ADAR1-mediated RNA editing is required for thymic self-tolerance and inhibition of autoimmunity

T cells play a crucial role in the adaptive immune system, and their maturation process is tightly regulated. Adenosine deaminase acting on RNA 1 (ADAR1) is the enzyme responsible for adenosine‐to‐inosine RNA editing in dsRNAs, and loss of ADAR1 activates the innate immune sensing response via melanoma differentiation‐associated protein 5 (MDA5), which interprets unedited dsRNA as non‐self. Although ADAR1 is highly expressed in the thymus, its role in the adaptive immune system, especially in T cells, remains elusive. Here, we demonstrate that T cell‐specific deletion of Adar1 in mice causes abnormal thymic T cell maturation including impaired negative selection and autoimmunity such as spontaneous colitis. This is caused by excessive expression of interferon‐stimulated genes, which reduces T cell receptor (TCR) signal transduction, due to a failure of RNA editing in ADAR1‐deficient thymocytes. Intriguingly, concurrent deletion of MDA5 restores thymocyte maturation and prevents colitis. These findings suggest that prevention of MDA5 sensing of endogenous dsRNA by ADAR1‐mediated RNA editing is required for preventing both innate immune responses and T cell‐mediated autoimmunity

Expression of aryl hydrocarbon receptor, inflammatory cytokines, and incidence of rheumatoid arthritis in Vietnamese dioxin-exposed people

Many Vietnamese citizens have been and continue to be inadvertently exposed to dioxins and dioxin-like compounds deposited in the country during the Vietnam War. Dioxins may be involved in the pathogenesis of inflammatory diseases in part via by affecting expression of aryl hydrocarbon receptor (Ahr) and inflammatory cytokines in animal models. As the role of the Ahr in dioxin-exposed people is not well defined, a study was conducted to examine gene expression levels of Ahr, inflammatory cytokines, and the incidence of diseases in dioxin-exposed citizens who had/still resided near a heavily dioxin-contaminated area in Vietnam. Whole blood from citizens at/around Da Nang airbase and control individuals living in unsprayed areas was collected. Serum levels of dioxins were analyzed by using a dioxins-responsive chemical-activated luciferase gene expression bioassay. Gene expression of Ahr, interleukin (IL)-1β, TNFα, IL-6, and IL-22 in whole blood was examined by quantitative real-time PCR. The results showed levels of dioxins and expression of Ahr, IL-1β, TNFα, and IL-6 were up-regulated while IL-22 expression was down-regulated in dioxin-exposed people. Various disease incidences in the study subjects was also examined. Interestingly, the incidence of rheumatoid arthritis (RA) in these individuals was increased compared to the estimated prevalence of this disease in the general Vietnamese population. Analyses also showed that expression levels of Ahr correlated to those of IL-6 and IL-22 in the dioxin-exposed people. Taken together, dioxins might be involved in an up-regulated expression of Ahr that might possibly relate to changes in level of inflammatory cytokines and, ultimately, in the incidence of select diseases in residents of Vietnam who had/continue to live near a dioxins-contaminated site

RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain.

Adenosine deaminase acting on RNA 1 (ADAR1), an enzyme responsible for adenosine-to-inosine RNA editing, is composed of two isoforms: nuclear p110 and cytoplasmic p150. Deletion of Adar1 or Adar1 p150 genes in mice results in embryonic lethality with overexpression of interferon-stimulating genes (ISGs), caused by the aberrant recognition of unedited endogenous transcripts by melanoma differentiation-associated protein 5 (MDA5). However, among numerous RNA editing sites, how many RNA sites require editing, especially by ADAR1 p150, to avoid MDA5 activation and whether ADAR1 p110 contributes to this function remains elusive. In particular, ADAR1 p110 is abundant in the mouse brain where a subtle amount of ADAR1 p150 is expressed, whereas ADAR1 mutations cause Aicardi-Goutières syndrome, in which the brain is one of the most affected organs accompanied by the elevated expression of ISGs. Therefore, understanding RNA editing-mediated prevention of MDA5 activation in the brain is especially important. Here, we established Adar1 p110-specific knockout mice, in which the upregulated expression of ISGs was not observed. This result suggests that ADAR1 p150-mediated RNA editing is enough to suppress MDA5 activation. Therefore, we further created Adar1 p110/Adar2 double knockout mice to identify ADAR1 p150-mediated editing sites. This analysis demonstrated that although the elevated expression of ISGs was not observed, only less than 2% of editing sites were preserved in the brains of Adar1 p110/Adar2 double knockout mice. Of note, we found that some sites were highly edited, which was comparable to those found in wild-type mice, indicating the presence of ADAR1 p150-specific sites. These data suggest that RNA editing at a very limited sites, which is mediated by a subtle amount of ADAR1 p150, is sufficient to prevents MDA5 activation, at least in the mouse brain