Innate immune system activation in zebrafish and cellular models of Diamond Blackfan Anemia.
Innate immune system activation in zebrafish and cellular models of Diamond Blackfan Anemia.
复制标题
DOI：
10.1038/s41598-018-23561-6
复制
发表时间：
2018-03-26
影响因子：
4.6
通讯作者：
Lin S
中科院分区：
文献类型：
--
作者：
Danilova N;Wilkes M;Bibikova E;Youn MY;Sakamoto KM;Lin S
核糖体蛋白（RP）缺乏导致与贫血、先天性缺陷和癌症相关的钻石黑扇贫血（DBA）。虽然p53激活是DBA的许多特征的原因，但免疫系统的作用还不太明确。先天免疫系统可以被来自DBA中发生的未加工的前rRNA、DNA损伤和细胞凋亡的内源性核酸激活。Toll样受体（TLR）和Mda5样传感器的识别诱导干扰素（IFN）和炎症。死亡细胞也可以激活补体系统。因此，我们分析了RP缺陷斑马鱼中这些途径的状态，发现干扰素、炎性细胞因子和介质以及补体的上调。我们还发现了IFN受体信号传导的上调，包括Mda5，Tlr3和Tlr9。TGF β家族成员激活素也在RP缺陷型斑马鱼和RPS19缺陷型人类细胞中上调，所述人类细胞包括来自DBA患者的淋巴细胞系、以及用RPS19 shRNA转导的胎肝细胞和K562细胞。用TLR3抑制剂治疗RP缺陷的斑马鱼降低了IFN活化、急性期反应和细胞凋亡，并改善了它们的造血和形态。补体和激活素的抑制剂也有有益的效果。我们的研究表明，先天免疫系统有助于RPS19缺陷的斑马鱼和人类细胞的表型。
Deficiency of ribosomal proteins (RPs) leads to Diamond Blackfan Anemia (DBA) associated with anemia, congenital defects, and cancer. While p53 activation is responsible for many features of DBA, the role of immune system is less defined. The Innate immune system can be activated by endogenous nucleic acids from non-processed pre-rRNAs, DNA damage, and apoptosis that occurs in DBA. Recognition by toll like receptors (TLRs) and Mda5-like sensors induces interferons (IFNs) and inflammation. Dying cells can also activate complement system. Therefore we analyzed the status of these pathways in RP-deficient zebrafish and found upregulation of interferon, inflammatory cytokines and mediators, and complement. We also found upregulation of receptors signaling to IFNs including Mda5, Tlr3, and Tlr9. TGFb family member activin was also upregulated in RP-deficient zebrafish and in RPS19-deficient human cells, which include a lymphoid cell line from a DBA patient, and fetal liver cells and K562 cells transduced with RPS19 shRNA. Treatment of RP-deficient zebrafish with a TLR3 inhibitor decreased IFNs activation, acute phase response, and apoptosis and improved their hematopoiesis and morphology. Inhibitors of complement and activin also had beneficial effects. Our studies suggest that innate immune system contributes to the phenotype of RPS19-deficient zebrafish and human cells.
登录
查看更多内容
影响因子：
4.4
作者：
Avondo F;Roncaglia P;Crescenzio N;Krmac H;Garelli E;Armiraglio M;Castagnoli C;Campagnoli MF;Ramenghi U;Gustincich S;Santoro C;Dianzani I
通讯作者：
Dianzani I
影响因子：
6.5
作者：
Danilova N;Sakamoto KM;Lin S
通讯作者：
Lin S
DOI：
10.1073/pnas.1615771114
发表时间：
2017-02-28
影响因子：
11.1
作者：
Feeley, Eric M.;Pilla-Moffett, Danielle M.;Coers, Joern
通讯作者：
Coers, Joern
影响因子：
20.3
作者：
Choesmel, Valerie;Bacqueville, Daniel;Gleizes, Pierre-Emmanuel
通讯作者：
Gleizes, Pierre-Emmanuel
影响因子：
20.3
作者：
Flygare, Johan;Aspesi, Anna;Ellis, Steven R.
通讯作者：
Ellis, Steven R.