Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

Abstract

Local inflammation includes elements — pain and vasodilation — that are neurally mediated. The systemic acute-phase response includes neurally mediated elements — fever and activation of the central hormonal stress response — that are mediated by the effects of immune factors on the hypothalamus. The cellular and molecular components of the innate immune system provide the first line of defence against invading pathogens, through recognition of pathogen-associated molecular patterns (PAMPs) and initial nonspecific cellular and humoral responses. Immune mediators and cytokines that are subsequently released by the innate immune system rapidly activate nonspecific neural responses that both amplify local immune responses to clear pathogens and trigger systemic neuroendocrine and regional neural responses that eventually return the system to a resting state. These neural responses include systemic hormonal responses (through the hypothalamic–pituitary–adrenal axis); regional neuronal responses (through the sympathetic and parasympathetic nervous systems) that innervate immune organs; and local neuronal responses (through the peripheral nervous system). Immune cells contain the molecular machinery to respond to neural signals, including receptors and signalling pathways. Neurotransmitters (including noradrenaline and acetylcholine), neuropeptides (including opioids, substance P, neuropeptide Y and calcitonin gene-related peptide and hormones (glucocorticoids) alter innate immune-cell function through these molecular mechanisms. The nervous system and innate immune system form a cohesive and integrated early host response to pathogens. This interplay constitutes an important feedback loop that optimizes innate inflammatory responses to invading pathogens. Prolonged or inappropriate central nervous system counter-regulatory responses could predispose the host to excess inflammation (in the context of inadequate hormonal suppression) or uncontrolled infection (in the context of excess or prolonged anti-inflammatory hormonal responses).