Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress

Hodes, Georgia E.; Pfau, Madeline L.; Leboeuf, Marylène; Golden, Sam A.; Christoffel, Daniel J.; Bregman, Dana; Rebusi, Nicole; Heshmati, Mitra; Aleyasin, Hossein; Warren, Brandon L.; Lebonté, Benoit; Horn, Sarah R.; Lapidus, Kyle; Stelzhammer, Viktoria; Wong, Erik H. F.; Bahn, Sabine; Krishnan, Vaishnav; Bolaños-Guzmán, Carlos A.; Murrough, James W.; Mérad, Miriam; Russo, Scott J.

doi:10.1073/pnas.1415191111

Cited by 575 publications

(575 citation statements)

References 45 publications

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“…Similar findings have been described in rodents (Avitsur et al, 2006;Brenhouse and Thompson, 2015;Hennessy et al, 2010b). Furthermore, early-life immune activation has been linked to greater neuroendocrine activation in the context of subsequent stressors (Shanks et al, 1995(Shanks et al, , 2000, and higher baseline levels of inflammation have been associated with greater stressinduced responses in animal models (Hodes et al, 2014) and humans (Eraly et al, 2014;Michopoulos et al, 2015). On the other hand, there is initial evidence that genes coding for pro-inflammatory cytokines could moderate the effect of childhood trauma on brain function.…”

Section: Synergysupporting

confidence: 63%

“…On the one hand, different lines of research suggest that antiinflammatory strategies could prevent the onset of clinical outcomes. First, higher baseline levels of inflammation have been associated with greater stress-induced responses in animal models (Hodes et al, 2014) and humans (Eraly et al, 2014;Michopoulos et al, 2015). Second, administration of anti-inflammatory agents, such as COX-2 inhibitors or IL-10, can buffer the expression of biological and clinical sequelae of early-life stress in rodents, including the reduction in prefrontal cortex parvalbumin levels and the onset of depressive-like symptoms (Brenhouse and Andersen, 2011b;Wieck et al, 2013).…”

Section: Reversibilitymentioning

confidence: 99%

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Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

Danese

Lewis

2016

Neuropsychopharmacol

294

191

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The brain and the immune system are not fully formed at birth, but rather continue to mature in response to the postnatal environment. The two-way interaction between the brain and the immune system makes it possible for childhood psychosocial stressors to affect immune system development, which in turn can affect brain development and its long-term functioning. Drawing from experimental animal models and observational human studies, we propose that the psychoneuroimmunology of early-life stress can offer an innovative framework to understand and treat psychopathology linked to childhood trauma. Earlylife stress predicts later inflammation, and there are striking analogies between the neurobiological correlates of early-life stress and of inflammation. Furthermore, there are overlapping trans-diagnostic patterns of association of childhood trauma and inflammation with clinical outcomes. These findings suggest new strategies to remediate the effect of childhood trauma before the onset of clinical symptoms, such as anti-inflammatory interventions and potentiation of adaptive immunity. Similar strategies might be used to ameliorate the unfavorable treatment response described in psychiatric patients with a history of childhood trauma.

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Section: Synergysupporting

confidence: 63%

Section: Reversibilitymentioning

confidence: 99%

Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

Danese

Lewis

2016

Neuropsychopharmacol

294

191

View full text Add to dashboard Cite

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“…Inflammation is also implicated in these psychiatric disorders (6)(7)(8)(9)(10)(47)(48)(49)(50). Recent studies showed that peripheral IL-6 is critical in regulating stress-related depression-like phenotypes in rodents (51)(52)(53). Because sEH plays an active role in the inflammatory response (18)(19)(20), it is possible that increased levels of sEH protein in the parietal cortex may play a role in the pathogenesis of these psychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Ren

Ishima

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

156

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Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depressionlike behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.brain-derived neurotrophic factor | depression | epoxyeicosatrienoic acid | soluble epoxide hydrolase | resilience

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“…In addition, studies have shown that individual differences in peripheral immune responses (IL-6 responses, in particular) are associated with the susceptibility of laboratory animals to social avoidance after repeated social defeat stress. This susceptibility to social avoidance can be reversed following peripheral administration of a monoclonal antibody to IL-6 that also does not cross the BBB (Hodes et al, 2014(Hodes et al, , 2015. Conversely, overexpression of IL-1 receptor antagonist in the brain blocked chronic stress-induced anhedonia as well as impairment in hippocampal neurogenesis, a primary mechanism through which chronic stress is believed to induce depression Goshen et al, 2008).…”

Section: Immunological Mechanismsmentioning

confidence: 99%

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

Neuropsychopharmacol

118

124

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A wealth of data has been amassed that details a complex, yet accessible, series of pathways by which the immune system, notably inflammation, can influence the brain and behavior. These data have opened the window to a diverse array of novel targets whose potential efficacy is tied to specific neurotransmitters and neurocircuits as well as specific behaviors. What is clear is that the impact of inflammation on the brain cuts across psychiatric disorders and engages dopaminergic and glutamatergic pathways that regulate motivation and motor activity as well as the sensitivity to threat. Given the ability to identify patient populations with increased inflammation, the precision of interventions can be further tuned, in conjunction with the ability to establish target engagement in the brain through the use of multiple neuroimaging strategies. After a brief overview of the mechanisms by which inflammation affects the brain and behavior, this review examines the extant literature on the efficacy of anti-inflammatory treatments, while forging guidelines for future intelligent clinical trial design. An examination of the most promising therapeutic strategies is also provided, along with some of the most exciting clinical trials that are currently being planned or underway.

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Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress

Cited by 575 publications

References 45 publications

Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

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