Nucleic acid sensing in the central nervous system: Implications for neural circuit development, function, and degeneration

Abstract

Nucleic acids are a critical trigger for the innate immune response to infection, wherein pathogen-derived RNA and DNA are sensed by nucleic acid sensing receptors. This subsequently drives the production of type I interferon and other inflammatory cytokines to combat infection. While the system is designed such that these receptors should specifically recognize pathogen-derived nucleic acids, it is now clear that self-derived RNA and DNA can also stimulate these receptors to cause aberrant inflammation and autoimmune disease. Intriguingly, similar pathways are now emerging in the central nervous system in neurons and glial cells. As in the periphery, these signaling pathways are active in neurons and glia to present the spread of pathogens in the CNS. They further appear to be active even under steady conditions to regulate neuronal development and function, and they can become activated aberrantly during disease to propagate neuroinflammation and neurodegeneration. Here, we review the emerging new roles for nucleic acid sensing mechanisms in the CNS and raise open questions that we are poised to explore in the future.

Keywords: neural circuits; neurodegeneration; neuroinflammation; nucleic acid sensing.

Figure 1:. Nucleic acid sensing machinery in cytosol and endosome.

A general overview of Cytosolic RNA sensing (left), Endosomal RNA/DNA sensing (middle), and Cytosolic DNA sensing (right) sensing pathways largely defined in the context of host defense against pathogens. ssRNA: single stranded RNA; dsRNA: double stranded RNA; RIG-I: retinoic acid-inducible gene I; MDA5: melanoma differentiation factor 5; LGP2: laboratory of genetics and physiology 2; MAVS: mitochondrial antiviral-signaling protein; TRAF: tumor necrosis factor receptor-associated factor; MAPK: mitogen-activated protein kinase; AP-1: activator protein-1; TAK1: transforming growth factor-β activated kinase 1; IKK: IκB kinase; IκB: inhibitor of kappa B; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; TBK1: TANK-binding kinase 1; IRF: interferon regulatory factor; IFN: interferon; ISGs: IFN-stimulated genes; dsDNA: double-strand DNA; rRNA: ribosomal RNA; TLR: Toll-like receptor; TRIF: Toll-interleukin receptor-domain-containing adapter-inducing IFN-β; MyD88: myeloid differentiation primary response protein 88; cGAS: cGAMP synthase; cGAMP: cyclic guanosine monophosphate–adenosine monophosphate; STING: stimulator of IFN genes; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment; AIM2: absent in melanoma 2; IFI16: IFN-γ inducible protein 16; CASP1: caspase 1; IL: interleukin. Figure made with Biorender.

Figure 2.. Aberrant nucleic acid sensing pathway activation during neurodegenerative disease.

A) Let7b mediated neurodegeneration through cell and non-cell autonomous mechanisms. B) Amyloid plaque-mediated type I IFN production in microglia. C) Neurons respond to cytoplasmic mtDNA released from mitochondrial damage through cGAS-STING (1). Increased c-JUN activity results in aberrant transcription of retrotransposable elements and downstream cGAS-STING activation (2). D) Microglia respond to cytoplasmic mtDNA release from mitochondrial damage through cGAS-STING. TLR: Toll-like receptor; Let-7: Lethal-7; IL: interleukin; MyD88: myeloid differentiation primary response protein 88; TNF-α: tumor necrosis factor alpha; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; IFN: Interferon; mtDNA: mitochondrial deoxyribose nucleic acid; IRF: interferon regulatory factor; c-JUN: transcription factor jun. Figure made with Biorender.

Figure 3.. Cell-autonomous nucleic acid sensing pathways regulate neuron development and function at steady state.

A) Activation of TLR3,7,8 in neurons negatively regulates neuronal morphology through restricting neurite outgrowth. TLR3 acts non-canonically through MyD88 to decrease expression of DISC1 and canonically through TRIF signaling has been shown to result in decreased neurite outgrowth (1). TLR7,8 act canonically through MyD88, leading to production of IL6 (2). B) TLR3,7 signaling drives action potentials in DRG neurons. TLR7 in DRG neurons responds to miRNAs, which triggers action potential firing (1). TLR3 activation enhances action potentials in DRG neurons through an undescribed mechanism (2). Let-7: Lethal-7; IL: interleukin; MyD88: myeloid differentiation primary response protein 88; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; TLR: toll-like receptor; DISC1: Disrupted in Schizophrenia 1; TRIF: Toll-interleukin receptor-domain-containing adapter-inducing IFN-β; DRG: Dorsal root ganglion; TRPA: Transient receptor potential cation channel, subfamily A. Figure made with Biorender.

Figure 4:. DNA Damage and the regulation of neural circuit development and function.

A) Aberrant neuronal activity during seizures drives dsDNA releases, which triggers microglial TLR9 to drive production of TNF-α and dampen neuronal excitability. B) Interferon responsive microglia drive removal of neurons with DNA damage during development, which allows for development of normal tactile sensitivity. C) After conditional fear conditioning, hippocampal neurons form dsDNA breaks, which are sensed by neuronal TLR9 and promote peri-neuronal net formation and proper formation of memory. dsDNA: double stranded deoxyribose nucleic acid; TLR: toll-like receptor; IL: interleukin; MyD88: myeloid differentiation primary response protein 88; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; IFN: interferon; TNF-α: tumor necrosis factor alpha; IRF: interferon regulatory factor; MAVS: mitochondrial antiviral-signaling protein. Figure made with Biorender.