B- to plasma-cell terminal differentiation entails oxidative stress and profound reshaping of the antioxidant responses.
Limited amounts of reactive oxygen species are necessary for cell survival and signaling, but their excess causes oxidative stress. H(2)O(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(2)O(2) facilitates B-cell proliferation and reveal a role for the Nrf2 pathway in the differentiation and function of IgM-secreting cells.
Bertolotti
Milena
M
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
Yim
Sun Hee
SH
Garcia-Manteiga
Jose M
JM
Masciarelli
Silvia
S
Kim
Yoo-Jin
YJ
Kang
Min-Hee
MH
Iuchi
Yoshihito
Y
Fujii
Junichi
J
Vené
Roberta
R
Rubartelli
Anna
A
Rhee
Sue Goo
SG
Sitia
Roberto
R
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum; D007075:Immunoglobulin M / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000276:immunology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010950:Plasma Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D015398:Signal Transduction
D000975:Antioxidants; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species