Regulation of CD11b by HIF-1α and the STAT3 signaling pathway contributes to the immunosuppressive function of B cells in inflammatory bowel disease
Regulation of CD11b by HIF-1α and the STAT3 signaling pathway contributes to the immunosuppressive function of B cells in inflammatory bowel disease
复制标题
HIF-1 α 和 STAT3 信号通路对 CD11b 的调节有助于炎症性肠病中 B 细胞的免疫抑制功能
DOI：
10.1016/j.molimm.2019.04.005
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发表时间：
2019-07-01
影响因子：
3.6
通讯作者：
Chu, Yiwei
中科院分区：
文献类型：
--
作者：
Qian, Tingting;Hong, Jiaxu;Chu, Yiwei
据报道，B细胞在自身免疫性疾病中具有抑制功能，这似乎需要增加B细胞上CD11b的表达。然而，对于如何在B细胞中诱导CD11b发挥这一功能，我们所知甚少。本研究发现，在葡聚糖硫酸钠（dextran sulfate sodium， DSS）诱导的结肠炎期间，B细胞中CD11b的高表达不仅发生在粘膜免疫器官，也发生在脾脏等全身免疫器官。由于炎症性肠病（IBD）小鼠模型中的炎症病变显示出明显的缺氧甚至缺氧，因此研究了结肠炎小鼠Peyer's patches （PP）的B细胞比野生型（WT）小鼠的幼稚B细胞表达更高水平的缺氧诱导因子-1 α (HIF-1 α)。转染HIF-1 α siRNA或抑制HIF-1 α蛋白可导致体外CD11b mRNA和蛋白水平的表达降低。然后将HIF-1 α特异性敲除的B细胞过继转移到rag1（-/-）小鼠。结果显示，CD11b在B细胞中表达降低，结肠炎加重。生物信息学启动子分析和ChIP实验表明HIF-1 α是CD11b的关键转录因子，并与p-STAT3同型二聚体协同形成复合物结合到HRE区域，这是MEK/ERK通路激活和IL-10分泌的保证。总之，我们的研究证明了缺氧相关转录因子HIF-1 α和p-STAT3在实验性炎症性肠病（IBD）中驱动B细胞CD11b转录和控制B细胞保护活性的关键功能。
B cells have been reported to have a suppressive function in autoimmune diseases, which appears to require an increase of CD11b expression on B cells. However, little is known how CD11b is induced in B cells to play the function. In this study, we found that the high expression of CD11b in B cells occurred not only in the mucosal immune organs, but also in systemically immune organs such as the spleen during dextran sulfate sodium (DSS)-induced colitis. Since the inflammatory lesions in mouse models of inflammatory bowel disease (IBD) were revealed to be significantly hypoxic or even anoxic, the B cells from colitic mice Peyer's patches (PP) were investigated to express higher levels of hypoxia-inducible factor-1 alpha (HIF-1 alpha) than naive B cells from wildtype (WT) mice. HIF-1 alpha siRNA transfection or HIF-1 alpha protein inhibition led to decreased CD11b expression at both the mRNA and protein levels in vitro. B cells with HIF-1 alpha specific knockdown were then adoptively transferred to Rag-1(-/-) mice. The result displayed that CD11b expression was decreased in B cells and an exacerbated colitis occurred. The bio-informatics promoter analysis and ChIP assay showed that HIF-1 alpha was the critical transcription factor for CD11b and cooperatively formed a complex with the p-STAT3 homodimers to bind onto hypoxia-responsive element (HRE) regions, which was guaranteed by MEK/ERK pathway activation and IL-10 secretion. In conclusion, our study demonstrated the key function of the hypoxia-associated transcription factor HIF-1 alpha together with p-STAT3 in driving CD11b transcription in B cells and controlling B cell's protective activity in experimental inflammatory bowel disease (IBD).