In rheumatoid arthritis (RA), T cells age prematurely and have defects in DNA repair mechanisms and a distinct metabolic signature. New research suggests that these characteristics might be linked to each other, and to inflammation, via the mitochondria.
Previous studies had identified low expression of the DNA repair nuclease MRE11A as being linked to the prematurely aged phenotype of RA T cells. In the new study, inducing low MRE11A expression in otherwise healthy T cells produced a phenotype similar to that of T cells from patients with RA, in which mitochondrial function was impaired. Interestingly, the low expression of MRE11A in RA T cells extended to the mitochondria, where it is also present, and was linked to DNA damage and leakage.
“We had to leave our comfort zone and transition from the nucleus to the mitochondria to study how MRE11A contributes to mitochondrial failure in RA T cells,” explains corresponding author Cornelia Weyand. “We developed techniques to study how mitochondrial DNA (mtDNA) leaks into the cytoplasm and how leaked mtDNA is recognized by DNA sensors.”
The researchers found that leaked mtDNA triggered the inflammasome in T cells with low MRE11A expression, causing the activation of caspase-1, the release of IL-1β and pyroptotic cell death. In a humanized model of RA in which human synovial tissue was engrafted into NSG mice, MRE11A knockdown in T cells resulted in increased caspase-1 activation and synovial tissue inflammation. By contrast, MRE11A overexpression in T cells reduced synovial inflammation in this model.
MRE11A knockdown in T cells resulted in increased caspase-1 activation and synovial tissue inflammation
“Implicating mtDNA repair in the tissue inflammatory response in RA comes as quite a surprise,” says Weyand. “We next want to explore the therapeutic implications of mitochondrial infidelity in RA. Can we prevent the leakage of mtDNA into the cytoplasm? Can we prevent pyroptotic T cell death? Can we repair the damaged DNA within the mitochondria, and will that rescue mitochondrial function?” Future studies will hopefully ascertain whether mtDNA repair is indeed a feasible therapeutic target for RA.
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Original article
Li, Y. et al. The DNA repair nuclease MRE11A functions as a mitochondrial protector and prevents T cell pyroptosis and tissue inflammation. Cell Metab. https://doi.org/10.1016/j.cmet.2019.06.016 (2019)
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Collison, J. Faulty mitochondrial DNA repair promotes inflammation in RA. Nat Rev Rheumatol 15, 576 (2019). https://doi.org/10.1038/s41584-019-0303-x
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DOI: https://doi.org/10.1038/s41584-019-0303-x
