Activation of Endogenous Retrovirus Triggers Microglial Immuno-Inflammation and Contributes to Negative Emotional Behaviors in Mice with Chronic Stress

AbstractBackgroundThe “missing” link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice.MethodsMale C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed.ResultsMice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genesMuERV-L,MusD, andIAPtranscription, cGAS–IFI16–STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation genep53significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors.ConclusionsOur results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.