Cocaine-mediated microglial activation involves the ER stress-autophagy axis

Minglei Guo, Ke Liao, Palsamy Periyasamy, Lu Yang, Yu Cai, Shannon E. Callen, Shilpa J Buch

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time-dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine-induced autophagy was confirmed by treating cells with inhibitors of autophagy (3-MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1-dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocainemediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases.

Original languageEnglish (US)
Pages (from-to)995-1009
Number of pages15
JournalAutophagy
Volume11
Issue number7
DOIs
StatePublished - Jan 1 2015

Fingerprint

Autophagy
Cocaine
Cocaine-Related Disorders
Aptitude
Microglia
Adaptive Immunity
Protein Transport
Innate Immunity
HIV Infections
HIV-1
Interleukin-6
Proteins

Keywords

  • Autophagy
  • BECN1
  • Cocaine
  • ER stress
  • MAP1LC3B
  • Microglial cells
  • Neuroinflammation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Cocaine-mediated microglial activation involves the ER stress-autophagy axis. / Guo, Minglei; Liao, Ke; Periyasamy, Palsamy; Yang, Lu; Cai, Yu; Callen, Shannon E.; Buch, Shilpa J.

In: Autophagy, Vol. 11, No. 7, 01.01.2015, p. 995-1009.

Research output: Contribution to journalArticle

Guo, Minglei ; Liao, Ke ; Periyasamy, Palsamy ; Yang, Lu ; Cai, Yu ; Callen, Shannon E. ; Buch, Shilpa J. / Cocaine-mediated microglial activation involves the ER stress-autophagy axis. In: Autophagy. 2015 ; Vol. 11, No. 7. pp. 995-1009.
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