HIV-1 Tat Protein Increases Microglial Outward K+ Current and Resultant Neurotoxic Activity

Abstract

Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (Kv) channels are involved in the regulation of microglia function, prompting us to hypothesize Kv channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of Kv channels in the response of microglia to HIV-1 Tat protein. Treatment of rat microglia with HIV-1 Tat protein (200 ng/ml) resulted in pro-inflammatory microglial activation, as indicated by increases in TNF-α, IL-1β, reactive oxygen species, and nitric oxide, which were accompanied by enhanced outward K+ current and Kv1.3 channel expression. Suppression of microglial Kv1.3 channel activity, either with Kv1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K+ channel blocker 4-Aminopyridine, or by knockdown of Kv1.3 expression via transfection of microglia with Kv1.3 siRNA, was found to abrogate the neurotoxic activity of microglia resulting from HIV-1 Tat exposure. Furthermore, HIV-1 Tat-induced neuronal apoptosis was attenuated with the application of supernatant collected from K+ channel blocker-treated microglia. Lastly, the intracellular signaling pathways associated with Kv1.3 were investigated and enhancement of microglial Kv1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial Kv1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders.

Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

“…Additionally, the increased K + efflux from Ols in an in vivo condition may affect neuronal function through elevating the levels of extracellular K + , instead of clearing K + released from neurons during axonal firings (Gipson and Bordey, 2002; Menichella et al, 2006). An earlier study from our laboratory also showed that blockade of K V 1.3 or knockdown K V 1.3 expression in microglial cells attenuated Tat-induced microglia neurotoxic activity (Liu et al, 2013). Taking together, these findings indicate that activation of K V 1.3 plays an important role in Tat-associated neurotoxicity.…”

Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

“…Additionally, the increased K + efflux from Ols in an in vivo condition may affect neuronal function through elevating the levels of extracellular K + , instead of clearing K + released from neurons during axonal firings (Gipson and Bordey, 2002; Menichella et al, 2006). An earlier study from our laboratory also showed that blockade of K V 1.3 or knockdown K V 1.3 expression in microglial cells attenuated Tat-induced microglia neurotoxic activity (Liu et al, 2013). Taking together, these findings indicate that activation of K V 1.3 plays an important role in Tat-associated neurotoxicity.…”

IL-17 Inhibits Oligodendrocyte Progenitor Cell Proliferation and Differentiation by Increasing K+ Channel Kv1.3

“…Although we demonstrated an enhancement of Kv1.3 expression after IL-17 treatment, the molecular mechanisms remain obscure. In microglial cells, Kv1.3 expression is elevated by ERK1/2 activation ( Liu et al, 2013 ), which is downstream molecular of IL-17. IL-17 may increase Kv1.3 expression potentially by activating ERK1/2 signal.…”

GPR18 drives FAAH inhibition-induced neuroprotection against HIV-1 Tat-induced neurodegeneration

“…Glia-based neuroinflammation has been linked to neuronal damage/death and specifically to the progression of synaptodendritic injury in HIV-related disease ( Block et al, 2007 ; Bruce-Keller, 1999 ; Green et al, 2019 ; Liu et al, 2013 ; Lu et al, 2011 ; Nath et al, 1999 ; Takeuchi, 2010 ), which in turn strongly correlates with HAND symptom severity ( Ellis et al, 2007 ; Masliah et al, 1992 ; Masliah et al, 1997 ). Dendritic spines are small, actin rich structures that are paramount in healthy neuronal signaling and are highly sensitive to changes in intracellular calcium ( Higley and Sabatini, 2008 ; Hotulainen and Hoogenraad, 2010 ; Maha- jan and Nadkarni, 2019 ).…”

Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

“…Additionally, the increased K + efflux from Ols in an in vivo condition may affect neuronal function through elevating the levels of extracellular K + , instead of clearing K + released from neurons during axonal firings (Gipson and Bordey, 2002; Menichella et al, 2006). An earlier study from our laboratory also showed that blockade of K V 1.3 or knockdown K V 1.3 expression in microglial cells attenuated Tat-induced microglia neurotoxic activity (Liu et al, 2013). Taking together, these findings indicate that activation of K V 1.3 plays an important role in Tat-associated neurotoxicity.…”

IL-17 Inhibits Oligodendrocyte Progenitor Cell Proliferation and Differentiation by Increasing K+ Channel Kv1.3

“…Although we demonstrated an enhancement of Kv1.3 expression after IL-17 treatment, the molecular mechanisms remain obscure. In microglial cells, Kv1.3 expression is elevated by ERK1/2 activation ( Liu et al, 2013 ), which is downstream molecular of IL-17. IL-17 may increase Kv1.3 expression potentially by activating ERK1/2 signal.…”

GPR18 drives FAAH inhibition-induced neuroprotection against HIV-1 Tat-induced neurodegeneration

“…Glia-based neuroinflammation has been linked to neuronal damage/death and specifically to the progression of synaptodendritic injury in HIV-related disease ( Block et al, 2007 ; Bruce-Keller, 1999 ; Green et al, 2019 ; Liu et al, 2013 ; Lu et al, 2011 ; Nath et al, 1999 ; Takeuchi, 2010 ), which in turn strongly correlates with HAND symptom severity ( Ellis et al, 2007 ; Masliah et al, 1992 ; Masliah et al, 1997 ). Dendritic spines are small, actin rich structures that are paramount in healthy neuronal signaling and are highly sensitive to changes in intracellular calcium ( Higley and Sabatini, 2008 ; Hotulainen and Hoogenraad, 2010 ; Maha- jan and Nadkarni, 2019 ).…”

Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

“…Additionally, the increased K + efflux from Ols in an in vivo condition may affect neuronal function through elevating the levels of extracellular K + , instead of clearing K + released from neurons during axonal firings (Gipson and Bordey, 2002; Menichella et al, 2006). An earlier study from our laboratory also showed that blockade of K V 1.3 or knockdown K V 1.3 expression in microglial cells attenuated Tat-induced microglia neurotoxic activity (Liu et al, 2013). Taking together, these findings indicate that activation of K V 1.3 plays an important role in Tat-associated neurotoxicity.…”

IL-17 Inhibits Oligodendrocyte Progenitor Cell Proliferation and Differentiation by Increasing K+ Channel Kv1.3

“…Although we demonstrated an enhancement of Kv1.3 expression after IL-17 treatment, the molecular mechanisms remain obscure. In microglial cells, Kv1.3 expression is elevated by ERK1/2 activation ( Liu et al, 2013 ), which is downstream molecular of IL-17. IL-17 may increase Kv1.3 expression potentially by activating ERK1/2 signal.…”

GPR18 drives FAAH inhibition-induced neuroprotection against HIV-1 Tat-induced neurodegeneration

“…Glia-based neuroinflammation has been linked to neuronal damage/death and specifically to the progression of synaptodendritic injury in HIV-related disease ( Block et al, 2007 ; Bruce-Keller, 1999 ; Green et al, 2019 ; Liu et al, 2013 ; Lu et al, 2011 ; Nath et al, 1999 ; Takeuchi, 2010 ), which in turn strongly correlates with HAND symptom severity ( Ellis et al, 2007 ; Masliah et al, 1992 ; Masliah et al, 1997 ). Dendritic spines are small, actin rich structures that are paramount in healthy neuronal signaling and are highly sensitive to changes in intracellular calcium ( Higley and Sabatini, 2008 ; Hotulainen and Hoogenraad, 2010 ; Maha- jan and Nadkarni, 2019 ).…”