Hypertension (HTN) is now defined as an immune disorder. CD8 effector T cells are the major players in the infiltration of target organs in hypertension, moreover it is still unknown the intracellular signaling mediating the differentiation from naïve T cells to effector T cells. Phosphatidylinositol-3-kinase gamma (PI3Kg), a lipid kinase mainly expressed in immune and cardiovascular systems, is a typical signaling downstream of G protein coupled receptors that regulate cell trafficking and migration of effector CD8 T cells. In the past, my laboratory have described a crucial role of PI3Kg in hypertension. Here we will test the hypothesis that this signaling could be a critical regulator of immune cells trafficking in hypertension and we will deepen the contribution of these cells in altering mechanisms relevant to blood pressure (BP) regulation.
By taking advantage of a knock in mouse model, expressing a constitutively active PI3Kg isoform (PI3Kg CX/CX), we will realize the experimental settings allowing to assess the role of PI3Kg in the crosstalk between immune cells and hypertension.
We suppose that PI3Kg signaling in CD8 T cells is crucial for their accumulation in target organs of hypertension, likely contributing to blood pressure increase.
Hypertension is one of the principal risk factors for cardiovascular disease as stroke, heart failure, cerebrovascular and kidney diseases. The majority of patients is resistant to all ongoing antihypertensive treatments, suggesting that there are still unidentified mechanisms underlying the increase of blood pressure. The Mosaic Theory of hypertension highlight that many factors, including genetics, environment, neural, mechanical and hormonal perturbations interact to raise blood pressure. If the etiology is multifactorial, the cause can be ascribable to more than a simple organ. In particular, the investigation of immune system could be crucial to understand novel insights in hypertension.
Many evidence shows that the immune system decisively contributes to the development of the hypertensive disease. Harrison and coworkers showed that immune cells were crucial players in HTN in mice chronically treated with AngiotensinII (AngII) and that mice deprived of lymphocytes are protected from AngII-induced hypertension. Additionally, by the same group, it was found that CD8 KO mice, but not CD4 KO mice, were protected from HTN, leading to a further knowledge of the immune mechanisms involved in the onset of the disease.
Previously, my lab found that upon AngII, T cells egress from the spleen infiltrating target organs of hypertension as kidneys and vessels where cause the end-organ damage (Carnevale D et al. Immunity 2014). In particular, in the marginal zone of the spleen of mice, chronic infusion of AngII activate the co-stimulation pathway promoting the differentiation from naïve T cells to effector T cells. In literature, it was reported that PI3Kg is a crucial intracellular signaling regulating the activation of CD8 T cells into effector cells. It is more intriguing to notice that hypertension is prevalent in some of the most common autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus. In fact, it has been shown that T cells play a central role in the development of autoimmune diseases, partly through the production of pro-inflammatory and immunomodulatory cytokines and also through the production of antibodies from B cells by a T-cell dependent process. Very interesting, it has been shown that the pharmacological inhibition of PI3Kg is able to hamper the development of glomerulonephritis in SLE in mice, thus advancing the hypothesis that the same mechanisms could be recruited also in hypertension. On this notice, the final objective of this project is to unravel the signaling activated in CD8 effector T cells during the co-stimulation pathway in hypertensive mice. This goal given the possibility to investigate molecular mechanisms regulating the immune system responses upon hypertensive hits as potent therapeutic targets. PI3Kg inhibitors could be beneficial in modulating the immune response involved in hypertension with a translational potential more elevated for precision biomedicine in the field of hypertension. Based on this innovative view of hypertension as a neuroimmune disorder, it is plausible to think of new therapeutic strategies based on immunotherapy that, unlike cancer, would aim to suppress specifically a subgroup of CD8 T cells.