Lipid Immunometabolism in cardiovascular disease: focus on molecular mechanisms and pharmacological targets - Fabrizia Bonacina, PhD
Immune cells adapt their cellular metabolism in response to not-self or danger signals to cope with increased energetic and biosynthetic demand required for efficient effector response during atherosclerosis. We have identified metabolic “checkpoints” such as the apolipoprotein E (ApoE) or the low-density lipoprotein receptor (LDL-R), that by fine-tuning cellular cholesterol homeostasis affect immune cell activation. We have shown that the LDL-R is required for efficient activation of a subset of T lymphocytes, namely CD8+ T cells. Cholesterol uptake by LDL-R favours the localization of mammalian target of Rapamycin complex 1 (mTORC1) on lysosomal membrane, an event required for its activation. This represents a key step for CD8+ T cell metabolic and functional reprogramming during activation. Indeed CD8+ T cells from Ldlr-/- mice present a decreased proliferation and cytokine production compared to WT cells and a similar phenotype is observed in CD8+ T cells from subjects carrying mutations on the LDLR gene, affected by familial hypercholesterolemia (FH), translating our findings in the human context. Indeed, FH patients present an impaired immune response that contributes to the increased inflammatory burden and cardiovascular severity. By testing the efficacy of adoptive cell transfer with engineered T regulatory lymphocytes in experimental models, we demonstrated that this approach ameliorates atherosclerosis progression paving the road for immune cell selective targeting of cellular metabolism in the context of the immunoinflammatory response associated to cardiovascular diseases.
Dr. Bonacina obtained the degree in Pharmacy at the University of Milan in 2012 with a thesis entitled "Pentraxin 3 and arterial thrombosis: experimental studies", under the supervision of Prof. Alberico Luigi Catapano and Giuseppe Danilo Norata. She attended the Doctoral School in Pharmacological Sciences of the University of Milan (XXVIII Cycle) and defended a thesis entitled: "Role of the long pentraxin 3 (PTX3) in cardiometabolic disease". As a Post Doc she started integrating key concepts of metabolism with immune cell response and as visiting scientist for one year in the group of Prof. Federica Marelli-Berg, at the William Harvey Research Institute of Queen Mary University in London, deepened her expertise in immunometabolism. Since 2016, Dr. Bonacina holds the position of Research Fellow B in the lab of Lipoprotein, Immunity and Atherosclerosis, under the supervision of Prof. A.L. Catapano and G.D. Norata. Dr. Bonacina is the recipient of a grant from Ministry of Health (Bando Giovani Ricercatori 2016, GR-2013-02355011) and more recently of a grant for young researchers of Cariplo Foundation (Ricerca Biomedica condotta da Giovani Ricercatori, 2019-1560). Dr. Bonacina has published 21 peer reviewed papers with a total IF of 207,009 and an average IF of 9,857. Current activities of Dr. Bonacina are devoted to investigate pharmacological targets that, by acting on cell immunometabolism, could improve the immune response associated with cardio-metabolic diseases.