C-FGF23 peptide alleviates hypoferremia during acute inflammation.
C-FGF23 peptide alleviates hypoferremia during acute inflammation.
复制标题
DOI：
10.3324/haematol.2019.237040
复制
发表时间：
2021-02-01
期刊：
影响因子：
10.1
通讯作者：
Sitara D
中科院分区：
文献类型：
--
作者：
Agoro R;Park MY;Le Henaff C;Jankauskas S;Gaias A;Chen G;Mohammadi M;Sitara D
低铁血症是对感染和炎症的急性期反应，目的是减少病原体对铁的利用。Toll样受体（TLR）是先天免疫系统的关键感受器，其激活主要通过铁激素铁调素的升高诱导低铁血症。相反，刺激红细胞生成通过诱导红细胞生成素应答激素erythroferrone抑制铁调素表达。缺铁刺激骨细胞分泌的蛋白质FGF23的转录。在这里，我们假设，诱导FGF23响应于TLR 4激活是一个有效的贡献者低铁血症，因此，其活性的损害可能会减轻脂多糖（LPS），TLR 4激动剂诱导的低铁血症。我们使用FGF 23的C末端尾来损害野生型小鼠中的内源性全长FGF 23信号传导，并研究其对低铁血症的影响。我们的数据显示，FGF23早在响应于LPS时作为促炎细胞因子被诱导，随后除了降低血清铁和转铁蛋白饱和度之外，还上调铁调素和下调促红细胞生成素（Epo）表达。此外，LPS诱导的肝和循环铁调素通过FGF 23信号传导破坏显著降低。因此，由TLR4活化引起的肝脏和脾脏中的铁螯合被FGF 23信号传导抑制完全消除，导致血清铁和转铁蛋白饱和缺陷的减轻。综上所述，我们的研究首次强调了抑制FGF 23信号传导可加重LPS诱导的急性低铁血症。
Hypoferremia results as an acute phase response to infection and inflammation aiming to reduce iron availability to pathogens. Activation of toll-like receptors (TLR), the key sensors of the innate immune system, induces hypoferremia mainly through the rise of the iron hormone hepcidin. Conversely, stimulation of erythropoiesis suppresses hepcidin expression via induction of the erythropoietin-responsive hormone erythroferrone. Iron deficiency stimulates transcription of the osteocyte- secreted protein FGF23. Here we hypothesized that induction of FGF23 in response to TLR4 activation is a potent contributor to hypoferremia and, thus, impairment of its activity may alleviate hypoferremia induced by lipopolysaccharide (LPS), a TLR 4 agonist. We used the C-terminal tail of FGF23 to impair endogenous full-length FGF23 signaling in wildtype mice, and investigated its impact on hypoferremia. Our data show that FGF23 is induced as early as pro-inflammatory cytokines in response to LPS, followed by upregulation of hepcidin and downregulation of erythropoietin (Epo) expression in addition to decreased serum iron and transferrin saturation. Further, LPS-induced hepatic and circulating hepcidin were significantly reduced by FGF23 signaling disruption. Accordingly, iron sequestration in liver and spleen caused by TLR4 activation was completely abrogated by FGF23 signaling inhibition, resulting in alleviation of serum iron and transferrin saturation deficit. Taken together, our studies highlight for the first time that inhibition of FGF23 signaling alleviates LPS-induced acute hypoferremia.
登录
查看更多内容
影响因子：
20.3
作者：
Arezes, Joao;Foy, Niall;Drakesmithm, Hal
通讯作者：
Drakesmithm, Hal
影响因子：
13.6
作者：
Babitt, Jodie L.;Lin, Herbert Y.
通讯作者：
Lin, Herbert Y.
影响因子：
6.1
作者：
Bansal, Shweta;Friedrichs, William E.;Fanti, Paolo
通讯作者：
Fanti, Paolo
DOI：
10.1152/ajprenal.90742.2008
发表时间：
2009-08-01
影响因子：
4.2
作者：
Gattineni, Jyothsna;Bates, Carlton;Baum, Michel
通讯作者：
Baum, Michel
影响因子：
7.4
作者：
Haase VH
通讯作者：
Haase VH