Central regulation of stress-evoked peripheral immune responses

Abstract

Stress-linked psychiatric disorders, including anxiety and major depressive disorder, are associated with systemic inflammation. Recent studies have reported stress-induced alterations in haematopoiesis that result in monocytosis, neutrophilia, lymphocytopenia and, consequently, in the upregulation of pro-inflammatory processes in immunologically relevant peripheral tissues. There is now evidence that this peripheral inflammation contributes to the development of psychiatric symptoms as well as to common co-morbidities of psychiatric disorders such as metabolic syndrome and immunosuppression. Here, we review the specific brain and spinal regions, and the neuronal populations within them, that respond to stress and transmit signals to peripheral tissues via the autonomic nervous system or neuroendocrine pathways to influence immunological function. We comprehensively summarize studies that have employed retrograde tracing to define neurocircuits linking the brain to the bone marrow, spleen, gut, adipose tissue and liver. Moreover, we highlight studies that have used chemogenetic or optogenetic manipulation or intracerebroventricular administration of peptide hormones to control somatic immune responses. Collectively, this growing body of literature illustrates potential mechanisms through which stress signals are conveyed from the CNS to immune cells to regulate stress-relevant behaviours and comorbid pathophysiology.

Fig. 1:. CNS innervation of immunologically-relevant peripheral tissues.

Summary of time course studies identifying CNS regions innervating the bone marrow^,, spleen^,, gut^–, adipose tissue^, and liver^, following trans-synaptic retrograde tracing using pseudorabies viruses (PRVs). CNS regions where PRV was identified are shown on the x-axis, with days after PRV injection indicated on the y-axis. AP, area postrema; ARH, arcuate nucleus of the hypothalamus; BNST, bed nucleus of the stria terminalis; DMH, dorsomedial nucleus of the hypothalamus; DMN, deep mesencephalic nucleus; DMV, dorsal motor nucleus of the vagus; Gi, gigantocellular reticular nucleus; Hipp: hippocampus; LC, locus coeruleus; LH, lateral nucleus of the hypothalamus; LPGi, lateral paragigantocellular nucleus; NTS, nucleus of the solitary tract; PAG, periaqueductal grey; PO, preoptic area; PRN, pontine reticular nucleus; PVH, paraventricular nucleus of the hypothalamus; RCH, retrochiasmatic nucleus; RPa, raphe pallidus; SCH, suprachiasmatic nucleus; SLC, subcoeruleus nucleus; VMH, ventromedial nucleus of the hypothalamus; VTA, ventral tegmental area; ZI, zona incerta.

Fig. 2:. Control of peripheral immunity by central stress centres.

Schematic outlining the regulation of peripheral immune responses by CNS regions involved in stress and reward processing. Activation of the paraventricular nucleus of the hypothalamus (PVH) decreases bone marrow chemokine (C-X-C motif) ligand 12 (CXCL12) expression, induces monocytosis and lymphocytopenia, increases splenic plasma cell (PC) formation and IgG production, and promotes the accumulation of type 2 innate lymphoid cells (ILC2) in adipose tissue through activation of the HPA axis, SNS, or splenic nerve^,,,. Motor circuit activity, driven by the motor cortex (MO) stimulates neutrophilia via skeletal muscle production of cytokines such as CXCL1. Monocytosis, neutrophilia and leukocytopenia contribute to depression-like behaviour and impair influenza A clearance. Adipose tissue ILC2s are associated with decreased weight gain and improved glucose tolerance. Ventral tegmental area (VTA) stimulation increases the numbers of B cells in circulation to improve bacterial clearance. Central amygdala (CeA) CRH neuron stimulation also contributes to PC formation. Dorsal motor nucleus of the vagus (DMV) activation, acting via the vagus nerve, inhibits tumour necrosis factor α (TNF) expression in the spleen and macrophage infiltration in the liver^,. Orexin (ORX) expression in the lateral nucleus of the hypothalamus (LH) also upregulates mTOR, S6K and sXbp1 in the liver to limit hepatic inflammation. Insular cortex (INS) neurons drive processes that can trigger inflammatory responses in the colon, including activation of CD4+, CD8+, and γδT cells, and expression of IL6 and TNF. HPA axis: hypothalamic-pituitary-adrenal axis, SNS: sympathetic nervous system, CRH: corticotropin-releasing hormone, mTOR: mammalian target of rapamycin, S6K: S6 kinase, sXbp1: spliced X-box binding protein 1.

Fig. 3:. Breakdown of body barriers during stress [.

Chronic stress or stress-relevant disorders, such as anxiety and depression, compromise the blood-brain barrier (BBB) and gut epithelial barrier. In the nucleus accumbens (NAc), stress triggers pro-inflammatory tumour necrosis factor α (TNF) and/or nuclear factor-κB (NFКB) signaling pathways in endothelial cells and downregulation of the tight junction protein claudin-5 (CLDN5)^,. Simultaneously, inflammatory monocytes expressing high levels of Ly6C (Ly6C^hi monocytes) and neutrophils are recruited to the NAc, where these cells (or their secreted factors, such as interleukin 6 (IL6) and matrix metalloproteinase 8 (MMP8)) can enter the brain parenchyma through the damaged BBB to directly influence neuronal excitability^,. In the intestine, stress increases IL17⁺ T cell and mast cell accumulation, which may contribute to decreases in CLDN5, occludin (OCLN), and tight junction protein 2 (ZO-2), allowing lipopolysaccharide (LPS) to enter circulation from the gut lumen to activate pro-inflammatory signaling pathways via toll-like receptor 4 (TLR4)^,–.