Neurotrophins modulate the expression of chemokine receptors in the brain

Abstract

In the central nervous system, chemokines are primarily mediators of inflammatory processes. Their receptors, in particular, CXCR4 and CCR5, serve as co-factors along with CD4 that permit Human immunodeficiency virus-1 (HIV) infection. Moreover, experimental evidence has shown that CXCR4 and CCR5 mediate the neurotoxic effects of the HIV envelope protein gp120, suggesting that these receptors could also promote the neuropathogenesis observed in HIV-positive individuals. Therefore, a better understanding of the molecular mechanisms governing the expression of chemokine receptors in the brain may lead to improved therapies that reduce HIV neurotoxicity. This study presents evidence that the expression of chemokine receptors in the brain is modulated by two neurotrophins in an area-specific manner. This new evidence suggests that the neurotrophins may be an adjunct therapy to reduce HIV-mediated neuronal injury evoked by chemokine receptor activation.

Fig. 1

Immunohistochemical analysis of CCR5 and CXCR4 immunoreactivity in mouse brain. a–d, sections were stained with CCR5 (red) and NeuN (green) antibodies. e–h, sections were stained with CXCR4 (green) and NeuN (red) antibodies as described in the Materials and Methods section. Orange denotes co-localization. a and e, cerebellar cortex; b and f, hippocampus; c and g, striatum; d and h, cerebral cortex. White arrows indicate neuronal cell bodies, and purple arrows indicate fibers. Images are higher magnifications (60×) of inserts. Bar = 20 µm; bar in inserts are 100 µm

Fig. 2

NGF and NT-3 heterozygous mice exhibit higher levels of CXCR4 mRNA than wild type. The mRNA levels for CCR5 and CXCR4 were determined in 4-month-old C57BL/6 mice using qRT-PCR as described in the Materials and Methods section. a NGF het mice, b NT-3 het mice. Data were normalized to β-actin mRNA and expressed as arbitrary units (AU, mean±SEM of five independent samples). *p<0.05, **p<0.005 vs wild type using a one-way ANOVA and Student’s t-test