Cardiotrophin-Like Cytokine Factor 1 Exhibits a Myeloid-Biased Hematopoietic-Stimulating Function
Cardiotrophin-Like Cytokine Factor 1 Exhibits a Myeloid-Biased Hematopoietic-Stimulating Function
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DOI：
10.3389/fimmu.2019.02133
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发表时间：
2019-09-10
影响因子：
7.3
通讯作者：
Rafei, Moutih
中科院分区：
文献类型：
--
作者：
Pasquin, Sarah;Tormo, Aurelie;Rafei, Moutih
心营养因子样细胞因子1 （CLCF1）与细胞因子受体样因子1 （CRLF1）复合物分泌。由编码CLCF1或CRLF1的基因突变引起的综合征表明CLCF1在免疫系统的发育和调节中起重要作用。在小鼠中，CLCF1诱导b细胞扩增，增强体液反应并触发自身免疫。有趣的是，CRLF1的失活会阻碍CLCF1的分泌，导致骨髓（BM）祖细胞数量显著减少，而CLCFI杂合小鼠的循环白细胞显著减少。因此，我们假设CLCF1可能参与造血功能的调节。为了验证这一假设，在体外用递增剂量的CLCF1处理被定义为Lin(-)Sca1(+)c-kit(+) （LSK）的小鼠造血祖细胞。CLCF1存在时，LSK细胞的频率和计数显著增加，这可能是由CLCF1诱导的几种可溶性因子介导的，包括IL-6、G-CSF、IL-1 β、IL-10和VEGF。CLCF1给药于未患病的C57BL/6小鼠，导致循环髓样细胞显著增加，这伴随着BM中LSK和髓样细胞计数的增加。同样，在亚致死照射或同源骨髓移植（BMT）后给小鼠CLCF1可加速LSK恢复，同时持续增加BM来源的CD11b（+）细胞。总之，我们的观察结果确立了CLCF1在调节造血功能中具有重要且不可预见的作用，并倾向于髓细胞分化。
Cardiotrophin-like cytokine factor 1 (CLCF1) is secreted as a complex with the cytokine receptor-like factor 1 (CRLF1). Syndromes caused by mutations in the genes encoding CLCF1 or CRLF1 suggest an important role for CLCF1 in the development and regulation of the immune system. In mice, CLCF1 induces B-cell expansion, enhances humoral responses and triggers autoimmunity. Interestingly, inactivation of CRLF1, which impedes CLCF1 secretion, leads to a marked reduction in the number of bone marrow (BM) progenitor cells, while mice heterozygous for CLCFI display a significant decrease in their circulating leukocytes. We therefore hypothesized that CLCF1 might be implicated in the regulation of hematopoiesis. To test this hypothesis, murine hematopoietic progenitor cells defined as Lin(-)Sca1(+)c-kit(+) (LSK) were treated in vitro with ascending doses of CLCF1. The frequency and counts of LSK cells were significantly increased in the presence of CLCF1, which may be mediated by several CLCF1 -induced soluble factors including IL-6, G-CSF, IL-1 beta, IL-10, and VEGF. CLCF1 administration to non-diseased C57BL/6 mice resulted in a pronounced increase in circulating myeloid cells, which was concomitant with augmented LSK and myeloid cell counts in the BM. Likewise, CLCF1 administration to mice following sub-lethal irradiation or congeneic BM transplantation (BMT) resulted in accelerated LSK recovery along with a sustained increase in BM-derived CD11b(+) cells. Altogether, our observations establish an important and unforeseen role for CLCF1 in regulating hematopoiesis with a bias toward myeloid cell differentiation.