Written by Brett Weiss
Stress causes an immune system response, which affects the brain as well. Hence, stress causes “neuroimmune” responses whereby long-term changes in the brain can occur. Stressful experiences include minor daily events or hassles that can perpetuate and culminate into more chronic periods of distress. Other stressful experiences can include severe and brief threats that change life-long outlooks and alter stress physiology. In accordance with this, about 22% of Americans have reported extreme stress in daily life, while 44% report that their stress increased in the last year (Deak et al., 2015). Furthermore, decades of medical research have associated life stress with development of pathological disease states, such as psychiatric disorders including Major Depressive Disorder and Post-traumatic Stress Disorder (Deak et al., 2015). Neurodegenerative disorders associated with life stress include Alzheimers Disease and Parkinson’s Disease (Deak et al., 2015). Furthermore, systemic disorders associated with life stress include cardiovascular disease, diabetes, and inflammatory diseases (Deak et al., 2015). The sympathetic nervous system and hypothalamic-pituitary-adrenal axis, which facilitate the “fight or flight” response, drive many downstream physiological effects from stress, which include the release of substances (cytokines, chemokines, etc.) from the immune system. The “fight or flight” response promotes survival in the face of physiological (injury, infection, etc.) and psychological (predator exposure, social dominance, etc.) threats (Deak et al., 2015). Bidirectional communication also occurs between the immune system and the brain, facilitating a balance (homeostasis) in response to environmental stressors. Depending upon the stressor, the neuroimmune response may be beneficial or detrimental (Deak et al, 2015). For instance, in an adaptive scenario, the neuroimmune response may lead to an individual mounting a beneficial response to an infection or social threat with physiological constraints ending the response. On the other hand, proinflammatory cytokines, substances that the immune system releases, may circulate in the blood given exposure to chronic or repeated stress, which has associated with mood disturbances such as anxiety and depression (Deak et al., 2015). The following will explain how neuroimmune system balance occurs and how stress may disrupt it.
The neuroimmune response to stress separates into two categories: early (acute) response and long-term (chronic) response to repeated stressors. The early response to stress entails activation of the sympathetic nervous system along with the hypothalamic-pituitary-adrenal axis for the “fight or flight” response. During this response, increases in inflammatory factors from the immune systems release into the brain, namely IL-1 and PGE2. A post-stress recovery period from 24 to 72 hours after the initial stressor takes place. During the post-stress recovery period, the individual has reduced food and water intake, along with impaired social behavior. A sensitization of fever and sensitization for hypothalamic-pituitary-adrenal axis activity persists from 24 to 72 hours after the stressor as well (Deak et al., 2017). The post-stress recovery period compares to a sickness-like response. With long-term, repeated stressors (chronic stress), neuroinflammation often results. Mechanisms through which neuroinflammation ensues involve a multitude of inflammatory signaling pathways. Norepinephrine (also called ‘noradrenaline’) constitutes the primary driver of these neuroinflammatory signaling pathways. Norepinephrine gets released through action of the sympathetic nervous system in the “fight or flight” response. An emerging class of neuroimmune response intermediaries, danger, damage, and disease signals (DAMPs), get released in the body in response to tissue trauma and repeated stressors and are capable of activating inflammatory signaling. These signals interact with pathogen recognition receptors (PRRs) which bind to bacteria and viruses and also danger, damage, and disease signals (DAMPs) that are activated through stress and/or damage (Deak et al., 2017). Another interesting notion is that bacteria from the gut may be stress sensitive. In response to stress challenges, the bacteria may mobilize and incur a mild ‘endogenous infection (Deak et al., 2017).’ Alterations in and mobilization of gut bacteria could constitute a mechanism whereby people get sick with long-term (chronic) stress.
Mechanisms exist in the neuroimmune system that constrain the neuroimmune response. For example, the stress hormone cortisol gets released with activity of the hypothalamic-pituitary-adrenal axis in the “fight or flight” response. Cortisol has anti-inflammatory actions in the brain (Deak et al., 2017). Thus, cortisol may counteract the neuroinflammatory response from stress challenges. The hypothalamic-pituitary-adrenal axis action in the “fight or flight” response can also induce stress-dependent microglia activation. Microglia are part of the neuroimmune response in that they repair and provide support for neurons under stressful conditions.
A model system of how stressors can alter the balance (homeostasis) of the neuroimmune system entails myeloid cells derived from bone marrow with activity induced through repeated social stress. This model shows how repeated stressors, especially early in life, contribute to aberrant neuroimmune responses and anxiety-like behavior (Deak et al., 2015). Myeloid cells are cells from bone marrow that get released due to sympathetic nervous system activity in the “fight or flight” response. The myeloid cells then travel to different parts of the brain: the hippocampus (involved in learning, memory, and mood regulation), the amygdala (involved in fear learning or conditioning and interpretation of fear-eliciting events), and the prefrontal cortex (involved in executive function and impulse control). Once in the brain, the myeloid cells release cytokines and other inflammatory-inducing substances from the immune system. The repeated “fight or flight” response and parasympathetic nervous system activity of this model gets induced through repeated social defeat. In repeated social defeat, rats are used and presented with an aggressive male intruder for up to six consecutive nights. The rats then display persistent anxiety-like behavior. After 24 days of having the repeated social defeat removed, the number of myeloid cells in the brain returns to normal; however, a reservoir of ‘primed’ myeloid cells remains in the spleen in response to the initial repeated social defeat. When the spleen with myeloid cell reservoir is removed from these rats, anxiety is abrogated and trafficking of myeloid cells to the brain following one exposure to repeated social defeat is prevented (Deak et al., 2015). This example shows how long-lasting changes to the neuroimmune system can take place in response to repeated and traumatic stressors.
One disorder which associates with repeated and traumatic stressors includes depression. Interestingly, the “pathogen host defense” hypothesis of depression says that a “sickness behavior” results from environmental challenges, stress perception, and immune activation. This set of “sickness behaviors” may have evolved to protect ancestral humans from pathogens and predators but today manifests as depressed mood and behavior in modern-day humans as environmental challenges have shifted from predators in immediate survival to psychosocial demands (Bekhbat & Neigh, 2019). At any rate, studies have shown that psychological stress induces the immune activation from the same physiological pathways as physiological stress (from pathogens and other physical injuries). Thus, the process whereby psychological stress induces inflammation is commonly referred to as “sterile” inflammation, which associates with the pathophysiology of depression (Bekhbat & Neigh, 2019).
From the adaptive, short-term (acute) response to stressors and environmental challenges to the often maladaptive and damaging long-term (chronic) response, neuroimmune mechanisms play a role whereby the immune system and the brain have bidirectional communication. A balance or homeostasis must result from this crosstalk in order to avoid metabolic, neurological, and psychiatric pathology. Constraints such as cortisol with anti-inflammatory properties along with the supportive effects of microglia must function to avoid long-term consequences of repeated stressors. An example of a neuroimmune response to repeated social defeat in rats, with potential translatability to humans, include the actions of myeloid cells that release from bone marrow in response to sympathetic nervous system activity in the “fight or flight” response. Mechanisms contributing to inflammation through neuroimmune activity may facilitate an increased risk for disorders such as depression, along with a host of other disorders of the brain, cardiovascular system, and metabolic system.
Deak T, Kudinova A, Lovelock DF, Gibb BE, & Hennessy MB (2017). “A multispecies approach for understanding neuroimmune mechanisms of stress.” Dialogues Clin Neurosci. 19(1): 37-53.
Deak T, Quinn M, Cidlowski JA, Victoria NC, Murphy AZ, & Sheridan JF (2015). “Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease.” Stress. 18(4): 367-380.
Mandakh B & Neigh GN (2018). “Sex differences in the neuro-immune consequences of stress: Focus on depression and anxiety.” Brain Behav Immun. 67: 1-12.