A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication

Abstract

The crucial role of the immune system in hypertension is now widely recognized. We previously reported that hypertensive challenges couple the nervous drive with immune system activation, but the physiological and molecular mechanisms of this connection are unknown. Here, we show that hypertensive challenges activate splenic sympathetic nerve discharge to prime immune response. More specifically, a vagus-splenic nerve drive, mediated by nicotinic cholinergic receptors, links the brain and spleen. The sympathetic discharge induced by hypertensive stimuli was absent in both coeliac vagotomized mice and in mice lacking α7nAChR, a receptor typically expressed by peripheral ganglionic neurons. This cholinergic-sympathetic pathway is necessary for T cell activation and egression on hypertensive challenges. In addition, we show that selectively thermoablating the splenic nerve prevents T cell egression and protects against hypertension. This novel experimental procedure for selective splenic denervation suggests new clinical strategies for resistant hypertension.

Molecular and Functional Neuroscience in Immunity

“…Interestingly, stimulation of afferent vagus nerve fibers also has protective effects in this model, which suggests other brain-mediated mechanisms (98). Functional integration of the vagus nerve and splenic nerve is also implicated in the regulation of adaptive immune responses and B cell antibody production in the spleen during Streptococcus pneumonia (121) and in controlling T cell activation and egress from the spleen in experimental hypertension (122). Further molecular mapping of these circuits using genetic approaches (120) will advance understanding of their functional organization and indicate new therapeutic approaches.…”

Mechanisms and Therapeutic Relevance of Neuro-immune Communication

“…This is consistent with studies demonstrating that: 1) efferent vagus nerve fibers innervate the celiac ganglia and the superior mesenteric ganglion (Berthoud and Powley, 1993; Berthoud and Powley, 1996); and 2) the celiac ganglia and the superior mesenteric ganglion are the source of spleen-projecting catecholaminergic fibers (Bellinger et al, 1989; Nance and Burns, 1989; Li et al, 2010). The discovery of the inflammatory reflex generated a great deal of interest in studying the vagus nerve-splenic nerve axis in the regulation of immune function in a variety of conditions, including antibody secretion following exposure of B cells to blood-borne antigen and modulating cell trafficking and splenic lymphoid architecture (Mina-Osorio et al, 2012), IBD (Ji et al, 2013; Munyaka et al, 2014), renal ischemia-reperfusion injury (Inoue et al, 2016), and T cell activation and egression from the spleen in experimental hypertension (Carnevale et al, 2016). In addition, research initially performed to further characterize T-ChAT cells led to the important discovery that a specific subset of these cells mediate blood pressure regulation (Olofsson et al, 2016).…”

Perivascular adipose tissue inflammation in vascular disease

“…T cell recruitment to PVAT may be controlled by the sympathetic nervous system in PVAT and the adventitia (Marvar et al , ; Guzik and Mikolajczyk, ; Itani et al , ). Recent evidence suggests a central role for T cells of splenic origin in the initiation of inflammation in hypertension (Carnevale et al , , ). These studies from Lembo and Carnevale's group show elegantly that hypertensive challenges activate splenic sympathetic nerve discharge to prime immune response and stimulate immune cell egression from the spleen into target organs, including PVAT (Carnevale et al , , ).…”