Interferon-γ mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice.
Interferon-γ mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice.
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DOI：
10.1002/art.37958
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发表时间：
2013-07
影响因子：
--
通讯作者：
Behrens, Edward M.
中科院分区：
文献类型：
--
作者：
Canna, Scott W.;Wrobel, Julia;Chu, Niansheng;Kreiger, Portia A.;Paessler, Michele;Behrens, Edward M.
巨噬细胞活化综合征（Macrophage Activation Syndrome，MAS）是一种以发热、全血细胞减少和全身性炎症为特征的细胞因子风暴综合征。它在临床上类似于噬血细胞性嗜酸性组织细胞增多症（HLH），后者是由细胞毒性受损的宿主病毒感染引起的。MAS和HLH的小鼠模型说明干扰素-γ（IFN-γ）是噬血细胞作用和免疫病理学的驱动刺激。我们试图了解Toll样受体9（TLR 9）诱导的暴发性MAS的小鼠模型的炎症贡献者。用IL-10受体阻断抗体和TLR 9激动剂处理野生型（WT）、转基因和精氨酸抑制小鼠，并评价MAS参数。暴发性MAS的特征是IFN-γ、IL-12和IL-6显著升高。血清IFN-γ与某些肝细胞群中IFN-γ产生增强相关，但IFN-γ+细胞较少。令人惊讶的是，IFN-γKO小鼠发生了与WT小鼠不同的免疫病理学和噬血细胞作用。然而，IFN-γKO小鼠没有贫血，并且具有更多数量的脾红细胞前体。IFN-γKO小鼠中IL-12中和表型模拟疾病。有趣的是，I型干扰素有助于高细胞因子血症和体重减轻的严重程度，但它们的缺乏并没有影响MAS的表现。这些数据表明，暴发性MAS和噬血细胞作用可以独立于IFN-γ、IL-12或I型干扰素而出现。他们还表明，IFN-γ介导的红细胞生成异常，而不是噬血细胞作用，是暴发性TLR 9-MAS贫血的主要原因。因此，我们的数据建立了一个新的机制，急性贫血的炎症，但表明，多种触发因素可导致噬血细胞疾病。
Macrophage Activation Syndrome (MAS) is a devastating cytokine storm syndrome complicating many inflammatory diseases and characterized by fever, pancytopenia, and systemic inflammation. It is clinically similar to Hemophagocytic Lymphohistiocytosis (HLH), which is caused by viral infection of a host with impaired cellular cytotoxicity. Murine models of MAS and HLH illustrate Interferon-γ (IFN-γ) as the driving stimulus for hemophagocytosis and immunopathology. We sought to understand the inflammatory contributors to a murine model of Toll-like Receptor 9 (TLR9)-induced fulminant MAS. Wild-type (WT), transgenic, and cytokine-inhibited mice were treated with an IL-10 receptor blocking antibody and TLR9 agonist, and parameters of MAS were evaluated. Fulminant MAS was characterized by dramatic elevations in IFN-γ, IL-12, and IL-6. Serum IFN-γ correlated with enhanced IFN-γ production within some hepatic populations, but fewer IFN-γ+ cells. Surprisingly, IFN-γKO mice developed immunopathology and hemophagocytosis comparably to WT mice. However, IFN-γKO mice did not become anemic and had greater numbers of splenic erythroid precursors. IL-12 neutralization phenocopied disease in IFN-γKO mice. Interestingly, Type I interferons contributed to the severity of hypercytokinemia and weight loss, but their absence did not otherwise affect MAS manifestations. These data demonstrate that both fulminant MAS and hemophagocytosis can arise independently of IFN-γ, IL-12, or Type I interferons. They also suggest that IFN-γ-mediated dyserythropoiesis, not hemophagocytosis, is the dominant cause of anemia in fulminant TLR9-MAS. Thus, our data establish a novel mechanism for the acute anemia of inflammation, but suggest that a variety of triggers can result in hemophagocytic disease.
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影响因子：
20.3
作者：
Lykens, Jennifer E.;Terrell, Catherine E.;Jordan, Michael B.
通讯作者：
Jordan, Michael B.
在体内小鼠红细胞生成过程中，全局DNA脱甲基化。
DOI：
10.1126/science.1207306
发表时间：
2011-11-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Shearstone JR;Pop R;Bock C;Boyle P;Meissner A;Socolovsky M
通讯作者：
Socolovsky M
影响因子：
3.9
作者：
Maruyama, Junko;Inokuma, Shigeko
通讯作者：
Inokuma, Shigeko
DOI：
10.1016/s0889-8588(05)70521-9
发表时间：
1998-04-01
影响因子：
2.4
作者：
Janka, G;Imashuku, S;Henter, JI
通讯作者：
Henter, JI
影响因子：
5.1
作者：
Grom, AA;Villanueva, J;Filipovich, A
通讯作者：
Filipovich, A