Description
A Critical Role for Cysteinyl-leukotrienes in HIV-1 Associated Brain Injury
Nina Y. Yuan1, Kathryn E. Medders1, Ana B. Sanchez2, Ricky Maung1, Amanda J. Roberts3, Marcus Kaul1,2
1School of Medicine, Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521, USA; 2Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; 3Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA
Infection with human immunodeficiency virus-1 (HIV-1) gives rise to injury of neuronal synapses and dendrites and can lead to neuronal loss. HIV-1 neurotoxicity is mediated by macrophages and microglia and we recently found that p38 MAPK signaling is essential for the neurotoxic phenotype of the cells. Knock-down of p38 MAPK with siRNA in macrophages led downstream to depletion of cysteinyl-leukotriene synthase (LTC4S) and concomitantly abrogated HIV-induced neurotoxicity. Moreover, we found that pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CysLTR1) protected cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected macrophages. Transgenic mice expressing HIV-1 envelope glycoprotein 120 in their central nervous system (HIVgp120tg) show neuronal injury, differential gene expression patterns and compromised spatial learning and memory that recapitulate findings in neurocognitively impaired HIV patients. HIVgp120tg brains also display increased expression of two key components of the cysteinyl-leukotriene signaling cascade, ALOX5AP and CysLTR1. Finally, we found that genetic ablation of LTC4S in HIVgp120tg mice prevented impairment of spatial learning and memory. In summary, our studies suggest a critical role for cysteinyl-leukotrienes in vivo in HIV-1 associated brain injury and behavioral impairment.
Supported by grants from the NIH, MH087332, MH104131, MH105330 and P50 DA026306 (P5) (to M.K.)