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Current HIV Research
ISSN (Print): 1570-162X
ISSN (Online): 1873-4251
VOLUME: 12
ISSUE: 3
DOI: 10.2174/1570162X12666140526123119









HIV-1 Tat Disrupts CX3CL1-CX3CR1 Axis in Microglia via the NF-κBYY1 Pathway

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Author(s): Ming Duan, Honghong Yao, Yu Cai, Ke Liao, Pankaj Seth and Shilpa Buch
Pages 189-200 (12)
Abstract:
Microglia are critical for the pathogenesis of HIV-associated dementia not only by acting as conduits of viral entry but also as reservoirs for productive and latent virus infection, and as producers of neurotoxins. Interaction between CX3CL1 (fractalkine) and FKN receptor (CX3CR1) is highly functional in the brain, and is known to regulate a complex network of paracrine and autocrine interactions between neurons and microglia. The aim of the present study was to determine which extent of HIV-1 Tat protein causes the alteration of CX3CR1 expression and to investigate the regulatory mechanism for CX3CR1 expression. Here we showed that exposure of primary microglia and BV2 cells to exogenous Tat protein resulted in down-regulation of CX3CR1 mRNA and protein expression, with a concomitant induction of proinflammatory responses. Next, we further showed that NF-κB activation by Tat treatment negatively regulated CX3CR1 expression. Since a YY1 binding site ~10kb upstream of CX3CR1 promoter was predicted in rats, mice and humans, the classical NF-κB-YY1 regulatory pathway was considered. Our findings indicated that Tat repressed CX3CR1 expression via NF-κB-YY1 regulatory pathway. To gain insight into the effect of Tat on CX3CL1-CX3CR1 communication, calcium mobilization, MAPK activation and microglial migration, respectively, were tested in microglial cells after successive treatment with Tat and CX3CL1. The results suggested that Tat disrupted the responses of microglia to CX3CL1. Taken together, these results demonstrate that HIV-1 Tat protein suppresses CX3CR1 expression in microglia via NF-κB-YY1 pathway and attenuates CX3CL1-induced functional response of microglia.
Graphical Abstract:
Keywords:
CX3CL1, CX3CR1, HIV-1 Tat protein, microglia, NF-κB, YY1.
Affiliation:
Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center (DRC 8011), University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.