Many cardiovascular diseases are characterized by a hemodynamic overload applied on cardiac walls, activating biological processes that culminate in cardiac remodeling. Cardiac remodeling has an early adaptive phase defined as hypertrophy of the left ventricular that can eventually evolve in a maladaptive phase towards heart failure. In our previous studies, we demonstrated the importance of a communication between the brain and the spleen by a cholinergic-sympathetic pathway passing through the coeliac ganglion. This neural reflex is crucial for T cells acivation in the spleen and their egression towards target organ in the pre-hypertension induced by chronic Angiotensin II infusion in mice. Aim of the present project is to investigate whether the cholinergic-sympathetic connection could be implicated in the adaptive phase of cardiac remodeling before the establishment of chronic mechanisms. To outline this issue, we will use a murine model of transverse aortic coartaction (TAC) to induce cardiac remodeling for studying the involvement of the cholinergic-sympathetic pathway in the activation of adaptive immunity in the early phase of the process. This pathway will be studied by electrophysiological recordings of the sympathetic splenic nerve activity (SSNA) in mice subjected to TAC and in sham mice used as controls. Mice will recorded on the 4th day after TAC or sham procedure. Furthermore, SSNA in TAC and sham mice will be recorded before and after the procedure of coeliac vagotomy in order to investigate whether the coeliac branch of the vagus nerve is involved in the pathway that modulates the immune responses during the cardiac remodeling. The realization of these objectives together with those proposed in my postdoc project sets the basis for translational strategies that consider the brain-to-spleen pathway as a possible therapeutic target in cardiac remodeling to prevent heart failure.
The present work aims at investigating the importance of the cholinergic-sympathetic reflex in the regulation of immune responses in the adaptive phase of cardiac remodeling induced by TAC. An interesting aspect is the possibility that the interaction between these two systems, the immune and autonomic nervous system, can be involved in an early phase of cardiac remodeling before the transition towards the heart failure. Previous important studies by Tracey and colleagues revealed the existence of an "inflammatory reflex" characterized for the first time in endotoxemia induced by the administration of bacterial toxin, lipopolysaccharide (LPS), in mice (Rosas Ballina et al. PNAS 2008). In this nervous circuit, nervous signals are transmitted from the vagus nerve to the coeliac ganglion, from which the splenic nerve originates to terminate in the spleen. The spleen is a primary lymphoid organ and thus a reservoir of immune cells. Tracey and colleagues found that the activation of the splenic drive by an electrical stimulation of the cervical vagus nerve regulates a subset of T cells in the white pulp of the spleen (Rosas-Ballina et al. PNAS 2008; Rosas-Ballina et al. Science 2011). Thus, although the parasympathetic and the sympathetic system in the splanchnic district have always been considered separately, the "inflammatory reflex" integrates the two systems at the level of the coeliac ganglion. We published that this cholinergic-sympathetic connection, established between the coeliac vagus nerve and the splenic nerve, primes immune T cells in the spleen in hypertension (Carnevale et al. Nat Comm 2016). We also demonstrated that after the denervation of splenic artery mice treated with AngII were protected from the elevation of blood pressure induced by this hypertensive hit (Carnevale et al. Nat Comm 2016). This innovative research has given rise to a growing interest in the field of neuro-immune reflexes in cardiovascular system providing a possible target for a translational approach. Additionally, results obtained by my postdoc project are in line with the concept that the brain-to-spleen pathway could be a possible regulator of inflammatory conditions characterizing many cardiovascular diseases, as myocardial infarction and hypertension induced by stress or obesity.
In this project, I focus my attention on heart failure that is one of the leading causes of mortality and mortality worldwide and it is the final stage of several overload cardiomyopathies, preceded by an early adaptive hypertrophic response and characterized by the inflammation.
The spleen represents the target of the neural reflex connecting the coeliac branch of the vagus nerve and the splenic nerve. In this scenario, we will try to highlight essential mechanisms for the development of new therapies that modulate signals at the level of the parasympathetic and sympathetic nervous system until the spleen. Furthermore, results of this project will represent an important advancement for new biological targets with innovative approaches at an early stage of the pathology before the establishment of chronic mechanisms. This project, for the first time, combines different skills in engineering, biology and microsurgery with the aim to understand the communication between systems and organs still unknown.