Genome integrity and inflammation in the nervous system

Abstract

Preservation of genomic integrity is crucial for nervous system development and function. DNA repair deficiency results in several human diseases that are characterized by both neurodegeneration and neuroinflammation. Recent research has highlighted a role for compromised genomic integrity as a key factor driving neuropathology and triggering innate immune signaling to cause inflammation. Here we review the mechanisms by which DNA damage engages innate immune signaling and how this may promote neurological disease. We also consider the contributions of different neural cell types towards DNA damage-driven neuroinflammation. A deeper knowledge of genome maintenance mechanisms that prevent aberrant immune activation in neural cells will guide future therapies to ameliorate neurological disease.

Keywords: Astrocyte; DNA damage; Microglia; Nervous system; Neuroinflammation.

Figure 1:. DNA damage response and innate immune activation.

DNA damage signaling can result in cell cycle arrest, apoptosis or senescence depending upon the type of DNA damage and strength of stimulus. Transient cell cycle arrest is beneficial as it pauses proliferation to allow cells to repair DNA damage. However, DNA damage-induced cellular senescence (e.g. telomere erosion) can cause inflammation through induction of SASP. Failure of DNA repair can result in micronuclei formation and accumulation of cytoplasmic DNA. DNA in the micronuclei is recognized by cGAS/STING pathway leading to activation of immune signaling and inflammation. TREX1 exonuclease and DNase2 nucleases suppress accumulation of DNA by degrading various DNA fragments and inhibiting inflammation.

Figure 2:. Recognition of DNA by innate immune sensors.

TLR9 is an endosomal DNA sensor that recognizes CpG DNA commonly found in pathogens. Upon recognition of CpG DNA in endosomes, TLR9 interacts with adaptor protein MyD88. After TLR9 engagement, MyD88 acts as a platform to recruit IRAK family members, which leads to nuclear translocation of proinflammatory NF-κB and IRF3 transcription factors and expression of various inflammatory cytokines and Type I interferons. Cytosolic DNA can be recognized by additional DNA sensors. For instance, IFI16 and DNA repair proteins such as, MRE11 and Ku70 can also recognize cytoplasmic DNA. These sensors can activate IRF3 mediated type I interferon signaling through the STING pathway.

Figure 3:. Recognition of DNA by AIM2 and cGAS/STING.

DNA damage is recognized by a diverse set of innate immune sensors. AIM2 is a cytoplasmic sensor that detects double stranded DNA of host or microbial origin. Upon DNA binding, AIM2 assembles a multiprotein complex with the help of adaptor ASC and catalytic effector procaspase 1. This complex is known as an inflammasome, where procaspase 1 undergoes autoproteolytic cleavage for activation. Active Caspase 1 induces proinflammatory cell death called Pyroptosis by cleaving Gasdermin D. Caspase1 also cleaves cytokines IL1beta (and others) which are released through Gasdermin D pores to induce inflammatory signaling. cGAS is another type of DNA sensor that detects single and double stranded DNA and DNA-RNA hybrids. cGAS (cyclic GMP-AMP Synthase) activation upon DNA binding results in the generation of second messenger cyclic GMP-AMP (cGAMP), which is a ligand of STING (Stimulator of Interferon Genes) an endoplasmic reticulum-localized protein. Activated STING translocates from the endoplasmic reticulum to the Golgi and recruits Kinases TBK1 and the IKK complex, which phosphorylates the IRF3 transcription factor and NF-κB inhibitor IκBα, respectively. Phosphorylated IRF3 dimerizes and translocates to the nucleus resulting in the activation of type I interferon signaling. IκBα phosphorylation activates NF-κB resulting in activation of proinflammatory signaling.

Figure 4:. Multiple neural cell types contribute to neuroinflammation.

DNA damage-induced inflammation can result from various types of DNA damage and can affect multiple neural cell types, which collectively impact neural homeostasis. Key responders to genome instability are glial cells; the microglia and astrocytes, which can also substantially impact neurons. The multifaceted effect of DNA damage in the nervous system can lead to complex outcomes involving different types of DNA damage and can affect different neural cells and/or tissues, and may contribute to a range of neurological diseases, including Aicardi-Goutières Syndrome, ataxia telangiectasia, Alzheimer’s and Parkinson’s disease.