Periodic Reporting for period 4 - SymPAtHY (A neurosplenic pathway coupling Immunity and Hypertension)
Berichtszeitraum: 2022-06-01 bis 2022-11-30
Hypertension (HTN) is still a leading cause of morbidity and mortality worldwide. Although several therapeutic strategies have been developed against the main components involved in blood pressure (BP) regulation, the prevalence of uncontrolled HTN continues to rise, suggesting that there are still unidentified mechanisms, which sustain the increase of BP.
Researches developed in the last decade evidenced a decisive contribution of the immune system in the onset of HTN and in the ensuing target organ damage. A variety of groups contributed to expand the knowledge on the role played by the various immune cell types that orchestrate a coordinated response to hypertensive stimuli. Intriguingly, in the same period in which researchers in HTN field started to dissect the role of immune system, immunologists made important advances revealing that neural circuits modulate immunity. This observation was particularly interesting for investigators in the field of pathophysiology of hypertensive disease. In fact, neural control and, particularly, the sympathetic nervous system (SNS) has been considered the archetypical mechanism exerting an over-riding impact on BP. Historically, SNS regulation of BP has been attributed to modulation of key physiological parameters like vascular and renal function, but it is also well known that immune organs are directly innervated by SNS. My group previously discovered that hypertensive stimuli activate the SNS that innervates the spleen and promotes priming of adaptive immunity (Carnevale D., et al, Immunity 2014; Carnevale D., et al, Nat Commun 2016; Carnevale D., et al, Cardiovasc Res 2018).
SymPAtHY is born from the purpose to identify new pathways of neural regulation of immune responses relevant for BP regulation and target organ damage ensuing from chronic HTN. To this aim, we put together different expertise tackling neuroscience, immunology and cardiovascular tasks. The project’s strategy has been conceived with 3 main aims, organized in work packages that have investigated, in experimental models of HTN: 1) brain control of immunity; 2) neuroimmune responses orchestrated in the spleen; 3) mechanisms of cross-talk established at the vascular-immune interface in peripheral target organs of high BP.
The realization of SymPAtHY objectives allowed an important step forward in the field of cardiovascular diseases, for at least two reasons. First, HTN is one of the most diffuse and impactful cardiovascular risk factors, significantly contributing to the elevated morbidity and mortality for major cardio and cerebrovascular events. Hence, the identification of new mechanisms of disease onset and progression has the potential to advance the therapeutic strategies to fight the insidious impact of HTN on the worldwide population. Second, the neuroimmune mechanisms investigated in the framework of SymPAtHY project are partly shared by other cardiovascular diseases. This allowed us to translate the impact of results obtained to other diseases with huge impact on the society and healthcare system (like heart failure and atherosclerosis, etc).
Researches developed in the last decade evidenced a decisive contribution of the immune system in the onset of HTN and in the ensuing target organ damage. A variety of groups contributed to expand the knowledge on the role played by the various immune cell types that orchestrate a coordinated response to hypertensive stimuli. Intriguingly, in the same period in which researchers in HTN field started to dissect the role of immune system, immunologists made important advances revealing that neural circuits modulate immunity. This observation was particularly interesting for investigators in the field of pathophysiology of hypertensive disease. In fact, neural control and, particularly, the sympathetic nervous system (SNS) has been considered the archetypical mechanism exerting an over-riding impact on BP. Historically, SNS regulation of BP has been attributed to modulation of key physiological parameters like vascular and renal function, but it is also well known that immune organs are directly innervated by SNS. My group previously discovered that hypertensive stimuli activate the SNS that innervates the spleen and promotes priming of adaptive immunity (Carnevale D., et al, Immunity 2014; Carnevale D., et al, Nat Commun 2016; Carnevale D., et al, Cardiovasc Res 2018).
SymPAtHY is born from the purpose to identify new pathways of neural regulation of immune responses relevant for BP regulation and target organ damage ensuing from chronic HTN. To this aim, we put together different expertise tackling neuroscience, immunology and cardiovascular tasks. The project’s strategy has been conceived with 3 main aims, organized in work packages that have investigated, in experimental models of HTN: 1) brain control of immunity; 2) neuroimmune responses orchestrated in the spleen; 3) mechanisms of cross-talk established at the vascular-immune interface in peripheral target organs of high BP.
The realization of SymPAtHY objectives allowed an important step forward in the field of cardiovascular diseases, for at least two reasons. First, HTN is one of the most diffuse and impactful cardiovascular risk factors, significantly contributing to the elevated morbidity and mortality for major cardio and cerebrovascular events. Hence, the identification of new mechanisms of disease onset and progression has the potential to advance the therapeutic strategies to fight the insidious impact of HTN on the worldwide population. Second, the neuroimmune mechanisms investigated in the framework of SymPAtHY project are partly shared by other cardiovascular diseases. This allowed us to translate the impact of results obtained to other diseases with huge impact on the society and healthcare system (like heart failure and atherosclerosis, etc).
To accomplish SymPAtHY objectives our team focused the efforts on three main areas of investigation. 1) identification of the brain areas controlling neural modulation of immunity; 2) immune mechanisms; 3) effects of neuroimmune mechanisms on cardiovascular function. The work done was divided into two main competences. On the one hand, we established all the technological setup and experimental models required for the project. On the other hand, we focused on the scientific tasks planned.
The expected outcomes in terms of technological deliverables were accomplished and in some instances were beyond expectations. In brief, we established three transgenic models for blocking the Angiotensin II signaling in specific brain areas. In addition, we also refined procedures for direct measurement of the neuroimmune drive on the spleen by microneurographic approaches. Lastly, we developed a completely innovative system for directly studying the interactions established by immune and vascular cells in hypertension. In priciple, these technological achievements have the potential to be transferred to other pathophysiological contexts of interest. In fact, the implementation of microneurographic tecniques was instrumental to develop tools for bioelectronic medicine relevant for various settings where immune/inflammatory mechanisms are involved. Second, the organ culture system set up to investigate cellular and molecular interactions esblished between vascular and immune cells will be an invaluable tool for studying the vascular-immune interfaces of various pathophysiological conditons.
In terms of scientific relevance of the work done, the results obtained clarified the role of central nervous system in controlling the neural regulation of immune responses involved in onset of HTN and in ensuing target organ damage. We also elucidated the molecular mechanisms regulating the neuroimmune crosstalk established in the spleen when hypertensive challenges promote an enhancement of sympathetic outflow directed to the immune system. Lastly, we have defined unique and novel mechanisms that immune cells, activated by hypertensive stimuli, exploit to take the control of vascular functions at key target tissues of hight blood pressure. The identification of the above functions appears as an invaluable tool for the development of new therapeutic approaches, based on pathways already druggable for other diseases.
The expected outcomes in terms of technological deliverables were accomplished and in some instances were beyond expectations. In brief, we established three transgenic models for blocking the Angiotensin II signaling in specific brain areas. In addition, we also refined procedures for direct measurement of the neuroimmune drive on the spleen by microneurographic approaches. Lastly, we developed a completely innovative system for directly studying the interactions established by immune and vascular cells in hypertension. In priciple, these technological achievements have the potential to be transferred to other pathophysiological contexts of interest. In fact, the implementation of microneurographic tecniques was instrumental to develop tools for bioelectronic medicine relevant for various settings where immune/inflammatory mechanisms are involved. Second, the organ culture system set up to investigate cellular and molecular interactions esblished between vascular and immune cells will be an invaluable tool for studying the vascular-immune interfaces of various pathophysiological conditons.
In terms of scientific relevance of the work done, the results obtained clarified the role of central nervous system in controlling the neural regulation of immune responses involved in onset of HTN and in ensuing target organ damage. We also elucidated the molecular mechanisms regulating the neuroimmune crosstalk established in the spleen when hypertensive challenges promote an enhancement of sympathetic outflow directed to the immune system. Lastly, we have defined unique and novel mechanisms that immune cells, activated by hypertensive stimuli, exploit to take the control of vascular functions at key target tissues of hight blood pressure. The identification of the above functions appears as an invaluable tool for the development of new therapeutic approaches, based on pathways already druggable for other diseases.
SymPAtHY has made an important progress beyond the state of the art in developing experimental procedures for finely modulating the neural activity controlling immune organs. Novel approaches of bioelectronic medicine were developed with the specific aim of tuning the nerve activity controlling neurotransmitter release in the spleen. We expect that the technological approaches developed will allow moving forward in the immunomodulation of various diseases, beyond HTN and cardiovascular diseases.