Skip to Main Content

Stress-induced Dysregulation in Microglial HMGB1 Signaling

Tine Franklin, Department of Psychiatry, Yale University

Substance use disorders (SUD), defined as the dependence to substances such as but not limited to alcohol, nicotine and illicit drugs, affect as high as 9% of Americans [1]. Mounting evidence suggests that the dysregulation of innate immune system plays a role in the pathophysiology of SUD [2-4]. Stress, a major risk factor for the development of addiction, has been shown to promote drug seeking and dependence relapse in several pre-clinical, population-based and epidemiology studies [5]. Stress-induced risk for SUD may be partially mediated by stress-induced dysregulation in innate immune pathways. High mobility group box protein 1 (HMGB1), an endogenous ligand for innate immune receptors, has been implicated in SUD and is significantly elevated in the brains of lifelong addicts [4].

HMGB1 upregulation and extracellular signaling is mediated by stress [6, 7]. Chronic stress has been shown to induce persistent dysregulation of HMGB1 expression and release in resident microglia [8], which may contribute to the pathogenesis of addiction. Here we propose to identify the long-lasting effects of stress on HMGB1-mediated signaling by identifying persistent stress-induced HMGB1 post-translational modifications in microglia. In addition, we aim to identify differences in the proteomic signature of resident microglia, the innate immune cells of the brain, in the presence and absence of microglial HMGB1 signaling to identify alterations in protein expression that may increase risk for the addiction. 

Literature Cited

  1. Tolliver, B.K. and R.F. Anton, Assessment and treatment of mood disorders in the context of substance abuse. Dialogues Clin Neurosci, 2015. 17(2): 181-90.
  2. Bachtell, R.K., et al., Glial and neuroinflammatory targets for treating substance use disorders. Drug Alcohol Depend, 2017. 180: 156-170.
  3. Crews, F.T., et al., The role of neuroimmune signaling in alcoholism. Neuropharmacology, 2017. 122: 56-73.
  4. Crews, F.T., et al., Toll-like receptor signaling and stages of addiction. Psychopharmacology (Berl), 2017. 234(9-10): 1483-1498.
  5. Sinha, R., Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci, 2008. 1141: 105-30.
  6. Franklin, T.C., C. Xu, and R.S. Duman, Depression and sterile inflammation: Essential role of danger associated molecular patterns. Brain Behav Immun, 2017.
  7. Wohleb, E.S., et al., Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci, 2016. 17(8): 497-511.
  8. Franklin, T.C., et al., Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior. Biol Psychiatry, 2018. 83(1): 50-60.