Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens
Esther M. Sternberg
Abstract | The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regionallevels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can beconsidered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.
Cell-surface receptors that are coupled to G-proteins, and have seven transmembranespanning domains. The acetylcholine, adrenergic and neuropeptide receptors are all members of this family. Typically, activation of the G-protein-coupled receptor produces a diffusiblesecond messenger that, in turn, triggers various biochemical cascades.
Section on Neuroendocrine Immunology and Behaviour, National Institute of Mental Health, National Institutes of Health, 5625 Fishers Lane, Room 4N-13, MSC-9401, Rockville, Maryland 20852, USA. e-mail: email@example.com doi:10.1038/nri1810
The local acute-phase inflammatory response is characterized by rubor(redness), dolor (pain) and calor (heat). Although these are all cardinal clinical features of inflammation, their proximal triggers are neural in origin. Similarly, the systemic acute-phase response also involves key neural elements — fever and activation of the central hormonal-stress response — mediated by the effects of immune factors on the hypothalamus. The cellular and molecular components of theinnate immune system provide the first line of defence against invading pathogens1, through recognition of pathogen-associated molecular patterns (PAMPs), and initial nonspecific cellular and humoral responses2. However, immune mediators and cytokines that are subsequently released by the innate immune system rapidly activate neural responses that both amplify local immune responses to clearpathogens and trigger systemic neuroendocrine and regional neural responses that eventually return the system to a resting state. Although this interplay constitutes an important feedback loop that optimizes innate inflammatory responses to invading pathogens, prolonged or inappropriate central nervous system (CNS) counter-regulatory responses might also predispose the host to excess inflammation (in thecontext of inadequate hormonal suppression) or uncontrolled infection (in the context of excess or prolonged anti-inflammatory hormonal responses). These can lead to pathological and lethal effects, including toxic shock, tissue damage and death. In this Review, I describe how specific elements of the CNS and innate immune system interact, present
evidence indicating that these two systemsform a cohesive and integrated early host response to pathogens, and identify areas for future research efforts to fully elucidate this interaction.
General principles and areas of controversy The nervous system has several characteristics that make it an ideal partner with the innate immune system in immediate nonspecific host defence. It reacts rapidly (in the order of milliseconds to minutes)to many types of nonspecific environmental stimuli. Neurotransmitters and neuropeptides often bind to G-protein-coupled receptors that activate the same secondary signalling pathways (such as those including protein kinase A, cyclic AMP and protein kinase C) as signals triggered by immune mediators. Immune mediators often interact with neurotransmitter receptors3 and also modulate neural pathways...