B-to plasma-cell terminal differentiation entails oxidative stress and profound reshaping of the antioxidant responses

Milena Bertolotti, Sun Hee Yim, Jose M. Garcia-Manteiga, Silvia Masciarelli, Yoo Jin Kim, Min Hee Kang, Yoshihito Iuchi, Junichi Fujii, Roberta Vené, Anna Rubartelli, Sue Goo Rhee, Roberto Sitia

Research output: Contribution to journalArticlepeer-review

Abstract

Limited amounts of reactive oxygen species are necessary for cell survival and signaling, but their excess causes oxidative stress. H2O 2 and other reactive oxygen species are formed as byproducts of several metabolic pathways, possibly including oxidative protein folding in the endoplasmic reticulum. B-to plasma-cell differentiation is characterized by a massive expansion of the endoplasmic reticulum, finalized to sustain abundant immunoglobulin (Ig) synthesis and secretion. The increased production of disulfide-rich Ig might cause oxidative stress that could serve signaling roles in the differentiation and lifespan control of antibody-secreting cells. Here we show that terminal B-cell differentiation entails redox stress, NF-E2-related factor-2 (Nrf2) activation, and reshaping of the antioxidant responses. However, plasma-cell differentiation was not dramatically impaired in peroxiredoxin (Prx)1-, 2-, 3-, and 4-, glutathione peroxidase 1-, and Nrf2-knockout splenocytes, suggesting redundancy and robustness in antioxidant systems. Endoplasmic reticulum (ER)-resident Prx4 increases dramatically during differentiation. In its absence, IgM secretion was not significantly affected, but more high-molecular-weight covalent complexes accumulated intracellularly. Our results suggest that the early intracellular production of H 2O2 facilitates B-cell proliferation and reveal a role for the Nrf2 pathway in the differentiation and function of IgM-secreting cells.

Original languageEnglish
Pages (from-to)1133-1144
Number of pages12
JournalAntioxidants and Redox Signaling
Volume13
Issue number8
DOIs
Publication statusPublished - Oct 15 2010

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

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