Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function

Akiko Nagamachi, Yuichiro Nakata, Takeshi Ueda, Norimasa Yamasaki, Yasuhiro Ebihara, Kohichiro Tsuji, Zen Ichiro Honda, Keiyo Takubo, Toshio Suda, Hideaki Oda, Toshiya Inaba, Hiroaki Honda

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Abstract

A20 is a negative regulator of NF-κB, and mutational loss of A20 expression is involved in the pathogenesis of autoimmune diseases and B-cell lymphomas. To clarify the role of A20 in adult hematopoiesis, we generated conditional A20 knockout mice (A20flox/flox) and crossed them with Mx-1Cre (MxCre+) and ERT2Cre (ERT2Cre+) transgenic mice in which Cre is inducibly activated by endogenous interferon and exogenous tamoxifen, respectively. A20flox/flox MxCre+ (A20Mx) mice spontaneously exhibited myeloid proliferation, B cell apoptosis, and anemia with overproduction of pro-inflammatory cytokines. Bone marrow transplantation demonstrated that these changes were caused by hematopoietic cells. NF-κB was constitutively activated in A20Mx hematopoietic stem cells (HSCs), which caused enhanced cell cycle entry and impaired repopulating ability. Tamoxifen stimulation of A20flox/flox ERT2Cre+ (A20ERT2) mice induced fulminant apoptosis and subsequent myeloproliferation, lymphocytopenia, and progressive anemia with excessive production of pro-inflammatory cytokines, as observed in A20Mx mice. These results demonstrate that A20 plays essential roles in the homeostasis of adult hematopoiesis by preventing apoptosis and inflammation. Our findings provide insights into the mechanism underlying A20 dysfunction and human diseases in which A20 expression is impaired.

Original languageEnglish
Article numbere87425
JournalPloS one
Volume9
Issue number1
DOIs
Publication statusPublished - 2014 Jan 31

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Nagamachi, A., Nakata, Y., Ueda, T., Yamasaki, N., Ebihara, Y., Tsuji, K., Honda, Z. I., Takubo, K., Suda, T., Oda, H., Inaba, T., & Honda, H. (2014). Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function. PloS one, 9(1), [e87425]. https://doi.org/10.1371/journal.pone.0087425