Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function.
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 (A20(flox/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. A20(flox/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 A20(flox/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.
Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
Akiko
A
Nagamachi
Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
Yuichiro
Y
Nakata
Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
Takeshi
T
Ueda
Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
Norimasa
N
Yamasaki
Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
Yasuhiro
Y
Ebihara
Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
Kohichiro
K
Tsuji
Health Care Center and Graduate School of Humanities and Sciences, Institute of Environmental Science for Human Life, Ochanomizu University, Bunkyo-ku, Tokyo, Japan.
Zen-ichiro
Z
Honda
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Keiyo
K
Takubo
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Toshio
T
Suda
Department of Pathology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.
Hideaki
H
Oda
Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
Toshiya
T
Inaba
Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
Hiroaki
H
Honda
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D044767:Ubiquitin-Protein Ligases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse