Persistent Increase in Microglial RAGE Contributes to Chronic Stress–Induced Priming of Depressive-like Behavior

Franklin, Tina; Wohleb, Eric S.; Zhang, Yi; Fogaça, Manoela V.; Hare, Brendan D.; Duman, Ronald S.

doi:10.1016/j.biopsych.2017.06.034

Cited by 146 publications

(135 citation statements)

References 86 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…Acute stressors induce microglial activation in many brain regions [34,54], and the effects of chronic stress on microglial activation are heterogeneous due to multiple variables, including the stress paradigm (timing and types of stressors) [30,[55][56][57][58] and the age of animals [59]. Consistent with previous studies [55][56][57][58], the current study demonstrated robust and persistent effects of CUS on microglial morphology.…”

Section: Discussionsupporting

confidence: 87%

CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination

et al. 2018

View full text Add to dashboard Cite

Circular RNAs (circRNAs), highly expressed in the central nervous system, are involved in various regulatory processes and implicated in some pathophysiology. However, the potential role of circRNAs in psychiatric diseases, particularly major depressive disorder (MDD), remains largely unknown. Here, we demonstrated that circular RNA DYM (circDYM) levels were significantly decreased both in the peripheral blood of patients with MDD and in the two depressive-like mouse models: the chronic unpredictable stress (CUS) and lipopolysaccharide (LPS) models. Restoration of circDYM expression significantly attenuated depressive-like behavior and inhibited microglial activation induced by CUS or LPS treatment. Further examination indicated that circDYM functions as an endogenous microRNA-9 (miR-9) sponge to inhibit miR-9 activity, which results in a downstream increase of target-HECT domain E3 ubiquitin protein ligase 1 (HECTD1) expression, an increase of HSP90 ubiquitination, and a consequent decrease of microglial activation. Taken together, the results of our study demonstrate the involvement of circDYM and its coupling mechanism in depression, providing translational evidence that circDYM may be a novel therapeutic target for depression.

show abstract

Section: Discussionsupporting

confidence: 87%

CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination

et al. 2018

View full text Add to dashboard Cite

show abstract

“…As the production of HMGB-1in the brain has been shown to be a function of age (Fonken et al, 2016), its persistent stimulation of microglia overtime is considered a risk factor for the development of neuroinflammatory pathologies and depression-like symptoms following traumatic brain injury (Fenn et al, 2014). Additionally, increased RAGE expression on microglia and microglia reactivity during periods of psychological stress mediated the induction of depressive phenotypes (Franklin et al, 2018). Other ligands of the TLR class capable of activating murine microglia and priming transcription NLRP3 include the analgesic morphine and fragments of extracellular matrix hyaluronic acid (Iyer et al, 2009).…”

Section: Priming and Activation Of The Nlrp3 Inflammasomementioning

confidence: 99%

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Herman

Pasinetti

2018

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

The production of inflammatory proteins by the innate immune system is a tightly orchestrated procedure that allows the body to efficiently respond to exogenous and endogenous threats. Recently, accumulating evidence has indicated that disturbances in the inflammatory response system not only provoke autoimmune disorders, but also can have deleterious effects on neuronal function and mental health. As inflammation in the brain is primarily mediated by microglia, there has been an expanding focus on the mechanisms through which these cells initiate and propagate neuroinflammation. Microglia can enter persistently active states upon their initial recognition of an environmental stressor and are thereafter prone to elicit amplified and persistent inflammatory responses following subsequent exposures to stressors. A recent focus on why primed microglia cells are susceptible to environmental insults has been the NLRP3 inflammasome. Its function within the innate immune system is regulated in such a manner that supports a role for the complex in gating neuroinflammatory responses. The activation of NLRP3 inflammasome in microglia results in the cleavage of zymogen inflammatory interleukins into functional forms that elicit a number of consequential effects in the local neuronal environment. There is evidence to support the principle that within primed neuroimmune systems a lowered threshold for NLRP3 activation can cause persistent neuroinflammation or the amplified production of inflammatory cytokines, such as IL-1β and IL-18. Over the course of an individual's lifetime, persistent neuroinflammation can subsequently lead to the pathophysiological signatures that define psychological disorders. Therefore, targeting the NLRP3 inflammasome complex may represent an innovative and consequential approach to limit neuroinflammatory states in psychiatric disorders, such as major depressive disorder.

show abstract

“…Alternatively, the oxidized state of HMGB-1, designated by the formation of disulfide linkages, is capable of potentiating proinflammatory signaling as discussed above but lacks chemotactic abilities (Yang et al, 2012 ). Although the majority of studies assessing the involvement of HMGB-1 in microglial priming have come from studies using inescapable foot shock (Yang et al, 2012 ; Weber et al, 2015 ), chronic unpredictable stress (Franklin et al, 2018 ), and single prolonged stress (Lai et al, 2018 ), exposure to social stressors such as social defeat is known to enhance the intracellular concentration of reactive oxygen species (ROS; see section Oxidative Stress/Reactive Oxygen Species). Therefore, it is highly plausible that HMGB-1 may also contribute to the emergence of social stress-induced behavioral deficits.…”

Section: Sources Of Stress-induced Neuroinflammationmentioning

confidence: 99%

Putative Inflammatory Sensitive Mechanisms Underlying Risk or Resilience to Social Stress

Finnell

Wood

2018

Front. Behav. Neurosci.

View full text Add to dashboard Cite

It has been well recognized that exposure to stress can lead to the onset of psychosocial disorders such as depression. While there are a number of antidepressant therapies currently available and despite producing immediate neurochemical alterations, they require weeks of continuous use in order to exhibit antidepressant efficacy. Moreover, up to 30% of patients do not respond to typical antidepressants, suggesting that our understanding of the pathophysiology underlying stress-induced depression is still limited. In recent years inflammation has become a major focus in the study of depression as several clinical and preclinical studies have demonstrated that peripheral and central inflammatory mediators, including interleukin (IL)-1β, are elevated in depressed patients. Moreover, it has been suggested that inflammation and particularly neuroinflammation may be a direct and immediate link in the emergence of stress-induced depression due to the broad neural and glial effects that are elicited by proinflammatory cytokines. Importantly, individual differences in inflammatory reactivity may further explain why certain individuals exhibit differing susceptibility to the consequences of stress. In this review article, we discuss sources of individual differences such as age, sex and coping mechanisms that are likely sources of distinct changes in stress-induced neuroimmune factors and highlight putative sources of exaggerated neuroinflammation in susceptible individuals. Furthermore, we review the current literature of specific neural and glial mechanisms that are regulated by stress and inflammation including mitochondrial function, oxidative stress and mechanisms of glutamate excitotoxicity. Taken together, the impetus for this review is to move towards a better understanding of mechanisms regulated by inflammatory cytokines and chemokines that are capable of contributing to the emergence of depressive-like behaviors in susceptible individuals.

show abstract

Persistent Increase in Microglial RAGE Contributes to Chronic Stress–Induced Priming of Depressive-like Behavior

Abstract: Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure.

Cited by 146 publications

References 86 publications

CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination

CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Putative Inflammatory Sensitive Mechanisms Underlying Risk or Resilience to Social Stress

Contact Info

Product

Resources

About