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

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 +...

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Main Authors: Nagamachi, Akiko, Nakata, Yuichiro, Ueda, Takeshi, Yamasaki, Norimasa, Ebihara, Yasuhiro, Tsuji, Kohichiro, Honda, Zen-ichiro, Takubo, Keiyo, Suda, Toshio, Oda, Hideaki, Inaba, Toshiya, Honda, Hiroaki
Format: Online
Language:English
Published: Public Library of Science 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909109/
id pubmed-3909109
recordtype oai_dc
spelling pubmed-39091092014-02-04 Acquired Deficiency of A20 Results in Rapid Apoptosis, Systemic Inflammation, and Abnormal Hematopoietic Stem Cell Function Nagamachi, Akiko Nakata, Yuichiro Ueda, Takeshi Yamasaki, Norimasa Ebihara, Yasuhiro Tsuji, Kohichiro Honda, Zen-ichiro Takubo, Keiyo Suda, Toshio Oda, Hideaki Inaba, Toshiya Honda, Hiroaki Research Article 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. Public Library of Science 2014-01-31 /pmc/articles/PMC3909109/ /pubmed/24498102 http://dx.doi.org/10.1371/journal.pone.0087425 Text en © 2014 Nagamachi et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Nagamachi, Akiko
Nakata, Yuichiro
Ueda, Takeshi
Yamasaki, Norimasa
Ebihara, Yasuhiro
Tsuji, Kohichiro
Honda, Zen-ichiro
Takubo, Keiyo
Suda, Toshio
Oda, Hideaki
Inaba, Toshiya
Honda, Hiroaki
spellingShingle Nagamachi, Akiko
Nakata, Yuichiro
Ueda, Takeshi
Yamasaki, Norimasa
Ebihara, Yasuhiro
Tsuji, Kohichiro
Honda, Zen-ichiro
Takubo, Keiyo
Suda, Toshio
Oda, Hideaki
Inaba, Toshiya
Honda, Hiroaki
Acquired Deficiency of A20 Results in Rapid Apoptosis, Systemic Inflammation, and Abnormal Hematopoietic Stem Cell Function
author_facet Nagamachi, Akiko
Nakata, Yuichiro
Ueda, Takeshi
Yamasaki, Norimasa
Ebihara, Yasuhiro
Tsuji, Kohichiro
Honda, Zen-ichiro
Takubo, Keiyo
Suda, Toshio
Oda, Hideaki
Inaba, Toshiya
Honda, Hiroaki
author_sort Nagamachi, Akiko
title Acquired Deficiency of A20 Results in Rapid Apoptosis, Systemic Inflammation, and Abnormal Hematopoietic Stem Cell Function
title_short Acquired Deficiency of A20 Results in Rapid Apoptosis, Systemic Inflammation, and Abnormal Hematopoietic Stem Cell Function
title_full Acquired Deficiency of A20 Results in Rapid Apoptosis, Systemic Inflammation, and Abnormal Hematopoietic Stem Cell Function
title_fullStr Acquired Deficiency of A20 Results in Rapid Apoptosis, Systemic Inflammation, and Abnormal Hematopoietic Stem Cell Function
title_full_unstemmed Acquired Deficiency of A20 Results in Rapid Apoptosis, Systemic Inflammation, and Abnormal Hematopoietic Stem Cell Function
title_sort acquired deficiency of a20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function
description 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.
publisher Public Library of Science
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909109/
_version_ 1612053502540906496

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