Epigenetic Viral Mimicry in Neuroinflammation: Retrotransposons, cGAS–STING and Microglial Hysteresis

Endogenous retroviruses (ERVs), LINE-1 elements, and other endogenously active transposable-element families are now being studied for their role as a potential interface between epigenetic control and innate immunity. Here, we discuss how locus-specific failures in repressive complexes containing ATRX–DAXX–H3.3 and TRIM28–SETDB1–H3K9me3 may allow these elements to enter into unique molecular states that include double-stranded RNA, DNA/RNA hybrid molecules, RNA–protein complexes, reverse-transcription products, and RNA. Each of these states differs from the others in terms of its persistence, structural characteristics, and accessibility to sensors such as MDA5, RIG-I, cGAS–STING, and ZBP1, as well as host restriction pathways. We also emphasize that simply expressing a retroelement does not imply that it is competent to bind to a sensor and/or undergo productive retrotransposition. Rather, a distinction needs to be made between intermediate stages in the process of retrotransposition and productive retrotransposition itself. Therefore, the evidence needed to assign a specific sensor to a particular retroelement product must be presented. Furthermore, persistent stress caused by retroelement activity could converge with multiple cellular processes, such as p53–CDKN1A/p21-mediated cell-cycle arrest, PML-mediated nuclear organization, and lysosomal or metabolism-based changes leading to long-lived microglial states; however, demonstrating path dependence after removing the initiating perturbation would be required to demonstrate true hysteresis. Finally, downstream activation of complement pathways could have effects on synaptic function via separate CR3-dependent, trafficking-based, and contact-regulatory mechanisms. Overall, we recommend a locus-specific, structure-specific, and time-course-resolved approach for determining how the various states of endogenously active retroelements cross the genome–immunity boundary and contribute to neuroinflammatory dysfunction.