Peroxisome proliferator-activated receptor-gamma: potential molecular therapeutic target for HIV-1-associated brain inflammation

Abstract

BackgroundDespite the use of combination antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated brain inflammation. Primary cellular targets of HIV-1 in the brain are macrophages, microglia, and to a certain extent astrocytes which in response to infection release inflammatory markers, viral proteins [i.e., glycoprotein 120 (gp120)] and exhibit impaired glutamate uptake. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Compelling evidence suggests that PPARγ exerts anti-inflammatory properties in neurological disorders. The goal of this study was to examine the role of PPARγ in the context of HIV-1ADA gp120-induced inflammation in vitro, in primary cultures of rat astrocytes and microglia, and in vivo, in a rodent model of HIV-1ADA gp120-associated brain inflammation.MethodsPrimary mixed cultures of rat astrocytes and microglia were treated with PPARγ agonists (rosiglitazone or pioglitazone) and exposed to HIV-1ADA gp120. Inflammatory cytokines and indicator of oxidative stress response (TNFα, IL-1β, iNOS) were measured using qPCR, and glutamate transporter (GLT-1) was quantified by immunoblotting. In vivo, rats were administered an intracerebroventricular injection of HIV-1ADA gp120 and an intraperitoneal injection of PPARγ agonist (rosiglitazone) or co-administration with PPARγ antagonist (GW9662). qPCR and immunoblotting analyses were applied to measure inflammatory markers, GLT-1 and PPARγ.ResultsIn primary mixed cultures of rat astrocytes and microglia, HIV-1ADA gp120 exposure resulted in a significant elevation of inflammatory markers and a decrease in GLT-1 expression which were significantly attenuated with rosiglitazone or pioglitazone treatment. Similarly, in vivo, treatment with rosiglitazone reversed the gp120-mediated inflammatory response and downregulation of GLT-1. Furthermore, we demonstrated that the anti-inflammatory effects of PPARγ agonist rosiglitazone were mediated through inhibition of NF-κB.ConclusionOur data demonstrate that gp120 can induce an inflammatory response and decrease expression of GLT-1 in the brain in vitro and in vivo. We have also successfully shown that these effects can be reversed by treatment with PPARγ agonists, rosiglitazone or pioglitazone. Together our data suggest that targeting PPARγ signaling may provide an option for preventing/treating HIV-associated brain inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0957-8) contains supplementary material, which is available to authorized users.

Selective peroxisome proliferator‐activated receptor‐gamma modulator, INT131 exhibits anti‐inflammatory effects in an EcoHIV mouse model

“…Sterile stereotaxic technique was performed for all mouse brain injections as previously described by our group . In brief, 2%‐5% isoflurane was used to induce surgical anesthesia.…”

“…qPCR was applied to determine the transcript levels of inflammatory and oxidative stress markers as previously described. 32,33 Briefly, total RNA was extracted from cell culture or brain tissue using TRizol reagent. The concentration of RNA was quantified spectrophotometrically by measuring absorbance at 260 nm.…”

“…Sterile stereotaxic technique was performed for all mouse brain injections as previously described by our group. 32,33 In brief, 2%-5% isoflurane was used to induce surgical anesthesia. Prior to IC, animals were administered ketoprofen subcutaneously (5 mg/kg) to induce analgesic effect.…”

“…Previous studies from our laboratory have shown that exposure to full PPARγ agonists (rosiglitazone or pioglitazone) reversed HIV-1 envelope gp120 or EcoHIV induced mRNA expression of pro-inflammatory cytokines and oxidative stress markers in primary cultures of mixed rodent astrocytes and microglia. 32,33 Herein, we sought to investigate the anti-inflammatory potential of the SPPARγM, INT131 in an in vitro model of EcoHIVassociated inflammation. Treatment with INT131 reduced the expression of inflammatory markers TNFα, IL-1β, IL-6, CCL3, CXCL10, and C3 in a dose-dependent manner ( Figure 1).…”

“…[28][29][30][31] Our group has also demonstrated that treatment with PPARγ agonists rosiglitazone or pioglitazone can prevent gp120 and ecotropic HIV-1 (EcoHIV)-induced inflammatory responses. 32,33 These drugs are clinically available for anti-diabetic purposes; however, reported side effects such as weight gain and edema have recently limited their use. Although PPARγ agonists such as rosiglitazone and pioglitazone have been demonstrated to be potent anti-inflammatory agents, it is important to identify other PPARγ agonists that could offer a safer toxicity profile.…”