Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis

Cantres-Rosario, Yisel M.; Hernández, Natalia Carballo; Negron, Karla; Pérez-Laspiur, Juliana; Leszyk, John D.; Shaffer, Scott A.; Meléndez, Loyda M.

doi:10.1097/qad.0000000000000823

Cited by 15 publications

(31 citation statements)

References 56 publications

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“…Previous studies from our laboratory have demonstrated that HIV infection of macrophages and microglia induces secretion of cathepsin B and neurotoxicity (Rodriguez-Franco et al 2012; Cantres-Rosario et al 2015; Zenón et al 2015). However, the mechanism of cathepsin B release in HIV-1 infected macrophages is not known.…”

Section: Discussionmentioning

confidence: 99%

“…The consequences of increased cathepsin B secretion by macrophages have been extensively studied in our laboratory (Rodriguez-Franco et al 2012; Zenon et al 2014; Cantres-Rosario et al 2015; Zenón et al 2015). The MDM cultures with decreased cathepsin B secretion levels after HIV infection observed in our experiments have captured our attention since they also have low levels of ROS/RNS after HIV infection.…”

Section: Discussionmentioning

confidence: 99%

“…The inflammation process is promoted by increased secretion of IL-1B and TNF-α from HIV-infected macrophages, that stimulate astrocytosis, ROS and other potentially neurotoxic substances, including cathepsin B (Werneburg et al 2002). Cathepsin B is a lysosomal cysteine protease enzyme that plays an important role in antigen processing and presentation by macrophages and is normally controlled by its innate inhibitors, cystatins B and C. HIV infection of macrophages stimulates increased cathepsin B secretion that promotes neuronal apoptosis (Rodriguez-Franco et al 2012; Zenón et al 2014; Cantres-Rosario et al 2015; Zenón et al 2015). Cathepsin B is also increased in plasma and post-mortem brain tissues of patients with HAD.…”

Section: Introductionmentioning

confidence: 99%

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Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages

Rosario-Rodríguez

Colón

Borges-Vélez

et al. 2018

J Neuroimmune Pharmacol

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HIV-associated neurocognitive disorders (HAND) are prevalent despite combined antiretroviral therapy, affecting nearly half of HIV-infected patients worldwide. During HIV infection of macrophages secretion of the lysosomal protein, cathepsin B, is increased. Secreted cathepsin B has been shown to induce neurotoxicity. Oxidative stress is increased in HIV-infected patients, while antioxidants are decreased in monocytes from patients with HIV-associated dementia (HAD). Dimethyl fumarate (DMF), an antioxidant, has been reported to decrease HIV replication and neurotoxicity mediated by HIV-infected macrophages. Thus, we hypothesized that DMF will decrease cathepsin B release from HIV-infected macrophages by preventing oxidative stress and enhancing lysosomal function. Monocyte-derived macrophages (MDM) were isolated from healthy donors, inoculated with HIV-1 and treated with DMF following virus removal. After 12 days post-infection, HIV-1 p24 and total cathepsin B levels were measured from HIV-infected MDM supernatants using ELISA; intracellular reactive oxygen and nitrogen species (ROS/RNS) were measured from MDM lysates, and functional lysosomes were assessed using a pH-dependent lysosomal dye. Neurons were incubated with serum-free conditioned media from DMF-treated MDM and neurotoxicity was determined using TUNEL assay. Results indicate that DMF reduced HIV-1 replication and cathepsin B secretion from HIV-infected macrophages in a dose-dependent manner. Also, DMF decreased intracellular ROS/RNS levels, and prevented HIV-induced lysosomal dysfunction and neuronal apoptosis. In conclusion, the improvement in lysosomal function with DMF treatment may represent the possible mechanism to reduce HIV-1 replication and cathepsin B secretion. DMF represents a potential therapeutic strategy against HAND.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages

Rosario-Rodríguez

Colón

Borges-Vélez

et al. 2018

J Neuroimmune Pharmacol

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“…Our results confirm previous studies that show that HIV infection and cocaine use have a direct effect on increasing the expression of CATB (Zenón et al 2014 ). Although in this study we could not compare the effect of HAND on CATB expression due to limited number of samples, previous studies confirmed an increased CATB levels with HAND (Cantres-Rosario et al 2015 ).…”

Section: Resultsmentioning

confidence: 70%

Sigma-1 Receptor Antagonist (BD1047) Decreases Cathepsin B Secretion in HIV-Infected Macrophages Exposed to Cocaine

López

Gorantla

Segarra

et al. 2018

J Neuroimmune Pharmacol

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Pathogenesis of HIV-associated neurocognitive disorders (HAND) is mediated through the infiltration of perivascular macrophages into the brain with the secretion of viral, neurotoxic and inflammatory proteins. One of these proteins is cathepsin B (CATB), a lysosomal cysteine protease that induces neuronal apoptosis, and increases in plasma and cerebrospinal fluid from HIV-1 infected patients (Cantres-Rosario et al. AIDS 27(3):347–356, 2013 ). Cocaine further potentiates CATB neurotoxicity in vitro and in vivo (Zenón et al. J NeuroImmune Pharmacol 9(5):703–715, 2014 ). Modulation of sigma-1 (Sig1R) by cocaine increases oxidative species, cytokines and other factors that promote lysosomal disruption. However, the role of Sig1R in CATB secretion and HIV-1 replication in macrophages exposed to cocaine is unknown. We hypothesized that pharmacological modulation of Sig1R would alter CATB secretion from HIV-1 infected macrophages in vitro and in vivo. To test our hypothesis, monocyte derived-macrophages (MDM) from HIV-1 seronegative donors were isolated, infected with HIV-1 ADA, and pretreated with Sig1R antagonist (BD1047) or Sig1R agonist (PRE-084) prior to cocaine exposure and followed for 3,6,9 and 11 days post-infection (dpi). Experiments in vivo were conducted using the HIV encephalitis mouse model (HIVE) with BD1047 treatments prior to cocaine for 14 days. Results demonstrate that in presence of cocaine, BD1047 decreases CATB secretion at 11 dpi, while PRE-084 did not have an effect. In the mouse model, BD1047 treatment prior to cocaine decreased CATB expression, cleaved caspase-3 an p24 antigen levels, reduced astrocytosis, but did not increase MAP-2 or synaptophysin. Results demonstrate that Sig1R plays a role in the modulation of CATB levels in HIV-1 infected MDM exposed to cocaine in vitro and in vivo. Graphical Abstract ᅟ Electronic supplementary material The online version of this article (10.1007/s11481-018-9807-4) contains supplementary material, which is available to authorized users.

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“…One of the most recent studies investigating DMF and its possible role in treating HAND looks at lysosomal dysfunction and the release of neurotoxic cathepsin B from infected macrophages. Increased cathepsin B release has been evidenced in HIV-infected macrophages and promotes neuronal apoptosis [282][283][284] and infected macrophages treated with DMF showed decreases in HIV-1 replication, cathepsin B secretion and ROS/RNS production [285]. DMF has consistently shown evidence of reducing HIV-1 replication in macrophages and inhibiting the release of neurotoxic compounds in vitro, but conflicting results on neuronal cell viability prevents a definitive conclusion of DMF's role in HAND therapy.…”

Section: Dimethyl Fumaratementioning

confidence: 99%

Potential pharmacological approaches for the treatment of HIV-1 associated neurocognitive disorders

Omeragic

Kayode

Hoque

et al. 2020

Fluids Barriers CNS

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HIV associated neurocognitive disorders (HAND) are the spectrum of cognitive impairments present in patients infected with human immunodeficiency virus type 1 (HIV-1). The number of patients affected with HAND ranges from 30 to 50% of HIV infected individuals and although the development of combinational antiretroviral therapy (cART) has improved longevity, HAND continues to pose a significant clinical problem as the current standard of care does not alleviate or prevent HAND symptoms. At present, the pathological mechanisms contributing to HAND remain unclear, but evidence suggests that it stems from neuronal injury due to chronic release of neurotoxins, chemokines, viral proteins, and proinflammatory cytokines secreted by HIV-1 activated microglia, macrophages and astrocytes in the central nervous system (CNS). Furthermore, the blood-brain barrier (BBB) not only serves as a route for HIV-1 entry into the brain but also prevents cART therapy from reaching HIV-1 brain reservoirs, and therefore could play an important role in HAND. The goal of this review is to discuss the current data on the epidemiology, pathology and research models of HAND as well as address the potential pharmacological treatment approaches that are being investigated.

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Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis

Cited by 15 publications

References 56 publications

Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages

Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages

Sigma-1 Receptor Antagonist (BD1047) Decreases Cathepsin B Secretion in HIV-Infected Macrophages Exposed to Cocaine

Potential pharmacological approaches for the treatment of HIV-1 associated neurocognitive disorders

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