Differential roles of the ADAM9/NF-κB and the ADAM9/STAT3 feedback loops in HIV-1 Tat-induced microglial inflammatory response and subsequent neuronal apoptosis

ADAM has been implicated in causing several neurodegenerative diseases to progress. However, the precise function they play in HIV-associated neurocognitive disorders (HAND) remains incompletely elucidated. The HIV-1 transcriptional activator (Tat) has the capacity to evoke an inflammatory reaction within the microglia of the central nervous system. This, subsequently, initiates the Apoptosis of neuronal cells. In the present research, our attention was centered on the part that ADAM9 plays in the microglia's response to Tat. We discovered that the stimulation with soluble Tat remarkably enhanced the manifestation of ADAM9 by means of the NF-κB and STAT3 pathway. In contrast, inhibition of ADAM9 significantly reduced Tat-triggered NF-κB and STAT3 signaling. Moreover, both ADAM9/NF-κB and ADAM9/STAT3 feedback loops exacerbated Tat-induced microglia inflammatory responses. However, further studies showed that the ADAM9/NF-κB feedback loop more significantly promoted neuronal Apoptosis mediated by conditioned medium secreted by microglia after Tat stimulation. This study offers a novel perspective on the function of diverse feedback circuits in the etiopathogenesis of HAND. It can be posited that, when considered as a collective entity, ADAM9 may represent a viable candidate for therapeutic intervention in the context of preventing neuronal injury associated with HAND by modulating the inflammatory response of microglia and influencing neuronal injury.

ADAM9; HIV-associated neurocognitive disorder; NF-κB; Neuroinflammation; STAT3; Tat.