Fetal origin confers radioresistance on liver macrophages via p21cip1/WAF1

被引:31
作者
Soysa, Radika [1 ]
Lampert, Sarah [2 ]
Yuen, Sebastian [2 ]
Douglass, Alyse N. [1 ]
Li, Wanyu [3 ]
Pfeffer, Klaus [4 ]
Crispe, Ian N. [2 ,5 ]
机构
[1] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA
[2] Univ Washington, Dept Pathol, 1959 Northeast Pacific St, Seattle, WA 98195 USA
[3] Jilin Univ, Hosp 1, Dept Hepatol, Changchun, Jilin, Peoples R China
[4] Heinrich Heine Univ, Inst Med Microbiol & Hosp Hyg, Dusseldorf, Germany
[5] Univ Washington, Dept Immunol, Seattle, WA 98195 USA
基金
美国国家卫生研究院;
关键词
Cdkn1a; Irradiation; Kupffer cells; Monocytes; RiboTag; EXPRESSION PROFILES; CARDIAC MACROPHAGES; ANALYSIS REVEALS; KUPFFER CELLS; MYELOID CELLS; MICROGLIA; P21; MECHANISMS; MONOCYTES; PATHWAYS;
D O I
10.1016/j.jhep.2019.04.015
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Cells of hematopoietic origin, including macrophages, are generally radiation sensitive, but a subset of Kupffer cells (KCs) is relatively radioresistant. Here, we focused on the identity of the radioresistant KCs in unmanipulated mice and the mechanism of radioresistance. Methods: We employed Emr1- and inducible CX3Cr1-based fate-mapping strategies combined with the RiboTag reporter to identify the total KCs and the embryo-derived KCs, respectively. The KC compartment was reconstituted with adult bone-marrow-derived KCs (bm-KCs) using clodronate depletion. Mice were lethally irradiated and transplanted with donor bone marrow, and the radioresistance of bone-marrowor embryo-derived KCs was studied. Gene expression was analyzed using in situ mRNA isolation via RiboTag reporter mice, and the translatomes were compared among subsets. Results: Here, we identified the radioresistant KCs as the long-lived subset that is derived from CX3CR1-expressing progenitor cells in fetal life, while adult bm-KCs do not resist irradiation. While both subsets upregulated the Cdkn1a gene, encoding p21-(cip1)(/)(WAF1) protein, radioresistant embryo-derived KCs showed a greater increase in response to irradiation. In the absence of this molecule, the radioresistance of KCs was compromised. Replacement KCs, derived from adult hematopoietic stem cells, differed from radioresistant KCs in their expression of genes related to immunity and phagocytosis. Conclusions: Here, we show that, in the murine liver, a subset of KCs of embryonic origin resists lethal irradiation through Cdkn1a upregulation and is maintained for a long period, while bm-KCs do not survive lethal irradiation. Lay summary: Kupffer cells (KCs) are the tissue-resident macrophages of the liver. KCs can be originated from fetal precursors and from monocytes during the fetal stage and post-birth, respectively. Most immune cells in mice are sensitive to lethal-irradiation-induced death, while a subset of KCs resists radiation-induced death. These radioresistant KCs continue to live in the irradiated mice. We discovered that this relatively radioresistant KC subset are the fetal-derived KCs, and they achieve this through cell-cycle arrest. Understanding the radiobiology of KCs will provide valuable insights into the mechanisms that elicit radiation-induced liver disease. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
引用
收藏
页码:553 / 562
页数:10
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