Redox-sensitive signaling in inflammatory T cells and in autoimmune disease

Cornelia M. Weyand, Yi Shen, Jorg J. Goronzy

Research output: Contribution to journalReview articlepeer-review

24 Scopus citations

Abstract

Reactive oxygen species (ROS) are byproducts of oxygen metabolism best known for their damaging potential, but recent evidence has exposed their role as secondary messengers, which regulate cell function through redox-activatable signaling systems. In immune cells, specifically in T cells, redox-sensitive signaling pathways have been implicated in controlling several functional domains; including cell cycle progression, T effector cell differentiation, tissue invasion and inflammatory behavior. T cells from patients with the autoimmune disease rheumatoid arthritis (RA) have emerged as a valuable model system to examine the functional impact of ROS on T cell function. Notably, RA T cells are distinguished from healthy T cells based on reduced ROS production and undergo “reductive stress”. Upstream defects leading to the ROSlow status of RA T cells are connected to metabolic reorganization. RA T cells shunt glucose away from pyruvate and ATP production towards the pentose phosphate pathway, where they generate NADPH and consume cellular ROS. Downstream consequences of the ROSlow conditions in RA T cells include insufficient activation of the DNA repair kinase ATM, bypassing of the G2/M cell cycle checkpoint and biased differentiation of T cells into IFN-γ and IL-17–producing inflammatory cells. Also, ROSlow T cells rapidly invade into peripheral tissue due to dysregulated lipogenesis, excessive membrane ruffling, and overexpression of a motility module dominated by the scaffolding protein Tks5. These data place ROS into a pinnacle position in connecting cellular metabolism and protective versus auto-aggressive T cell immunity. Therapeutic interventions for targeted ROS enhancement instead of ROS depletion should be developed as a novel strategy to treat autoimmune tissue inflammation.

Original languageEnglish (US)
Pages (from-to)36-43
Number of pages8
JournalFree Radical Biology and Medicine
Volume125
DOIs
StatePublished - Sep 2018

Keywords

  • ATM
  • Glycolysis
  • NADPH
  • Podosomes
  • Reactive oxygen species
  • Reductive stress
  • Rheumatoid arthritis
  • TKS5
  • Tissue invasion

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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