In the cytoplasm, expanded repeats, long 3′UTRs in mRNA, double-stranded mitochondrial RNAs (mtRNAs), and unedited transcripts can activate PKR and MDA5, stimulating inflammation, type I IFN production, and neuronal apoptosis triggered by translational shutdown. Cytoplasmic DNA and mitochondrial DNA (mtDNA) can stimulate cGAS and AIM2 activity to induce inflammation and pyroptosis. Extracellular miRNA, HERV-K, cell free dsRNA, mtDNA, and NETs can activate TLRs in neighboring cells leading to pain transmission, neuronal growth control, inflammation, and type I IFN production.