MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation.
MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation.
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DOI：
10.1038/leu.2017.137
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发表时间：
2017-12
期刊：
影响因子：
11.4
通讯作者：
Zeiser R
中科院分区：
文献类型：
--
作者：
Stickel N;Hanke K;Marschner D;Prinz G;Köhler M;Melchinger W;Pfeifer D;Schmitt-Graeff A;Brummer T;Heine A;Brossart P;Wolf D;von Bubnoff N;Finke J;Duyster J;Ferrara J;Salzer U;Zeiser R
急性移植物抗宿主病（GVHD）是同种异体造血细胞移植后的主要免疫并发症，更好地了解这种疾病的分子调控有助于开发新的靶向治疗方法。在这里，我们发现移植受体的人microRNA-146a （miR-146a）基因中的G/C多态性，导致miR-146a水平降低，与发生严重急性GVHD的风险密切相关（n=289）。在小鼠中，造血系统中miR-146a的缺乏或受体型miR-146a -/-树突状细胞（dc）的转移会增强GVHD，而miR-146a模拟转染的dc则会改善疾病。在机制上，miR-146a的缺乏增强了JAK2 stat1通路的活性，导致ii类反激活因子（CIITA）的表达增加，并连续增加dc上的mhcii水平。抑制dc中JAK1/2或CIITA敲低可阻止miR-146a-/- dc诱导的GVHD恶化。与我们在小鼠中的研究结果一致，造血细胞中miR-146a多态性rs2910164的患者在单核细胞上显示更高的MHCII水平，这可以通过jak1 /2抑制来靶向。我们的研究结果表明，miR-146a多态性rs2910164在允许HCT之前识别出GVHD高风险患者。在功能上，我们发现miR-146a通过抑制促炎的JAK-STAT/CIITA/MHCII轴，在GVHD期间作为受体型DC激活的中心调节剂，这为选定患者的早期jak1 /2抑制提供了科学依据。
Acute Graft-versus-host disease (GVHD) is a major immunological complication after allogeneic hematopoietic cell transplantation and a better understanding of the molecular regulation of the disease could help to develop novel targeted therapies. Here we found that a G/C polymorphism within the human microRNA-146a (miR-146a) gene of transplant-recipients, which causes reduced miR-146a levels, was strongly associated with the risk of developing severe acute GVHD (n=289). In mice, deficiency of miR-146a in the hematopoietic system or transfer of recipient-type miR 146a-/- dendritic cells (DCs) enhanced GVHD, while miR-146a mimic-transfected-DCs ameliorated disease. Mechanistically, lack of miR-146a enhanced JAK2 STAT1-pathway activity, which led to higher expression of class II-transactivator (CIITA) and consecutively increased MHCII-levels on DCs. Inhibition of JAK1/2 or CIITA knockdown in DCs prevented miR-146a-/- DC-induced GVHD exacerbation. Consistent with our findings in mice, patients with the miR-146a polymorphism rs2910164 in hematopoietic cells displayed higher MHCII levels on monocytes, which could be targeted by JAK1/2-inhibition. Our findings indicate that the miR-146a polymorphism rs2910164 identifies patients at high risk for GVHD before allo HCT. Functionally we show that miR-146a acts as a central regulator of recipient-type DC activation during GVHD by dampening the pro-inflammatory JAK-STAT/CIITA/MHCII axis, which provides a scientific rationale for early JAK1/2-inhibition in selected patients.
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结核分枝杆菌对抗原呈递的调节：Toll 样受体的作用。
DOI：
10.1038/nrmicro2321
发表时间：
2010-04
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.4
作者：
Zeiser R;Burchert A;Lengerke C;Verbeek M;Maas-Bauer K;Metzelder SK;Spoerl S;Ditschkowski M;Ecsedi M;Sockel K;Ayuk F;Ajib S;de Fontbrune FS;Na IK;Penter L;Holtick U;Wolf D;Schuler E;Meyer E;Apostolova P;Bertz H;Marks R;Lübbert M;Wäsch R;Scheid C;Stölzel F;Ordemann R;Bug G;Kobbe G;Negrin R;Brune M;Spyridonidis A;Schmitt-Gräff A;van der Velden W;Huls G;Mielke S;Grigoleit GU;Kuball J;Flynn R;Ihorst G;Du J;Blazar BR;Arnold R;Kröger N;Passweg J;Halter J;Socié G;Beelen D;Peschel C;Neubauer A;Finke J;Duyster J;von Bubnoff N
通讯作者：
von Bubnoff N
影响因子：
4.4
作者：
Jurkin, Jennifer;Schichl, Yvonne M.;Strobl, Herbert
通讯作者：
Strobl, Herbert
DOI：
10.1073/pnas.0802682105
发表时间：
2008-05-20
影响因子：
11.1
作者：
Jazdzewski, Krystian;Murray, Elizabeth L.;de la Chapelle, Albert
通讯作者：
de la Chapelle, Albert
影响因子：
2.8
作者：
Yang, Yan;Zhang, Kui;Zhou, Rong
通讯作者：
Zhou, Rong