Reflex control of immunity

Abstract

Inflammation can cause damage and even death. What controls this primitive and potentially lethal innate immune response to injury and infection? Molecular and neurophysiological studies during the past decade have revealed a pivotal answer: immunity is coordinated by neural circuits that operate reflexively. The afferent arc of the reflex consists of nerves that sense injury and infection. This activates efferent neural circuits, including the cholinergic anti-inflammatory pathway, that modulate immune responses and the progression of inflammatory diseases. It might be possible to develop therapeutics that target neural networks for the treatment of inflammatory disorders.

Figure 1. Neural circuitry of the inflammatory reflex

The inflammatory reflex controls innate immune responses by a mechanism that targets the regulatory transcription factor nuclear factor-κB (NF-κB). Exogenous and endogenous molecular products of infection and injury interact with receptors that are expressed by cells of the innate immune system, including Toll-like receptors (TLRs) and NLRs (nucleotide-binding domain, leucine-rich-repeat-containing family, such as NALPs (NACHT-, LRR- and PYD-domain containing proteins) and nucleotide-binding oligomerization domain (NOD)-like receptors). Ligand–receptor interactions activate innate immune responses and induce the secretion of pro-inflammatory cytokines. These molecules also activate afferent sensory neurons, which constitute the sensory arc of the inflammatory reflex. Axons travelling in the vagus nerve relay this information as action potentials to the brain stem. This in turn activates the efferent arc, which is known as the cholinergic anti-inflammatory pathway. This inhibits innate immune responses in the spleen through inhibitory signals that arise in the brain stem, traverse the vagus nerve and signal through nicotinic acetylcholine receptor subunit α7 (α7nAChR), which is expressed by cytokine-producing immune cells. This leads to the suppression of NF-κB activation and the inhibition of innate immune responses. Note that the initiation of the inflammatory reflex by many possible ligands through key receptors is a crucial point of innate immune control. So, information from many stimulating molecules is processed by a smaller number of pattern recognition receptors that transduce signalling information to a small number of transcription factors, including NF-κB, that regulate innate immune responses. Maximal control is thereby derived from a circuit in which the inflammatory reflex targets this restricted point of information processing. dsRNA, double-stranded RNA; HMGB1, high-mobility group box 1 protein; IκB, inhibitor of NF-κB; IL-1α, interleukin 1α.

Figure 2. Mechanism of function of the efferent arc

In the cholinergic anti-inflammatory pathway, acetylcholine binding to nicotinic acetylcholine receptor subunit α7 (α7nAChR) leads to the inhibition of the phosphorylation of inhibitor of NF-κB (I κB), the downregulation of the activation of mitogen-activated protein kinases (MAPKs), inhibition of the release of intracellular Ca²⁺ stores and the formation of a heterodimeric protein complex with Janus kinase 1 (JAK2), which activates signal transducer and activator of transcription 2 (STAT3). Together, these signalling cascades lead to inhibition of pro-inflammatory cytokine release. JNK, JUN N-terminal kinase; NF-κB, nuclear factor κB; NLR, nucleotide-binding domain, leucine-rich-repeat-containing family; PLCγ, phospholipase Cγ; TLR, Toll-like receptor.

Figure 3. Functional anatomy of the inflammatory reflex

Afferent (sensory) neural signals to the brain stem are relayed by the vagus nerve to the nucleus of the solitary tract (nucleus tractus solitarius; NTS). Polysynaptic relays then connect to the outflow centres of the autonomic nervous system, the rostral ventrolateral medullary (RVLM) sympathoexcitatory neurons and the vagal motor neurons in the nucleus ambiguus (NA) and the dorsal vagal motor nucleus. Outflow arrives at the coeliac ganglion from either the vagus nerve or the preganglionic efferent nerves, which originate in the sympathetic trunk. Stimulating the vagus nerve suppresses innate immune responses and downregulates pro-inflammatory cytokine release in the spleen through a mechanism that depends on nicotinic acetylcholine receptor subunit α7 (α7nAChR). Note that, following the activation of the inflammatory reflex by sensory input to the brainstem, the signals are also relayed to the nuclei controlling the function of the hypothalamic–pituitary-–adrenal (HPA) axis, which increases glucocorticoid hormone release by the adrenal gland. This provides an important connection between the neural networks that can acutely provide compensatory signals to adjust immune responses, and the humoral anti-inflammatory mechanisms that can more chronically modulate innate and adaptive immune responses. The identity and mechanism of function of the set point centre is unknown. It establishes the magnitude of the set function of immune output around which compensatory reflex responses maintain homeostasis.

Figure 4. The set point of the immune system

The set point function of the immune response is defined by the magnitude of innate immune responses relative to the infection or injury stimulus. Increasing the set point or shifting the curve to the left increases the chance that tissue damage will occur from the response to infection or injury. Decreasing the set point or shifting the curve to the right reduces the probability that tissue damage will occur. The inflammatory reflex is the neural circuit that provides acute compensatory input to adjust the magnitude of the immune response relative to the set point. Note that chronic changes in other systems (for example, the hypothalamic–pituitary–adrenal axis) can increase or decrease the set point. In this example, depletion of glucocorticoids following adrenalectomy would significantly increase the set point.