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

ABSTRACT:

Background

Despite 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 PPAR? exerts anti-inflammatory properties in neurological disorders. The goal of this study was to examine the role of PPAR? in the context of HIV-1_ADA gp120-induced inflammation in vitro, in primary cultures of rat astrocytes and microglia, and in vivo, in a rodent model of HIV-1_ADA gp120-associated brain inflammation.

Methods

Primary mixed cultures of rat astrocytes and microglia were treated with PPAR? agonists (rosiglitazone or pioglitazone) and exposed to HIV-1_ADA gp120. Inflammatory cytokines and indicator of oxidative stress response (TNF?, IL-1?, iNOS) were measured using qPCR, and glutamate transporter (GLT-1) was quantified by immunoblotting. In vivo, rats were administered an intracerebroventricular injection of HIV-1_ADA gp120 and an intraperitoneal injection of PPAR? agonist (rosiglitazone) or co-administration with PPAR? antagonist (GW9662). qPCR and immunoblotting analyses were applied to measure inflammatory markers, GLT-1 and PPAR?.

Results

In primary mixed cultures of rat astrocytes and microglia, HIV-1_ADA 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 PPAR? agonist rosiglitazone were mediated through inhibition of NF-?B.

Conclusion

Our 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 PPAR? agonists, rosiglitazone or pioglitazone. Together our data suggest that targeting PPAR? signaling may provide an option for preventing/treating HIV-associated brain inflammation.

SUBMITTER: Omeragic A 

PROVIDER: S-EPMC5591559 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature