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.

Fig. 1. Canonical downstream signal pathways of nucleic acid sensing PRRs.

PKR is activated by cytoplasmic dsRNA to phosphorylate eIF2α, leading to global translation shutdown. MDA5/RIG-I are also activated by cytoplasmic dsRNA, and through MAVS, promote the production of inflammatory cytokines via NF-kB and type I IFN via IRF-3. Cytoplasmic dsDNA activates cGAS and AIM2. Activated cGAS induces STING activation through the production of cGAMP, which in turn induces the production of inflammatory cytokines via NF-kB and type I IFN via IRF3. Activated AIM2 induces inflammasome formation and caspase 1 activation, which further cleaves and activates inflammatory cytokines (IL-Ib, IL-18) and gasdermin D, ultimately causing pyroptosis. TLR3 detects dsRNA in the endosome and induces the production of cytokines and type I IFN via TRIF. TLR 7/8 and TLR9 detect ssRNA and dsDNA in the endosome, respectively, and promote the production of inflammatory cytokines and type I IFN via MyD88.

Fig. 2. Extracellular and intracellular self-nucleic acids.

(A) Extracellular nucleic acids originating from neighboring live, dead, or dying cells. Released miRNAs, dsRNAs, HERV-K, mtDNA, and NETs can activate TLRs (TLR3, 7/8, and −9) in nearby responding cells. (B) Intracellular nucleic acids originating from the loss of regulators within cells. ADAR1 and TREX1 are major regulators of immunostimulatory self-RNA and self-DNA nucleic acids, respectively. Loss of these regulatory mechanisms can lead to hyperactivation of various PRRs and promotes neurodegeneration.

Fig. 3. Intra-and extracellular self-ligands of PRRs leading to downstream effects in the brain.

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.