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The contribution of tumor necrosis factor\u2010like ligand 1A (TL1A) in RA pathogenesis, especially on fibroblast\u2010like synoviocytes (FLS), has been suggested clinically. The present study investigated the role of TL1A in mitochondrial dysfunction, induced oxidative stress in mitochondria, apoptosis resistance and the inflammatory response in FLS obtained from RA patients (RA\u2010FLS). RA\u2010FLS were incubated with TL1A and tumor necrosis factor receptor 2 (TNFR2) antagonist. Respiratory function, mitochondrial membrane potential and respiration associated genes of mitochondria were measured in both TL1A stimulated and non\u2010stimulated RA\u2010FLS. Additionally, the effects of TL1A on reactive oxygen species (ROS) production in mitochondria, apoptosis and the inflammatory response in RA\u2010FLS were also assessed. The role of TL1A in association between ROS generation, especially mitochondrial type and the inflammatory response, was evaluated by measuring inflammation\u2010related cytokines and signaling pathways using ROS inhibitors, diphenyleneiodonium chloride and Mito\u2010TEMPO (Sigma\u2010Aldrich, Miamisburg, OH, USA). We found that TL1A induced mitochondrial dysfunction by weakening mitochondrial respiration and membrane potential, which was blocked by a TNFR2 antagonist. Increased ROS synthesis in impaired mitochondria was observed with MitoSOX (Invitrogen, CA, USA) immunofluorescence staining in TL1A\u2010stimulated RA\u2010FLS but inhibited by a TNFR2 antagonist. TL1A influenced apoptosis resistance and inflammatory mediators via TNFR2. Inhibition of mitochondria\u2010derived ROS compromised the production of inflammatory factors in TL1A\u2010stimulated RA\u2010FLS, suggesting that mitochondrial dysfunction mediated by the TL1A\/TNFR2 axis might amplify the inflammatory response via regulation of mitochondria\u2010derived ROS generation. Collectively, our results reveal that TL1A might be involved in making FLS more aggressive in RA pathogenesis via cell respiration interruption.<\/jats:p>","DOI":"10.1111\/febs.15181","type":"journal-article","created":{"date-parts":[[2020,1,17]],"date-time":"2020-01-17T22:55:20Z","timestamp":1579301720000},"page":"3088-3104","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["TL1A\/TNFR2\u2010mediated mitochondrial dysfunction of fibroblast\u2010like synoviocytes increases inflammatory response in patients with rheumatoid arthritis via reactive oxygen species generation"],"prefix":"10.1111","volume":"287","author":[{"given":"Mahmoud","family":"Al\u2010Azab","sequence":"first","affiliation":[{"name":"Department of Immunology College of Basic Medical Science Dalian Medical University Liaoning China"},{"name":"Department of Immunology Guangzhou Institute Pediatrics Guangzhou Women and Children Medical Centre Guangzhou 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