The Sixth Sense: Self-nucleic acid sensing in the brain

Abstract

Our innate immune system uses pattern recognition receptors (PRRs) as a first line of defense to detect microbial ligands and initiate an immune response. Viral nucleic acids are key ligands for the activation of many PRRs and the induction of downstream inflammatory and antiviral effects. Initially it was thought that endogenous (self) nucleic acids rarely activated these PRRs, however emerging evidence indicates that endogenous nucleic acids are able to activate host PRRs in homeostasis and disease. In fact, many regulatory mechanisms are in place to finely control and regulate sensing of self-nucleic acids by PRRs. Sensing of self-nucleic acids is particularly important in the brain, as perturbations to nucleic acid sensing commonly leads to neuropathology. This review will highlight the role of nucleic acid sensors in the brain, both in disease and homeostasis. We also indicate the source of endogenous stimulatory nucleic acids where known and summarize future directions for the study of this growing field.

Keywords: Brain; DNA sensing PRRs: cGAS, AIM2, TLR9; Neurodegeneration: Aicardi-Goutieres syndrome (AGS), Alzheimer's disease, Amyotrophic lateral sclerosis, Stroke, Traumatic brain injury; Neurodevelopment; Neuroinflammation; Nuecleic acid immunity; Pattern recognition receptors (PRRs); RNA sensing PRRs: MDA5, RIG-I, PKR, TLR3, TLR7/8.