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Antiretroviral-Mediated Microglial Activation Involves Dysregulated Autophagy and Lysosomal Dysfunction.
Tripathi, Ashutosh; Thangaraj, Annadurai; Chivero, Ernest T; Periyasamy, Palsamy; Callen, Shannon; Burkovetskaya, Maria E; Guo, Ming-Lei; Buch, Shilpa.
Afiliación
  • Tripathi A; Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. ashutosh.tripathi@unmc.edu.
  • Thangaraj A; Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. annadurai.thangaraj@unmc.edu.
  • Chivero ET; Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. ernest.chivero@unmc.edu.
  • Periyasamy P; Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. palsamy.periyasamy@unmc.edu.
  • Callen S; Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. scallen@unmc.edu.
  • Burkovetskaya ME; Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. mburkovetskaya@unmc.edu.
  • Guo ML; Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. minglei.guo@unmc.edu.
  • Buch S; Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. sbuch@unmc.edu.
Cells ; 8(10)2019 09 28.
Article en En | MEDLINE | ID: mdl-31569373
In the era of combined antiretroviral therapy (cART), as infected individuals continue to have longer lifespans, there is also an increased prevalence of HIV-associated neurocognitive disorders (HAND). Inflammation is one of the underlying features of HAND, with the role of viral proteins and antiretroviral drugs implicated in this process. Microglia are extremely sensitive to a plethora of stimuli, including viral products and cART. The current study was undertaken to understand the molecular mechanism(s) underlying cART-mediated activation of microglia. Herein we chose a combination of three commonly used drugs, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and dolutegravir (DTG). We demonstrated that exposure of microglia to this cART cocktail induced lysosomal membrane permeabilization (LMP), which subsequently resulted in impaired lysosomal functioning involving elevated pH and decreased cathepsin D (CTSD) activity. cART exposure of microglia resulted in increased formation of autophagosomes as demonstrated by a time-dependent increase of autophagy markers, with a concomitant defect in the fusion of the lysosomes with the autophagosome. Taken together, our findings suggest a novel mechanism by which cART impairs lysosomal functioning, resulting in dysregulated autophagy and increased neuroinflammation. Interventions aimed at lysosome protection could likely be envisioned as promising therapeutic targets for abrogating cART-mediated microglia activation, which in turn, could thus be considered as adjunctive therapeutics for the treatment of HAND pathogenesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Catepsina D / Microglía / Antirretrovirales / Quimioterapia Combinada / Lisosomas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Cells Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Catepsina D / Microglía / Antirretrovirales / Quimioterapia Combinada / Lisosomas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Cells Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza