The neuroimmunology of social-stress-induced sensitization

Abstract

Myriad clinical findings provide links between chronic stressors, inflammation, and mood disorders. Furthermore, traumatic or chronic exposure to psychological stressors may promote stress sensitization, in which individuals have long-term complications, including increased vulnerability to subsequent stressors. Post-traumatic stress disorder (PTSD) is a clinically relevant example of stress sensitization. PTSD alters neuronal circuitry and mood; however, the mechanisms underlying long-term stress sensitization within this disorder are unclear. Rodent models of chronic social defeat recapitulate several key physiological, immunological, and behavioral responses associated with psychological stress in humans. Repeated social defeat (RSD) uniquely promotes the convergence of neuronal, central inflammatory (microglial), and peripheral immune (monocyte) pathways, leading to prolonged anxiety, social withdrawal, and cognitive impairment. Moreover, RSD promotes stress sensitization, in which mice are highly sensitive to subthreshold stress exposure and recurrence of anxiety weeks after the cessation of stress. Therefore, the purpose of this Review is to discuss the influence of social-defeat stress on the immune system that may underlie stress sensitization within three key cellular compartments: neurons, microglia, and monocytes. Delineating the mechanisms of stress sensitization is critical in understanding and treating conditions such as PTSD.

Fig. 1 |. Social defeat stress activates the hypothalamic pituitary adrenal axis and sympathetic nervous system to promote the release of monocytes into circulation.

Social defeat stress increases the release of corticotrophhin-releasing hormone (CRH) in the hypothalamus. The release of CRH prompts the pituitary gland to release adrenocorticotropic hormone (ACTH) into circulation. In turn, the adrenal glands respond and release both glucocorticoids and catecholamines. Glucocorticoids feed back to the hypothalamus to stop the production of CRH. Parallel to this, social defeat activates the SNS. SNS activation results in the release of catecholamines (for example, norepinephrine) that act directly on primary and secondary lymphoid tissues (for example, bone marrow). Both glucocorticoids and catecholamines converge to increase the production, maturation, and release of monocytes into circulation. Created with BioRender.com.

Fig. 2 |. Repeated social defeat induces neuronal activation that coordinates peripheral and central immune responses that influence behavior and cognition.

SDS increases neuronal activation (for example, ΔFosB and phosphorylation of cAMP-response element binding protein (p-CREB)) in the fear and threat areas of the brain and expression of neuronal interleukin-1 receptor-1 (nIL-1R1). This leads to activation of the SNS and HPA, which drives myelopoiesis within the bone marrow. As a result, monocytes are released into the circulation, where there are high concentrations of glucocorticoids (GC) and IL-6. These monocytes have an increased inflammatory profile and can traffic to tissues including the brain. Concomitant with this response is the activation of microglia and brain endothelia with RSD. A reactive endothelium includes increased cell adhesion molecules (selectins and integrins) and interleukin-1 receptor-1 (eIL-1R1). Microglia actively release chemokines (C–C motif ligand 2, CCL2) and cytokines (IL-1β). This microglia activation following RSD results in the increased recruitment of inflammatory monocytes to the brain vasculature and perivascular space. These monocytes provide IL-1β to the endothelia. This convergence of neuronal, endothelial, and microglial activation and monocyte recruitment contributes to cognitive and behavioral changes following stress (for example, anxiety, social avoidance, reduced working memory). This schematic also shows various interventions and their effect on this paradigm. Administration of propranolol, a beta-2 antagonist, prevents SNS activation, neuronal and microglial activation, recruitment of peripheral monocytes, and the development of anxiety-like behavior. Clonazepam, a benzodiazepine, blocks neuronal and microglial activation and social avoidance after social defeat. Additionally, minocycline and PLX5662, a colony stimulating factor-1 receptor (CSF1R) antagonist, prevents microglial activation and the development of anxiety following stress. Knocking down the IL-1R1 (eIL-1R1^KD) on endothelia reduces neuroinflammation and attenuates anxiety-like behavior following RSD. Created with BioRender.com.

Fig. 3 |. Overview of repeated social defeat and stress sensitization of central and peripheral immune compartments.

The first box shows a ‘homeostatic’ state in the absence of stress. The second box shows acute stress with one cycle of social defeat (2 hours). This induced neuronal (cFos) activation in fear- and threat-appraisal regions and social avoidant behavior. In addition, microglia morphology in the amygdala was increased compared to controls. The third box shows RSD with six cycles of defeat. RSD promotes a reactive (+) endothelium, myelopoiesis in the BM, splenomegaly (HSCs), and neuronal (cFos, ΔFosB) and microglial (IL-1β and CCL2) activation. RSD also leads to behavioral deficits, including anxiety (open field, light dark), social avoidance, and cognitive deficits (Barnes maze, Morris water maze). After 24 days (fourth box), microglia remain in a primed pro-inflammatory state (IL-6 and CD14), and social avoidance behavior persists. The fifth box shows exacerbation (++) of immune responses and neuronal activation occur after an acute stress 24 days after the last cycle of RSD. The spleen becomes a reservoir for immune cells and releases monocytes into circulation following the acute defeat. These spleen-derived monocytes traffic to the reactive endothelium and can signal through IL-1R. Neurons show increased reactivity (increased p-CREB) and activation (cFos) in the fear- and threat-appraisal regions. Primed microglia are activated and release proinflammatory cytokines and chemokines (IL-1β, IL-6, CCL2). Behavioral deficits, including anxiety (open field), social avoidance, and cognitive deficits (Y-maze), are evident after stress sensitization. Created with BioRender.com.

Fig. 4 |. Microglia are primed and more reactive to peripheral immune challenges after repeated social defeat.

This schematic shows the priming effect of social defeat stress on microglia. Left, microglia isolated (ex vivo) from RSD mice 24 days after the last cycle of RSD were stimulated with LPS for 4 hours. These microglia had increased pro-inflammatory gene expression compared with controls. In the right box, mice were injected with LPS 24 days after the last cycle of RSD. After 24 hours, microglia from LPS-injected RSD mice had exaggerated gene expression of pro-inflammatory (IL-1β) and pathogen-associated molecular patterns (TLR-4 and CD14) compared with microglia from saline-treated mice. Mice treated with LPS after stress had increased social anxiety in response to a juvenile and decreased exploratory behavior. Created with BioRender.com.