HIV-1 Tat Disrupts CX3CL1-CX3CR1 Axis in Microglia via the NF-κBYY1 Pathway
Ming Duan, Honghong Yao, Yu Cai, Ke Liao, Pankaj Seth and Shilpa Buch
Affiliation: Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center (DRC 8011), University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Keywords: CX3CL1, CX3CR1, HIV-1 Tat protein, microglia, NF-κB, YY1.
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.
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