Toll-like receptor pathway gene expression is associated with human immunodeficiency virus-associated neurodegeneration

Abstract

The innate immune system is a significant component of the brain's defense against infection, especially as the blood-brain barrier restricts access of the members of the adaptive immune system, such as T and B cells. The innate immune system includes Toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns. Within the central nervous system, they are expressed on glial cells and their expression can be modulated by pathological states. Although their function is to recognize foreign pathogens and stimulate a protective immune response through the production of cytokines and interferons, there is emerging evidence that activation of these receptors can result in neurodegeneration. In the current study, the authors assessed the expression of TLR-related genes, using a customized Superarray gene chip, and correlated the expression findings with indices of neurodegeneration. We found that, using a stringent threshold for statistical significance to overcome the potential problem of multiple statistical testing, there were significant correlations between the expression of nine TLR-related genes and reduction in dendritic and synaptic staining. Two of these genes, TLR4 and SIGIRR, were validated by quantitative real-time polymerase chain reaction. Additionally, the authors demonstrated in vitro at the protein level that human primary astrocytes exposed to the toxic human immunodeficiency virus (HIV) envelope protein gp120 had a significant increase in TLR4 protein expression. In conclusion, these findings indicate that TLR-related gene expression may contribute to the development of HIV-related neurodegeneration.