Abstract
Clinical and population studies document that many patients with chronic inflammatory diseases, including autoimmune pathologies such as rheumatoid arthritis and systemic lupus erythematosus, present autonomic dysfunctions. In most cases, these dysfunctions are characterized by increased sympathetic activity, which may contribute to the high cardiovascular morbidity and mortality risks observed in these patients. Although the mechanisms underlying autonomic dysfunctions in chronic inflammatory diseases are not yet defined, accumulated evidence over the last few years, including those obtained by our group, allow us to suspect that the high levels of circulating inflammatory mediators observed in these pathologies could impact central sympathetic circuits. Recently, we found that high levels of TNF-alpha in the bloodstream increase carotid sinus nerve afferent activity, activating excitatory neurons in the nucleus tractus solitarius (NTS) that project to the rostral ventrolateral medulla (RVLM) where many presympathetic neurons are located. Activation of this carotid body-NTS-RVLM circuit was accompanied by increased splanchnic sympathetic nerve activity. Carotid body ablation attenuated neuronal activation and increased sympathetic activity. Furthermore, the increase in pro-inflammatory cytokines in plasma and spleen induced by TNF-alpha administration was exacerbated in animals without carotid bodies or splanchnic nerves. These data indicate that the carotid body detects elevated levels of TNF-alpha in the circulation and recruits an anti-inflammatory mechanism mediated by the sympathetic nervous system. The discovery of this new mechanism opens up several perspectives, including the possible causes of autonomic dysfunctions in autoimmune diseases. We hypothesized that, in autoimmune diseases, chronic systemic inflammation with high circulating levels of cytokines would activate this mechanism in a sustained manner, resulting in sympathetic hyperactivation and immunological, endocrine, and inflammatory consequences. To test this hypothesis, we will employ the TRAP2 system to gain permanent genetic access to central presympathetic neurons activated by circulating inflammatory mediators. We will use the TRAP2 system in combination with other technologies such as Cre-reporter mice, fluorescence-activated cell sorting (FACS sorting), single-cell RNA-Seq, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), in vivo electrophysiological recordings, immunophenotyping, and cytokine and hormone measurements. This integrative approach will allow a full characterization (neuroanatomical, molecular, and functional) of presympathetic neuron subpopulations that are activated by circulating inflammatory mediators to exert modulatory effects on the immune and endocrine systems, which, in turn, control the inflammatory response. Once identified and characterized, we will evaluate the contribution of these neuronal subpopulations to the development of autonomic dysfunctions in autoimmune diseases using preclinical models of rheumatoid arthritis and systemic lupus erythematosus. Furthermore, we will use human induced pluripotent stem cells (hiPSC) to generate sympathetic neurons and human monocytic cells lines to generate macrophages, develop in vitro models of human autonomic disorders, and evaluate their consequences on the phenotype and function of immune cells. With the present grant, we aim to achieve innovative results with enormous translational potential and to consolidate and expand the exchange between the host and partner institutions (Harvard Medical School). (AU)
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