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Kynurenic acid promotes A1 to A2 astrocyte conversion against HIV-associated neurocognitive disorder

Although extensive astrocyte activation is present in the CNS of patients suffering from HIV-associated neurocognitive disorder (HAND), little is known about the contribution of reactive astrocytes to HAND neuropathology. Here, we report that the imbalance between neurotoxic (A1 astrocytes) and protective astrocytes (A2 astrocytes) occurring in HIV-1 gp120 transgenic mice impedes the resolution of inflammation in the CNS, perpetuating neuron damage and cognitive deficits. Kynurenic acid (KYNA), a tryptophan metabolite with α7 nicotinic acetylcholine receptors (α7nAChR) inhibitory property, blunts gp120-induced A1 astrocyte activation while promoting A2 astrocyte formation through blockade of α7nAChR/JAK2/STAT3 signaling activation. Meanwhile, we provide evidence that α7nAChR deletion and tryptophan administration convert astrocyte phenotypes, ultimately facilitating neuronal and cognitive improvement in the gp120tg mice. These initial and determinant findings mark a turning point in our understanding of the role of α7nAChR in gp120-mediated astrocyte activation, which opens new opportunities to control reactive astrocyte generation through KYNA and tryptophan administration as a pharmacological approach for treating HAND.