Abstract Title

Alcohol and HIV-1 differentially regulate Toll Like Receptor (TLRs) expression and signaling in Primary Human Astrocytes

RAD Assignment Number

1512

Presenter Name

Richa Pandey

Abstract

About 69% of human immunodeficiency virus-1 (HIV-1)-positive individuals exhibit some form of HIV-associated neurocognitive disorders (HAND). Several studies have reported that HIV-1 virions, viral proteins and alcohol, individually have direct or indirect effects on HAND pathophysiology. Recently, we showed that alcohol activates astrocytes and regulates inflammation via cPLA2 in HAND. Toll-like receptors (TLRs) are a family of innate immune system receptors that respond to pathogen-derived and tissue damage-related ligands. TLR signaling in immune cells, astrocytes, microglia and neurons may play roles in the pathogenesis of multiple diseases. TLRs are a “missing” link in alcohol-mediated astrocytic response in context of HAND since TLR stimulation by alcohol in glial cells induces secretion of pro-inflammatory molecules. Thus, we explored the role of TLRs in alcohol-induced inflammation and cytotoxicity in primary human astrocytes with HAND. TLRs signaling gene array was performed to screen altered profiles for all 10 TLR family members and 74 downstream signaling molecules. Ingenuity pathway analysis (IPA) was performed to identify potential signaling nodes. Data suggested that HIV-1 and/or EtOH led to differential TLRs expression in astrocytes. We confirmed all 10 TLRs by real-time PCR in four independent astrocyte donors. Alcohol alone and with HIV-1, significantly upregulated TLR1, 2, 3, 4, 5 and 9 as compared to controls and HIV-1 alone. We propose that TLRs regulation plays an important role in astrocytes inflammation upon HIV-1 and EtOH exposure.

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Alcohol and HIV-1 differentially regulate Toll Like Receptor (TLRs) expression and signaling in Primary Human Astrocytes

About 69% of human immunodeficiency virus-1 (HIV-1)-positive individuals exhibit some form of HIV-associated neurocognitive disorders (HAND). Several studies have reported that HIV-1 virions, viral proteins and alcohol, individually have direct or indirect effects on HAND pathophysiology. Recently, we showed that alcohol activates astrocytes and regulates inflammation via cPLA2 in HAND. Toll-like receptors (TLRs) are a family of innate immune system receptors that respond to pathogen-derived and tissue damage-related ligands. TLR signaling in immune cells, astrocytes, microglia and neurons may play roles in the pathogenesis of multiple diseases. TLRs are a “missing” link in alcohol-mediated astrocytic response in context of HAND since TLR stimulation by alcohol in glial cells induces secretion of pro-inflammatory molecules. Thus, we explored the role of TLRs in alcohol-induced inflammation and cytotoxicity in primary human astrocytes with HAND. TLRs signaling gene array was performed to screen altered profiles for all 10 TLR family members and 74 downstream signaling molecules. Ingenuity pathway analysis (IPA) was performed to identify potential signaling nodes. Data suggested that HIV-1 and/or EtOH led to differential TLRs expression in astrocytes. We confirmed all 10 TLRs by real-time PCR in four independent astrocyte donors. Alcohol alone and with HIV-1, significantly upregulated TLR1, 2, 3, 4, 5 and 9 as compared to controls and HIV-1 alone. We propose that TLRs regulation plays an important role in astrocytes inflammation upon HIV-1 and EtOH exposure.