Adoptive transfer of CX3CR1 transduced-T regulatory cells improves homing to the atherosclerotic plaques and dampens atherosclerosis progression
| العنوان: | Adoptive transfer of CX3CR1 transduced-T regulatory cells improves homing to the atherosclerotic plaques and dampens atherosclerosis progression |
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| المؤلفون: | Giuseppe Danilo Norata, V. Zampoleri, Marinos Kallikourdis, M. Svecla, Elisa Martini, Alberico L. Catapano, Giangiacomo Beretta, Marco Cremonesi, Jasmine Nour, Fabio Pellegatta, Fabrizia Bonacina, A. Moregola |
| المصدر: | Cardiovasc Res |
| بيانات النشر: | Oxford University Press (OUP), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adult, Male, Adoptive cell transfer, Chemokine, Physiology, Aortic Diseases, CX3C Chemokine Receptor 1, Inflammation, T-Lymphocytes, Regulatory, Hyperlipoproteinemia Type II, Cell therapy, Transduction, Genetic, Physiology (medical), CX3CR1, medicine, Animals, Humans, Prospective Studies, CX3CL1, Cells, Cultured, Retrospective Studies, Mice, Knockout, biology, business.industry, Editorials, Genetic Therapy, Middle Aged, Atherosclerosis, medicine.disease, Adoptive Transfer, Plaque, Atherosclerotic, Mice, Inbred C57BL, Disease Models, Animal, Atheroma, Receptors, LDL, LDL receptor, Disease Progression, biology.protein, Cancer research, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business |
| الوصف: | Aim Loss of immunosuppressive response supports inflammation during atherosclerosis. We tested whether adoptive cell therapy (ACT) with Tregulatory cells (Tregs) engineered to selectively migrate in the atherosclerotic plaque would dampen the immune-inflammatory response in the arterial wall in animal models of Familial Hypercholesterolemia (FH). Methods and results FH patients presented a decreased Tregs suppressive function associated to an increased inflammatory burden. A similar phenotype was observed in Ldlr -/- mice accompanied by a selective increased expression of the chemokine CX3CL1 in the aorta but not in other districts (lymph nodes, spleen and liver). Treg overexpressing CX3CR1 were thus generated (CX3CR1+-Treg) to drive Treg selectively to the plaque. CX3CR1+-Treg were injected (i.v.) in Ldlr -/- fed high-cholesterol diet (WTD) for 8 weeks. CX3CR1+-Treg were detected in the aorta, but not in other tissues, of Ldlr -/- mice 24h after ACT, corroborating the efficacy of this approach. After 4 additional weeks of WTD, ACT with CX3CR1+-Treg resulted in reduced plaque progression and lipid deposition, ameliorated plaque stability by increasing collagen and smooth muscle cells content, while decreasing the number of pro-inflammatory macrophages. Shotgun proteomics of the aorta showed a metabolic rewiring in CX3CR1+-Treg treated Ldlr -/- mice compared to controls that was associated with the improvement of inflammation-resolving pathways and disease progression. Conclusion ACT with vasculotropic Treg appears as a promising strategy to selectively target immune activation in the atherosclerotic plaque. Translational relevance Improving pro-resolutive inflammatory response represents a promising therapeutic approach to control atherosclerosis progression. Meanwhile, selective immunosuppression at the atherosclerotic plaque looks critical to limit unspecific inhibition of inflammation in other tissues. Our work demonstrates that engineering of immunosuppressive T regulatory cells to be hijacked in the atherosclerotic plaque limits atherosclerosis progression by targeting local inflammation. |
| تدمد: | 1755-3245 0008-6363 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9cdb0361d68ff5dfc925c357ae6b4a14Test https://doi.org/10.1093/cvr/cvaa264Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9cdb0361d68ff5dfc925c357ae6b4a14 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17553245 00086363 |
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