Autonomic nervous system and immune system interactions

Abstract

The present review assesses the current state of literature defining integrative autonomic-immune physiological processing, focusing on studies that have employed electrophysiological, pharmacological, molecular biological, and central nervous system experimental approaches. Central autonomic neural networks are informed of peripheral immune status via numerous communicating pathways, including neural and non-neural. Cytokines and other immune factors affect the level of activity and responsivity of discharges in sympathetic and parasympathetic nerves innervating diverse targets. Multiple levels of the neuraxis contribute to cytokine-induced changes in efferent parasympathetic and sympathetic nerve outflows, leading to modulation of peripheral immune responses. The functionality of local sympathoimmune interactions depends on the microenvironment created by diverse signaling mechanisms involving integration between sympathetic nervous system neurotransmitters and neuromodulators; specific adrenergic receptors; and the presence or absence of immune cells, cytokines, and bacteria. Functional mechanisms contributing to the cholinergic anti-inflammatory pathway likely involve novel cholinergic-adrenergic interactions at peripheral sites, including autonomic ganglion and lymphoid targets. Immune cells express adrenergic and nicotinic receptors. Neurotransmitters released by sympathetic and parasympathetic nerve endings bind to their respective receptors located on the surface of immune cells and initiate immune-modulatory responses. Both sympathetic and parasympathetic arms of the autonomic nervous system are instrumental in orchestrating neuroimmune processes, although additional studies are required to understand dynamic and complex adrenergic-cholinergic interactions. Further understanding of regulatory mechanisms linking the sympathetic nervous, parasympathetic nervous, and immune systems is critical for understanding relationships between chronic disease development and immune-associated changes in autonomic nervous system function.

Figure 1

Traces of splenic sympathetic nerve discharge (SND) recorded during nonheated (A) and heated (B) experimental conditions in rats with intact splenic nerves. Note the heating-induced increase in splenic SND (B). As expected, splenic-denervation abolished splenic SND but not renal SND responses to heating (C). Expression of splenic interleukin-1β (IL-1β), interleukin-6 (IL-6), and growth-regulated oncogene 1 (GRO1) genes was significantly higher in heated splenic-intact compared with nonheated splenic-intact, and in heated splenic-intact compared with heated splenic-denervated rats (bottom). Black box, non-heated splenic-intact; gray box, heated splenic-intact; white box, heated splenic-denervated. Adapted with permission from Ganta et al. (96).

Figure 2

Schematic diagram illustrating how the subfornical organ (SFO) may link angiotension II (Ang II) to visceral sympathoexcitation. Ang II-mediated activation of NADPH oxidases and increased oxidative stress in the SFO, along with resulting endoplasmic reticulum stress, leads to stimulation of neural projections to the paraventricular nucleus (PVN), which signals downstream sympathetic pathways mediating increases in renal sympathetic nerve discharge. Adapted with permission from Davisson and Zimmerman (60).

Figure 3

Perivascular macrophages may provide a critical link between systemic inflammation, circulating cytokines, and sympathetic nerve discharge (SND) activation. Cyclooxygenase expression and synthesis of prostaglandin E2 (PGE₂) occurs in perivascular macrophages and endothelial cells of the brain microvasculature in response to immune activation. PGE₂ can gain access to the brain parenchyma, activate presympathetic neurons in sympathetic nuclei, including the paraventricular nucleus (PVN), and signal downstream sympathetic nuclei (rostral ventral lateral medulla, RVLM; intermediolateral nucleus of the spinal cord, IML) and pathways to increase renal SND. Adapted with permission from Serrats et al. (265).

Figure 4

Schematic diagram illustrating how central neural administration of interferon-α (IFN-α) may modulate splenic sympathetic nerve discharge (SND). The neural projection pathway from the medial preoptic area (MPO) to the paraventricular nucleus (PVN) is considered to be primarily inhibitory, and MPO neurons are suppressed by IFN-α microinjections. Therefore, MPO IFN-α administration leads to activation of PVN neurons secondary to disinhibition. The PVN has direct excitatory projections to the RVLM and the IML nucleus leading to activation of splenic SND. Adapted with permission from Katafuchi et al. (139).

Figure 5

Schematic diagram illustrating how central prostaglandin E2 (PGE₂) in the preoptic area (POA) of the hypothalamus mediates sympathetic activation. PGE₂ acts on EP₃ receptors to inhibit POA neurons that are inhibitory to neurons in the dorsal medial hypothalamus (DMH) and rostral raphe pallidus (rRPa), thus activating sympathetic outflow mediating cutaneous vasoconstriction and sympathetic neural pathways to adrenergic receptors (ARs). Adapted with permission from Morrison (200).

Figure 6

Schematic diagram illustrating intracellular signaling pathways in a macrophage involved in cytokine regulation by adrenergic and cholinergic agonists and receptors following lipopolysaccharide challenge. Norepinephrine (NE) binds to adrenergic receptors (ARs) and induces cyclic AMP and protein Kinase A (PKA) activation which inhibits pro-inflammatory cytokine production by inhibition of NF-κB nuclear translocation. Acetylcholine (ACh) binds to the α7nACh receptor and inhibits phosphorylation and nuclear translocation of NF-κB. In addition, ACh activates the JAK2/STAT3 pathway leading to increased transactivation of anti-inflammatory cytokines, and decreased transcription of high mobility group box 1 (HMGB1) and proinflammatory cytokines. LPS, lipopolysaccharide; TLR, toll like receptor; α7nACh, α7 nicotinic acetylcholine receptor. Adapted with permission from Sternberg (277).

Figure 7

Schematic diagram highlighting the critical roles that both arms of the autonomic nervous system (i.e., sympathetic nervous system and parasympathetic nervous system) play in regulating central neural and peripheral neuroimmune interactions. See text for details. (CNS, central nervous system; HPA, hypothalamic pituitary adrenal axis CVOs, circumventricular organs; BBB, Blood Brain Barrier; ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; NO, Nitric Oxide; Ach, acetylcholine; NE, norepinephrine; ARs, adrenergic receptors; α7nACh, α7 nicotinic acetylcholine receptor; M, macrophage; T, T cell (memory type); B, B cell, NK, natural killer cell; PGE₂, prostaglandin E2; IML, spinal intermediolateral nucleus; SFO, subfornical organ; MPO, medial preoptic nucleus; DMH, dorsomedial hypothalamus; PVN, paraventicular nucleus; NTS, nucleus tractus solitarius; DMV, dorsal motor nucleus of the vagus; NA, nucleus ambiguous; rRPa, rostral raphe pallidus; RVLM, rostral ventral lateral medulla; BAT, brown adipose tissue).