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Abstract Number: 2014

Loss-of-function of the DNA Repair Nuclease MRE11A Induces Mitochondrial Failure and Tissue Inflammation in Rheumatoid Arthritis

Yinyin Li 1, Yi Shen 1, Ke Jin 1, Zhenke Wen 1, Wenqiang Cao 1, Bowen Wu 1, Ru Wen 1, Lu Tian 1, Gerald Berry 1, Jorg Goronzy 1 and Cornelia Weyand1, 1Stanford University, Stanford, CA

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Metabolism, mitochondria and inflammasome activation, Rheumatoid arthritis (RA)

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Session Information

Date: Tuesday, November 12, 2019

Session Title: RA – Etiology & Pathogenesis Poster II

Session Type: Poster Session (Tuesday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Patients with rheumatoid arthritis (RA) accumulate tissue-invasive, pro-inflammatory CD4+ T cells. Such T cells are metabolically reprogrammed, favoring cytokine production, lipogenesis and membrane formation while reducing ATP production. Also, such T cells have low expression of the DNA repair nuclease MRE11A, have a defect in DNA repair and are prematurely aged. How defective DNA repair, metabolic rewiring and the propensity to induce tissue inflammation are mechanistically linked is unknown.

Methods: CD4+ T cells from seropositive RA patients and age-matched controls were isolated from human peripheral blood mononuclear cells. Nucleolytic activity of the DNA repair protein MRE11A was inhibited by gene knockdown or the pharmacologic inhibitor Mirin. Metabolic profiles and mitochondrial activity were examined by the Seahorse Analyzer and by quantifying metabolites. Inflammasome activation and lytic T cell death were measured by caspase-1 activation, IL-1β production and LDH release. Tissue inflammatory propensity of T cells was quantified in NSG mice engrafted with human synovial tissue and reconstituted with genetically or pharmacologically manipulated T cells.

Results: MRE11Alow CD4+ T cells from RA patients had low oxygen consumption and low ATP production, indicative of impaired mitochondrial function. The phenotype was reproduced with MRE11A knockdown in healthy T cells. Immunoblotting and imaging analysis localized MRE11A to the mitochondria. Pharmacologic and genetic inhibition of MRE11A resulted in leakage of mitochondrial DNA (mtDNA) into the cytoplasm, where it triggered assembly of the NLRP3 and AIM2 inflammasome and induced caspase-1-dependent pyroptotic cell death. Caspase-1 activation was a feature of T cells in lymph node biopsies of RA patients. MRE11A loss-of-function was associated with high propensity of T cells to induce synovial tissue inflammation in vivo, including the deposition of mtDNA in inflamed tissue sites. MRE11A overexpression was sufficient to restore mitochondrial function and prevent mtDNA leakage into the cytosol. Also, restoration of MRE11A expression suppressed pyroptotic T cell death and protected synovial tissue against inflammatory attack.

Conclusion: The DNA repair defect in RA T cells extends to mitochondrial DNA, impairing mitochondrial oxygen consumption and ATP generation and damaging mtDNA containment. The mitochondrial stress program associated with loss-of-function of the repair nuclease MRE11A triggers inflammasome assembly, caspase-1 activation and pyroptotic T cell death. The mechanistic connection between DNA repair, bioenergetic failure and pro-inflammatory T cell death provides novel therapeutic opportunities to manage immune aging and restore tissue homeostasis in rheumatoid arthritis.


Disclosure: Y. Li, None; Y. Shen, None; K. Jin, None; Z. Wen, None; W. Cao, None; B. Wu, None; R. Wen, None; L. Tian, None; G. Berry, None; J. Goronzy, None; C. Weyand, Kiniska Pharmaceuticals, 2.

To cite this abstract in AMA style:

Li Y, Shen Y, Jin K, Wen Z, Cao W, Wu B, Wen R, Tian L, Berry G, Goronzy J, Weyand C. Loss-of-function of the DNA Repair Nuclease MRE11A Induces Mitochondrial Failure and Tissue Inflammation in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/loss-of-function-of-the-dna-repair-nuclease-mre11a-induces-mitochondrial-failure-and-tissue-inflammation-in-rheumatoid-arthritis/. Accessed February 3, 2023.
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