Role of Dysregulated Autophagy in HIV Tat, Cocaine, and cART Mediated NLRP3 Activation in Microglia

Seema Singh, Annadurai Thangaraj, Ernest T. Chivero, Ming Lei Guo, Palsamy Periyasamy, Shilpa Buch

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Despite the ability of combination antiretroviral therapy (cART) to suppress viremia, there is persistence low levels of HIV proteins such as Transactivator of transcription (Tat) in the central nervous system (CNS), contributing to glial activation and neuroinflammation. Accumulating evidence also implicates the role of drugs of abuse in exacerbating neurological complications associated with HIV-1. The combined effects of HIV Tat, drugs of abuse, and cART can thus create a toxic milieu in the CNS. The present study investigated the combinatorial effects of HIV-Tat, cocaine, and cART on autophagy and NLRP3 inflammasome activation. We selected a combination of three commonly used cART regimens: tenofovir, emtricitabine, and dolutegravir. Our results demonstrated that exposure of mouse primary microglia (MPMs) to these agents—HIV Tat (25 ng/ml), cocaine (1 μM), and cART (1 μM each) resulted in upregulation of autophagy markers: Beclin1, LC3B-II, and SQSTM1 with impaired lysosomal functioning involving increased lysosomal pH, decreased LAMP2 and cathepsin D, ultimately leading to dysregulated autophagy. Our findings also demonstrated activation of the NLRP3 signaling in microglia exposed to these agents. We further demonstrated that gene silencing of key autophagy protein BECN1 significantly blocked NLRP3-mediated activation of microglia. Silencing of NLRP3, however, failed to block HIV Tat, cocaine, and cART-mediated dysregulation of the autophagy-lysosomal axis; these in vitro phenomena were also validated in vivo using iTat mice administered cocaine and cART. This study thus underscores the cooperative effects of HIV Tat, cocaine, and cART in exacerbating microglial activation involving dysregulated autophagy and activation of the NLRP3 inflammasome signaling. Graphical Abstract: [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)327-347
Number of pages21
JournalJournal of Neuroimmune Pharmacology
Volume18
Issue number3
DOIs
StatePublished - Sep 2023

Keywords

  • Autophagy
  • Cocaine
  • HIV Tat
  • Microglia activation
  • NLRP3
  • Neuroinflammation

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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