The sympathetic nervous response in inflammation

Abstract

Over the past decades evidence has accumulated clearly demonstrating a pivotal role for the sympathetic nervous system (SNS) and its neurotransmitters in regulating inflammation. The first part of this review provides the reader with an overview showing that the interaction of the SNS with the immune system to control inflammation is strongly context-dependent (for example, depending on the activation state of the immune cell or neuro-transmitter concentration). In the second part we focus on autoimmune arthritis as a well investigated example for sympathetically controlled inflammation to show that the SNS and catecholamines play a differential role depending on the time point of ongoing disease. A model will be developed to explain the proinflammatory effects of the SNS in the early phase and the anti-inflammatory effects of catecholamines in the later phase of autoimmune arthritis. In the final part, a conceptual framework is discussed that shows that a major purpose of increased SNS activity is nourishment of a continuously activated immune system at a systemic level using energy-rich fuels (glucose, amino acids, lipids), while uncoupling from central nervous regulation occurs at sites of inflammation by repulsion of sympathetic fibers and local adrenoceptor regulation. This creates zones of ‘permitted local inflammation’. However, if this ‘inflammatory configuration’ persists and is strong, as in autoimmunity, the effects are detrimental because of the resultant chronic catabolic state, leading to cachexia, high blood pressure, insulin resistance, and increased cardiovascular mortality, and so on. Today, the challenge is to translate this conceptual knowledge into clinical benefit.

Figures

Figure 1

Basic neuronal anti-inflammatory reflex. Local inflammation (the fire) is detected by vagal and sensory nerve fibers, which express receptors for inflammatory mediators, like interleukin (IL)-1β (red dots). An afferent signal is generated and transmitted to the brain (central nervous sytem (CNS)), which in turn leads to activation of the sympathetic nervous system (SNS), which has a complex impact on inflammation. Local release of SNS neurotransmitters, like norepinephrine, at the site of inflammation or in secondary lymphoid organs has a net anti-inflammatory outcome. On the other hand, non-specific immune stimulatory processes on a systemic level are supported, like recruitment of leukocytes, increased blood and lymph flow, but also increasing antigen processing and presentation and provision of energy-rich fuels. Ln, lymph node.

Figure 2

Catecholamine effects depend on the distance from catecholamine source. α- and β-adrenoceptors (ARs) show different binding affinities for catecholamines. Norepinephrine, the main neurotransmitter in the sympathetic nervous system (SNS), binds with higher affinity to α-ARs than β-ARs. Simultaneous expression of these receptors on immune cells (for example, macrophages (MΦ)) provides these cells with a passive means to determine the distance to the next catecholamine source. In close proximity to the catecholamine source (for example, sympathetic nerve terminal or catecholamine-producing tyrosine hydroxylase (TH)-positive cell) the concentration is high enough to activate β-ARs, whereas at a greater distance only α-ARs are activated. In the case of innate immune cells, like macrophages, this directly translates into anti-inflammatory (for example, increases in interleukin (IL)-10 via β-AR) or proinflammatory activity (for example, increases in tumor necrosis factor (TNF) via α-AR). Therefore, the simultaneous expression of α-ARs and β-ARs on immune cells provides a mean to regulate inflammatory processes dependent on the distance to the catecholamine source. We hypothesize that the body uses this system to promote local inflammation by repulsion of sympathetic nerve fibers from inflamed areas (zone of inflammation) and, at the same time, locally confines the inflammatory process by suppression of bystander activation in the zone of anti-inflammation.

Figure 3

Current model of sympathetic nervous system influence in arthritis. In early arthritis (left panel), the sympathetic nervous system (SNS) supports inflammation in the joint through a proinflammatory influence on adaptive immune cells; for example, increased specific antibody production by B cells and increased proinflammatory activity of T cells. The SNS also inhibits innate immune cells via stimulation of β2 adrenoceptors (β2ARs), although the net outcome of SNS influence in the early phase is proinflammatory. Then, during the transition phase, we hypothesize that the influence of the SNS changes from pro- to anti-inflammatory. In the later stages, central regulation of the inflammatory process is less important, since sympathetic nerve fibers are repelled from the inflamed area and secondary lymphoid organs. However, local sympathetic influence becomes increasingly important, indicated by the appearance of catecholamine-producing, tyrosine hydroxylase-positive (TH+) cells, which have a dominant anti-inflammatory effect. Possible mechanisms of action are paracrine and autocrine in manner; for example, inhibiting proinflammatory interleukin (IL)-7 receptor-positive B cells, increasing the activity of IL-10-producing anti-inflammatory B cells, or inhibiting innate immune cells via β2AR-mediated effects. AR, adrenoceptor; cAMP, cyclic adenosine monophosphate; CD, cluster of differentiation; FoxP3, forkhead box P3; IFN, interferon; MHC, major histocompatibility complex; pSTAT5, phosphorylated-signal transducer and activator of transcription 5; TCR, T-cell receptor; Th1, T helper 1 cell.

Figure 4

Morphologic adaptation to persistent inflammation. Centrally controlled increase of sympathetic nervous system (SNS) activity is a basic response to inflammation. The constant increase in SNS activity supports inflammation in several ways; for example, increasing blood flow, lymph flow, antigen presentation, and liberation of energy-rich fuels like lipids and glucose from adipose tissue and liver. However, the specific interaction with immune cells in secondary lymphoid organs and at local sites of inflammation (for example, joints) shows a net anti-inflammatory effect. Therefore, to mount an effective immune response, non-specific support of inflammation on a systemic level is maintained, while the anti-inflammatory influence on a local level is decreased and uncoupled from central regulation through repulsion of sympathetic nerve fibers and the appearance of tyrosine hydroxylase (TH) + catecholamine-producing cells during the inflammatory process. In the end, a systemic proinflammatory configuration is established, which helps to optimally clear the antigen. However, if inflammation persists, like during chronic inflammation, this constant increase in SNS activity and resultant catabolic state is detrimental to the body and results in known disease sequelae of chronic inflammatory conditions, like cachexia, diabetes, hyperlipidemia, high blood pressure, increased cardiovascular risk, and so on.