Reciprocal regulation of the neural and innate immune systems

Abstract

Innate immune responses are regulated by microorganisms and cell death, as well as by a third class of stress signal from the nervous and endocrine systems. The innate immune system also feeds back, through the production of cytokines, to regulate the function of the central nervous system (CNS), and this has effects on behaviour. These signals provide an extrinsic regulatory circuit that links physiological, social and environmental conditions, as perceived by the CNS, with transcriptional 'decision-making' in leukocytes. CNS-mediated regulation of innate immune responses optimizes total organism fitness and provides new opportunities for therapeutic control of chronic infectious, inflammatory and neuropsychiatric diseases.

Figure 1. CNS regulation of innate immune response gene programmes

a | The hypothalamic–pituitary–adrenal (HPA) axis distributes glucocorticoid hormones through the blood to regulate gene expression in virtually every cell of the body. Hormone activation of the glucocorticoid receptor in leukocytes results in profound suppression of both pro-inflammatory gene networks (for example, NF-κB-mediated transcription of pro-inflammatory cytokine genes, such as IL1B, IL6 and TNF) and antiviral gene programmes (for example, IRF-mediated transcription of type I interferon (IFN) genes, such as IFNA and IFNB). Activation of cytokine receptors in the hypothalamus triggers the production of glucocorticoids by the HPA axis. This constitutes the body’s primary systemic mechanism for negative feedback control of pro-inflammatory gene expression triggered by microbial pattern recognition receptors (PRRs). b | During fight-or-flight responses and acute injury, nerve fibres from the sympathetic nervous system (SNS) release the neurotransmitter noradrenaline into primary and secondary lymphoid organs, all other major organ systems (including the vasculature and perivascular tissues) and many peripheral tissues in which pro-inflammatory reactions occur. SNS nerve fibres can also stimulate the adrenal glands to release stored adrenaline into the systemic circulation. Both of these neuromediators regulate vascular function and stimulate leukocyte adrenergic receptors (for example, ADRB2) to activate transcription factors such as CREB and GATA family factors. SNS-induced transcriptional alterations can modulate haematopoiesis, redeploy leukocytes between tissue and blood, and repress IRF-mediated antiviral immune response gene programmes while enhancing many NF-κB-mediated pro-inflammatory programmes. ACTH, adrenocorticotropic hormone; ADRB2, β2-adrenergic receptor; CRH, corticotropin-releasing hormone; IL, interleukin; IRF, interferon regulatory factor; NF-κB, nuclear factor-κB; TNF, tumour necrosis factor.

Figure 2. Multi-circuit control of the innate immune transcriptome

Leukocyte transcription of immune response gene programmes is regulated by both intrinsic immunological signals representing local tissue and microbial conditions and extrinsic neural and endocrine signals representing global physiological and environmental conditions. Intrinsic circuits detect microorganisms via pattern recognition receptors (PRRs) and stimulate pro-inflammatory and antiviral immune response gene programmes via transcription factors such as nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs). The resulting production of innate immune effector molecules reduces microbial burden, and thereby feeds back to reduce PRR and antigen receptor signalling and immune response gene transcription. Extrinsic regulation of immune response gene transcription is mediated by central nervous system (CNS) integration of information regarding general physiological and ecological conditions. This can either globally suppress immune response gene transcription via the hypothalamic–pituitary–adrenal axis or steer immune response gene transcriptional profiles away from antiviral programmes and towards more robust pro-inflammatory gene expression. CNS-mediated transduction of information from the social and physical ecology allows extra-organismal environmental conditions to indirectly regulate the immune response gene transcriptional profiles of immune cells. SNS, sympathetic nervous system.