Immune and Neuroendocrine Mechanisms of Stress Vulnerability and Resilience

Abstract

Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore biological factors in favor of behavioral symptoms. Compounding this paucity of psychiatric biomarkers is a need for therapeutics to adequately treat the 30-50% of MDD patients who are unresponsive to traditional antidepressant medications. Interestingly, MDD is highly prevalent in patients suffering from chronic inflammatory conditions, and MDD patients exhibit higher levels of circulating pro-inflammatory cytokines. Together, these clinical findings suggest a role for the immune system in vulnerability to stress-related psychiatric illness. A growing body of literature also implicates the immune system in stress resilience and coping. In this review, we discuss the mechanisms by which peripheral and central immune cells act on the brain to affect stress-related neurobiological and neuroendocrine responses. We specifically focus on the roles of pro-inflammatory cytokine signaling, peripheral monocyte infiltration, microglial activation, and hypothalamic-pituitary-adrenal axis hyperactivity in stress vulnerability. We also highlight recent evidence suggesting that adaptive immune responses and treatment with immune modulators (exogenous glucocorticoids, humanized antibodies against cytokines) may decrease depressive symptoms and thus represent an attractive alternative to the current antidepressant treatments.

Figure 1

Immune mechanisms of stress vulnerability and resilience. (a) Circulating levels of pro-inflammatory cytokines (IL-1β and IL-6) are elevated in the blood of stress-susceptible animals and MDD patients altering neuronal, astrocytic and microglial functions. (b) Pro-inflammatory cytokines activate receptors at the cell surface of reactive astrocytes leading to enhanced expression of structural GFAP and release of inflammatory mediators and reduced expression of G-protein effectors and growth factors. (c) Activated microglia can release chemokine ligand 2 (CCL2) in the blood attracting patrolling immature Ly6C^high monocytes through binding of CCL2 to chemokine receptor 2 (CCR2). These monocytes can cross the blood–brain barrier and penetrate into the brain, particularly in stress-related brain regions expressing high levels of pro-inflammatory cytokine IL-1β, where they differentiate into phagocytic macrophages displaying a microglia-like morphology as assessed with microglia marker Iba1. (d) Activation of the NLRP3 inflammasome, constitutively expressed in macrophages and microglia, through Toll-like receptor 4 (TLR4) binding initiate pro-caspase-1 and pro-IL-1β cleavage leading to the secretion of pro-inflammatory IL-1β. Chronic stress also induces microglia hyper-ramification in rodent models of depression. (e) On the other hand, resilient animals do not display exacerbated immune responses following acute or chronic stressors. (f) In fact, lowering circulating pro-inflammatory cytokines levels by antidepressant treatment, humanized antibodies or IL-6^−/− bone marrow transplants reverse depression-like behaviors and promote a resilient phenotype. (g) Immunization through production of long-lived memory T-cell after exposure to CNS-related antigens could even help to build appropriate adaptive immune responses to future stressors. (h) Lower microglia reactivity and NLRP3 inflammasome activation could also be associated with resiliency as reduction of microglial activity by administration of the inhibitor minocycline abolishes the pro-ramifying effect of stress and reverses depression-like behaviors.

Figure 2

Neuroendocrine mechanisms of stress vulnerability and resilience. (a) Psychological stressors induce the activation of the hypothalamic-pituitary-adrenal axis (HPA), a circuit designed to properly modulate stress response and maintain physiological homeostasis that may be hyperactive in stress-susceptible animals and MDD patients. (b) Circulating glucocorticoids (GCs), which are synthetized and released from the adrenal glands following HPA activation, can cross the blood–brain barrier through P-glycoprotein (P-gp) transporters of endothelial cells and bind to GC receptors on brain cells including microglia and neurons. Prolonged GC binding on microglial receptors may maintain these CNS-resident immune cells in a pro-inflammatory state leading to the establishment of depression-like behaviors. (c) Severe early-life stressors, such as maternal separation, can affect GC receptor epigenetic regulation and promote repressive methylation reducing its expression at the cell surface and inducing GC resistance. (d) GCs play a major role in attenuation of inflammatory response by inducing apoptosis in immune cells, a process that might be involved in stress vulnerability. (e) Clinical studies reported sex differences in HPA response to stressors. Downregulation of DNA methyltransferase 3a (Dnmt3a) activity may promote resilience in a gender-specific manner by modulating gene expression in stress-related brain regions and possibly HPA axis response. The hormone oxytocin, which plays a role in social bonding, parturition and lactation, can reduce HPA axis activation inducing antidepressant effect. (f) Low circulating GC level and high expression of GC receptor in brain cells are associated with proper HPA axis response and a resilient phenotype. (g) Life experience such as high level of maternal care during childhood can positively alter epigenetic regulation of GC receptor gene, leading to enhanced GC receptor expression in brain and immune cells and reduced stress vulnerability. (h) Exogenous GC replacement with dehydroepiandrosterone (DHEA), a precursor for the synthesis of anabolic steroids released from the adrenal cortex with cortisol in response to stress, may blunt stress-induced HPA axis activation, promoting resilience.