Autonomic neural regulation of immunity

Abstract

The 'cytokine theory of disease' states that an overproduction of cytokines can cause the clinical manifestations of disease. Much effort has been expended to determine how cytokines are regulated in normal health. Transcriptional, translational and other molecular control mechanisms protect the host from excessive cytokine production. A recent discovery revealed an unexpected pathway that inhibits macrophage cytokine production. The inflammatory reflex is a physiological pathway in which the autonomic nervous system detects the presence of inflammatory stimuli and modulates cytokine production. Afferent signals to the brain are transmitted via the vagus nerve, which activates a reflex response that culminates in efferent vagus nerve signalling. Termed the 'cholinergic anti-inflammatory pathway', efferent activity in the vagus nerve releases acetylcholine (ACh) in the vicinity of macrophages within the reticuloendothelial system. ACh can interact specifically with macrophage a7 subunits of nicotinic ACh receptors, leading to cellular deactivation and inhibition of cytokine release. This 'hard-wired' connection between the nervous and immune systems can be harnessed therapeutically in animal models of inflammatory disease, via direct electrical stimulation of the vagus nerve, or through the use of cholinergic agonists that specifically activate the macrophage a7 subunit of the ACh receptor. Autonomic dysfunction has been associated with human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis; whether this dysfunction results from the inflammatory component of these diseases, or is actually an underlying cause, is now less clear. The description of the cholinergic anti-inflammatory now brings to the fore several new therapeutic strategies for inflammatory disease, and suggests that many of these diseases may actually be diseases of autonomic dysfunction.

Resilience in farm animals: biology, management, breeding and implications for animal welfare

“…The immune system shares with other cells and organs of the body the capacity to communicate via autocrine, paracrine and endocrine pathways and is intimately linked with the autonomic nervous system (Czura and Tracey 2005;Wrona 2006). Chemosensors provide the means for cellular and organ exchange and utilisation of resources and one medium for central regulation of these functions.…”

The inflammatory reflex – Introduction

“…As a consequence the efferent vagus nerve can restrict general inflammation in a fast, integrated and polarized fashion. However, it does not block induction of inflammation induced by TLR upon recognition of pathogen-associated molecular patterns (Microbial products) [8]. This novel anti-inflammatory aspect of the inflammatory reflex may be of great importance to unravel by developing agonists for the a-7 subunit receptor for potential clinical efficacy in sepsis.…”

“…Afferent signals to the brain including pain are then transmitted via the vagus nerve generating a reflex causing an anti-inflammatory response, which is partly mediated by the efferent branch of the vagus nerve. In this issue Tracey et al outlines this pathway, and explains that the cholinergic anti-inflammatory pathway inhibits acute cytokine release [8]. The stimulated vagus nerve releases acetylcholine, which interacts with a specific receptor on macrophages in the reticuloendothelial system.…”

“…Tracey et al have thus identified a synapse between the cholinergic nervous system and innate immunity, which requires expression of acetylcholine binding to nicotinic acetylcholine receptors. Indeed they demonstrate that nicotine and electrical vagus nerve stimulation significantly inhibit the release of TNF as well as HMGB1 from endotoxinstimulated macrophages [8]. HMGB1 is a 30-kDa nuclear and cytosolic protein widely studied as a transcription factor and growth factor that has recently been identified as a cytokine mediator of lethal systemic inflammation, arthritis and local inflammation [10][11][12].…”

The Immune System’s Moderating Response to Inflammation Relieves Autistic Behavior: Response to Peter Good

“…In excess, these cytokines would be toxic. The proinflammatory cytokine response is rapidly curtailed by IL-1ra, a specific IL-1 antagonist, and by anti-inflammatory cytokines, such as IL-10, TNFbinding protein and transforming growth factor-b (TGF-b) (Czura and Tracey 2005). Moreover, the inflammatory reaction with its sympathetic activation is buffered by the vagal cholinergic anti-inflammatory system (CAIS) (Tracey 2007;Thayer 2009).…”