TY - JOUR
T1 - Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis
AU - Yang, Zhen
AU - Shen, Yi
AU - Oishi, Hisashi
AU - Matteson, Eric L.
AU - Tian, Lu
AU - Goronzy, Jörg J.
AU - Weyand, Cornelia M.
N1 - Funding Information:
Supported by NIH (AR042527, AI044142, AI108906, HL058000, AI108891, and AG045779), the Govenar Discovery Fund, the Northern California Arthritis Foundation, and S. Cahill.
PY - 2016/3/23
Y1 - 2016/3/23
N2 - In patients with rheumatoid arthritis (RA), CD4+ T cells hyperproliferate during clonal expansion, differentiating into cytokine-producing effector cells that contribute to disease pathology. However, the metabolic underpinnings of this hyperproliferation remain unclear. In contrast to healthy T cells, naïve RA T cells had a defect in glycolytic flux due to the up-regulation of glucose-6-phosphate dehydrogenase (G6PD). Excess G6PD shunted glucose into the pentose phosphate pathway, resulting in NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) accumulation and reactive oxygen species (ROS) consumption. With surplus reductive equivalents, RA T cells insufficiently activated the redox-sensitive kinase ataxia telangiectasia mutated (ATM), bypassed the G2/M cell cycle checkpoint, and hyperproliferated. Moreover, insufficient ATM activation biased T cell differentiation toward the T helper 1 (TH1) and TH17 lineages, imposing a hyperinflammatory phenotype. We have identified several interventions that replenish intracellular ROS, which corrected the abnormal proliferative behavior of RA T cells and successfully suppressed synovial inflammation. Thus, rebalancing glucose utilization and restoring oxidant signaling may provide a therapeutic strategy to prevent autoimmunity in RA.
AB - In patients with rheumatoid arthritis (RA), CD4+ T cells hyperproliferate during clonal expansion, differentiating into cytokine-producing effector cells that contribute to disease pathology. However, the metabolic underpinnings of this hyperproliferation remain unclear. In contrast to healthy T cells, naïve RA T cells had a defect in glycolytic flux due to the up-regulation of glucose-6-phosphate dehydrogenase (G6PD). Excess G6PD shunted glucose into the pentose phosphate pathway, resulting in NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) accumulation and reactive oxygen species (ROS) consumption. With surplus reductive equivalents, RA T cells insufficiently activated the redox-sensitive kinase ataxia telangiectasia mutated (ATM), bypassed the G2/M cell cycle checkpoint, and hyperproliferated. Moreover, insufficient ATM activation biased T cell differentiation toward the T helper 1 (TH1) and TH17 lineages, imposing a hyperinflammatory phenotype. We have identified several interventions that replenish intracellular ROS, which corrected the abnormal proliferative behavior of RA T cells and successfully suppressed synovial inflammation. Thus, rebalancing glucose utilization and restoring oxidant signaling may provide a therapeutic strategy to prevent autoimmunity in RA.
UR - http://www.scopus.com/inward/record.url?scp=84961841635&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961841635&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aad7151
DO - 10.1126/scitranslmed.aad7151
M3 - Article
C2 - 27009267
AN - SCOPUS:84961841635
SN - 1946-6234
VL - 8
JO - Science translational medicine
JF - Science translational medicine
IS - 331
M1 - 331ra38
ER -