Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function.
Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function.
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DOI：
10.1371/journal.pone.0087425
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Honda H
中科院分区：
文献类型：
--
作者：
Nagamachi A;Nakata Y;Ueda T;Yamasaki N;Ebihara Y;Tsuji K;Honda Z;Takubo K;Suda T;Oda H;Inaba T;Honda H
A20 是 NF-κB 的负调节因子，A20 表达的突变缺失与自身免疫性疾病和 B 细胞淋巴瘤的发病机制有关。为了阐明 A20 在成年造血中的作用，我们生成了条件性 A20 基因敲除小鼠 (A20flox/flox)，并将其与 Mx-1Cre (MxCre +) 和 ERT2Cre (ERT2Cre +) 转基因小鼠杂交，其中 Cre 分别被内源性干扰素和外源性他莫昔芬诱导激活。 A20flox/flox MxCre + (A20Mx) 小鼠自发地表现出骨髓增殖、B 细胞凋亡和贫血，并伴有促炎细胞因子的过量产生。骨髓移植证明这些变化是由造血细胞引起的。 NF-κB 在 A20Mx 造血干细胞 (HSC) 中被组成型激活，导致细胞周期进入增强并损害再增殖能力。他莫昔芬对 A20flox/flox ERT2Cre + (A20ERT2) 小鼠的刺激诱导了暴发性细胞凋亡以及随后的骨髓增殖、淋巴细胞减少和进行性贫血，并伴随促炎细胞因子的过量产生，正如在 A20Mx 小鼠中观察到的那样。这些结果表明，A20 通过防止细胞凋亡和炎症，在成人造血的稳态中发挥重要作用。我们的研究结果提供了对 A20 功能障碍和 A20 表达受损的人类疾病的潜在机制的见解。
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.
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DOI：
10.1038/nri3062
发表时间：
2011-09-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Kiel, MJ;Yilmaz, ÖH;Morrison, SJ
通讯作者：
Morrison, SJ
影响因子：
20.3
作者：
Chu, Yuanyuan;Vahl, J. Christoph;Schmidt-Supprian, Marc
通讯作者：
Schmidt-Supprian, Marc
影响因子：
30.8
作者：
Matmati, Mourad;Jacques, Peggy;van Loo, Geert
通讯作者：
van Loo, Geert
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A