Neuroimmunology of depression

Abstract

Depression is one of the leading causes of disability worldwide and a major contributor to the global burden of disease, yet the cellular and molecular etiology of depression remain largely unknown. Major Depressive Disorder (MDD) is associated with a variety of chronic physical inflammatory and autoimmune disorders, and mood disorders may act synergistically with other medical disorders to worsen patient outcomes. Here, we outline the neuroimmune complement, explore the evidence for altered immune system function in MDD, and present some of the potential mechanisms by which immune cells and molecules may drive the onset and course of MDD. These include pro-inflammatory signaling, alterations in the hypothalamic-pituitary-adrenal axis, dysregulation of the serotonergic and noradrenergic neurotransmitter systems, neuroinflammation, and meningeal immune dysfunction. Finally, we discuss the interactions between current antidepressants and the immune system and propose the possibility of immunomodulatory drugs as potential novel antidepressant treatments.

Keywords: Antidepressants; Brain; Depression; HPA axis; Meninges; Neuroimmunology.

Fig. 1

Immune complement of the meninges. The three layers of the meninges, the pia mater, arachnoid mater, and dura mater, make up the physical barrier between the brain/central nervous system and the outside environment. Blood and lymphatic vessels move through these layers, and the passage of immunoreactive substances into the brain is tightly regulated by a variety of immune cells: mast cells, T cells, B cells, macrophages, astrocytes, and dendritic cells. This meningeal immune complement regulates, and is modulated by, the brain and brain immune cells. Figure made in part with Biorender.com.

Fig. 2

The HPA axis in stress, immune signaling, and depression. In response to acute stress, the hypothalamus in the brain secretes corticotropin-releasing hormone (CRH), which causes the nearby anterior pituitary to release adrenocorticotropic hormone (ACTH) into the circulatory system such that it reaches the adrenal cortex near the kidneys, causing the release of glucocorticoids like cortisol, which drives the stress response. Glucocorticoids can drive both pro- and anti-inflammatory pathways, modulating brain function and mood. Under normal conditions, cortisol also activates glucocorticoid receptors (GR) throughout the HPA axis to dampen HPA signaling in a classical negative feedback mechanism. However, chronic stress reduces GR function in the HPA axis, removing inhibition and causing increased glucocorticoid signaling, favoring pro-inflammatory pathways that drive depression. Figure made in part with Biorender.com.