, 109, III-27–III-32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Habas, K.; Shang, L. Alterations in intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in human endothelial cells. Tissue Cell 2018, 54, 139–143. [Google Scholar] [CrossRef] [Green Version]
- Cutolo, M.; Montagna, P.; Soldano, S.; Contini, P.; Paolino, S.; Pizzorni, C.; Seriolo, B.; Sulli, A.; Brizzolara, R. CTLA4-Ig/CD86 interactions in cultured human endothelial cells: Effects on VEGFR-2 and ICAM1 expression. Clin. Exp. Rheumatol. 2015, 33, 250–254. [Google Scholar]
- Taggart, D.; Andreou, T.; Scott, K.J.; Williams, J.; Rippaus, N.; Brownlie, R.J.; Ilett, E.J.; Salmond, R.J.; Melcher, A.; Lorger, M. Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8 + T cell trafficking. Proc. Natl. Acad. Sci. USA 2018, 115, E1540–E1549. [Google Scholar] [CrossRef] [Green Version]
- Steyers, C.M.; Miller, F.J. Endothelial Dysfunction in Chronic Inflammatory Diseases. Int. J. Mol. Sci. 2014, 15, 11324–11349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, K.; Lv, S.; Liu, B.; Liu, Z.; Luo, Y.; Kong, W.; Xu, Q.; Feng, J.; Wang, X. CTLA4-IgG ameliorates homocysteine-accelerated atherosclerosis by inhibiting T-cell overactivation in apoE−/− mice. Cardiovasc. Res. 2012, 97, 349–359. [Google Scholar] [CrossRef] [PubMed]
- Schneider, H. Reversal of the TCR Stop Signal by CTLA-4. Science 2006, 313, 1972–1975. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- He, S.; Li, M.; Ma, X.; Lin, J.; Li, D. CD4 + CD25 + Foxp3 + Regulatory T Cells Protect the Proinflammatory Activation of Human Umbilical Vein Endothelial Cells. Arter. Thromb. Vasc. Boil. 2010, 30, 2621–2630. [Google Scholar] [CrossRef] [Green Version]
- De Coaña, Y.P.; Wolodarski, M.; Poschke, I.; Yoshimoto, Y.; Yang, Y.; Nyström, M.; Edbäck, U.; Brage, S.E.; Lundqvist, A.; Masucci, G.V.; et al. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget 2017, 8, 21539–21553. [Google Scholar] [CrossRef] [Green Version]
- Weber, J.S.; Hamid, O.; Chasalow, S.D.; Wu, D.Y.; Parker, S.M.; Galbraith, S.; Gnjatic, S.; Berman, D.M. Ipilimumab Increases Activated T Cells and Enhances Humoral Immunity in Patients With Advanced Melanoma. J. Immunother. 2012, 35, 89–97. [Google Scholar] [CrossRef]
- Ammirati, E.; Cianflone, D.; Vecchio, V.; Banfi, M.; Vermi, A.C.; De Metrio, M.; Grigore, L.; Pellegatta, F.; Pirillo, A.; Garlaschelli, K.; et al. Effector memory T cells are associated with atherosclerosis in humans and animal models. J. Am. Heart Assoc. 2012, 1, e000125. [Google Scholar] [CrossRef] [Green Version]
- Van Dijk, R.A.; Duinisveld, A.J.F.; Schaapherder, A.F.; Mulder-Stapel, A.; Hamming, J.F.; Kuiper, J.; De Boer, O.J.; Van Der Wal, A.C.; Kolodgie, F.D.; Virmani, R.; et al. A Change in Inflammatory Footprint Precedes Plaque Instability: A Systematic Evaluation of Cellular Aspects of the Adaptive Immune Response in Human Atherosclerosis. J. Am. Heart Assoc. 2015, 4, 001403. [Google Scholar] [CrossRef] [Green Version]
- Matsumoto, T.; Sasaki, N.; Yamashita, T.; Emoto, T.; Kasahara, K.; Mizoguchi, T.; Hayashi, T.; Yodoi, K.; Kitano, N.; Saito, T.; et al. Overexpression of Cytotoxic T-Lymphocyte–Associated Antigen-4 Prevents Atherosclerosis in Mice. Arter. Thromb. Vasc. Boil. 2016, 36, 1141–1151. [Google Scholar] [CrossRef] [Green Version]
- Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J. Exp. Clin. Cancer Res. 2019, 38, 255. [Google Scholar] [CrossRef]
- Alkharabsheh, O.; Kannarkatt, P.; Kannarkatt, J.; Karapetyan, L.; Laird-Fick, H.S.; Al-Janadi, A. An overview of the toxicities of checkpoint inhibitors in older patients with cancer. J. Geriatr. Oncol. 2018, 9, 451–458. [Google Scholar] [CrossRef] [PubMed]
- Hu, Y.-B.; Zhang, Q.; Li, H.-J.; Michot, J.M.; Liu, H.-B.; Zhan, P.; Lv, T.-F.; Song, Y. Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: A meta-analysis. Transl. Lung Cancer Res. 2017, 6, S8–S20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bar, J.; Markel, G.; Gottfried, T.; Percik, R.; Leibowitz-Amit, R.; Berger, R.; Golan, T.; Daher, S.; Taliansky, A.; Dudnik, E.; et al. Acute vascular events as a possibly related adverse event of immunotherapy: A single-institute retrospective study. Eur. J. Cancer 2019, 120, 122–131. [Google Scholar] [CrossRef]
- Newman, J.L.; Stone, J.R. Immune checkpoint inhibition alters the inflammatory cell composition of human coronary artery atherosclerosis. Cardiovasc. Pathol. 2019, 43, 107148. [Google Scholar] [CrossRef] [PubMed]
- Rohm, I.; Atiskova, Y.; Drobnik, S.; Fritzenwanger, M.; Kretzschmar, D.; Pistulli, R.; Zanow, J.; Krönert, T.; Mall, G.; Figulla, H.R.; et al. Decreased Regulatory T Cells in Vulnerable Atherosclerotic Lesions: Imbalance between Pro- and Anti-Inflammatory Cells in Atherosclerosis. Mediat. Inflamm. 2015, 2015, 1–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Poels, K.; van Leent, M.M.T.; Reiche, M.E.; Kusters, P.J.H.; Huveneers, S.; de Winther, M.P.J.; Mulder, W.J.M.; Lutgens, E.; Seijkens, T.T.P. Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerotic Plaque Inflammation and Progression in Hyperlipidemic Mice. Cells 2020, 9, 1987. https://doi.org/10.3390/cells9091987
Poels K, van Leent MMT, Reiche ME, Kusters PJH, Huveneers S, de Winther MPJ, Mulder WJM, Lutgens E, Seijkens TTP. Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerotic Plaque Inflammation and Progression in Hyperlipidemic Mice. Cells. 2020; 9(9):1987. https://doi.org/10.3390/cells9091987
Chicago/Turabian StylePoels, Kikkie, Mandy M. T. van Leent, Myrthe E. Reiche, Pascal J. H. Kusters, Stephan Huveneers, Menno P. J. de Winther, Willem J. M. Mulder, Esther Lutgens, and Tom T. P. Seijkens. 2020. "Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerotic Plaque Inflammation and Progression in Hyperlipidemic Mice" Cells 9, no. 9: 1987. https://doi.org/10.3390/cells9091987