Neuroimmune mechanisms of depression

Abstract

Current diagnosis of depression is based solely on behavioral symptomatology. The available US Food and Drug Administration-approved treatments for depression have come from serendipitous discovery and are ineffective in nearly 30-50% of patients, which is thought to reflect a lack of specificity in targeting underlying pathophysiological mechanisms. Recent evidence has identified depression-related disruptions in a neuroimmune axis that interfaces the immune system and CNS to control behavior. This Review examines the evidence in patients and in animal models of depression that demonstrates how the peripheral immune system acts on the brain to alter an individual's response to stress, ultimately contributing to their vulnerability to mood disorders.

Figure 1. Circuits of the neuro-immune axis

The autonomic nervous system connects peripheral immune organs with the central nervous system and regulates homeostatic and inflammatory functions. A) Sympathetic nerves innervate Nestin⁺ bone marrow niche cells. Circadian release of NE activates β₃ adrenergic receptors (b₃AR) on perivascular Nestin⁺ niche cells, which leads to rhythmic downregulation of CXCL12 and the subsequent release of hematopoietic stem cells (HSC) into the blood stream during the resting period. B) The inflammatory reflex: nerve endings of the vagus nerve sense inflammatory mediators and transport the signals to the brain stem. From there, the signal travels via efferent cholinergic vagal nerves to the celiac ganglion and through adrenergic fibers of the splenic nerve and delivers NE to β₂ adrenergic receptors (b₂AR) on a subset of splenic T cells, which in turn secrete acetylcholine (ACh) that binds to α7 nicotinic acetylcholine receptors (a₇nAChR) on marginal zone macrophages and suppresses the production of inflammatory cytokines, such as TNF-α and IL-1β^, . C) Activation of the hypothalamic-pituitary-adrenocortical (HPA) axis leads to glucocorticoid (GC) release from the adrenal glands that exerts anti-inflammatory effects through binding of GC to cytosolic glucocorticoid receptor (GR) and inhibition of IL-6 release by monocytes.

Figure 2. Inflammation and the brain

In response to chronic stress, there is an increase in circulating monocyte levels, notably LY6C^hi. These monocytes are then lured by chemotactic cytokines in brain regions associated with anxiety and depression. A) Once in the brain, monocytes and cytokines affect neuronal synaptic plasticity by modifying cell signaling and gene expression through activation of cytokines receptors, corticotropin-releasing hormone receptor 1 (CRF₁) or toll-like receptor 4 (TLR₄), by either cytokines themselves, corticotropin-releasing factor (CRF), pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular pattern molecules (DAMPs). B) Synaptic changes such as down-regulation of CX₃CL₁ are detected by microglia inducing cytokine release and monocytes recruitment. A proportion of recruited monocytes will remain in the brain and adopt microglia-like properties. C) Cytokines can penetrate into the brain via passive or active mechanisms. Alteration of tight junction protein expression can result in the formation of transient holes allowing small circulating molecules such as cytokines to passively diffuse between endothelial cells. Binding of cytokines to specific receptors on endothelial cell can also induce production and subsequent release of inflammatory mediators into the brain. Finally, if the BBB is weakened and become more permeable monocytes can burrow through affecting neighboring astrocytes, which engulf blood vessels with their astrocytic end-feet. Circulating cytokines into the brain activate microglia stress response and may induce persistent synaptic changes.