Toll-like receptor 9 and interferon-γ receptor signaling suppress the B-cell fate of uncommitted progenitors in mice.
Toll-like receptor 9 and interferon-γ receptor signaling suppress the B-cell fate of uncommitted progenitors in mice.
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DOI：
10.1002/eji.201445319
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发表时间：
2015-05
影响因子：
5.4
通讯作者：
Behrens EM
中科院分区：
文献类型：
--
作者：
Baratono SR;Chu N;Richman LP;Behrens EM
全身炎症反应综合征描述了一组不同的细胞因子风暴障碍，不同的免疫原和细胞因子导致器官病理的变化。细胞因子风暴产生的严重炎症导致广泛的器官病理，包括T和B淋巴细胞计数的变化。这项研究探讨了TLR9和干扰素-γR刺激在减少T细胞和B细胞在高炎症小鼠模型中的作用。我们证明在TLR9和干扰素-γ驱动的从Ly-6D+共同淋巴祖细胞(CLP)阶段开始的过度炎症中，早期B细胞的淋巴生成严重受损，在多个阶段具有不同的抑制发展的作用。我们发现，在体外，TLR9信号直接降低B细胞的产量，而增加T细胞的产量。干扰素-γ在体外也能直接抑制B细胞和T细胞的分化，体内也能被TLR9诱导。LY-6D−基因芯片和RT-PCRs分析表明，HOXa9和EBF-1是被TLR9诱导炎症改变的转录因子。我们的工作表明，在持续的TLR9和干扰素-γ驱动的炎症中，细胞和分子靶点导致B细胞淋巴生成减少，这可能与许多感染和自身免疫/炎症环境有关。
Systemic inflammatory response syndrome describes a heterogeneous group of cytokine storm disorders, with different immunogens and cytokines leading to variations in organ pathology. The severe inflammation generated by the cytokine storm results in widespread organ pathology including alterations in T-and B-lymphocyte counts. This study explores the roles of TLR9 and IFN-γR stimulation in decreasing T- and B-cell lymphopoiesis in a mouse model of hyperinflammation. We demonstrate that early B-cell lymphopoiesis is severely compromised during TLR9 and IFN-γ driven hyperinflammation from the Ly-6D+ common lymphoid progenitor (CLP) stage onwards with different effects inhibiting development at multiple stages. We show that TLR9 signaling directly decreases in vitro B-cell yields while increasing T-cell yields. IFN-γ also directly inhibits B-cell and T-cell differentiation in vitro as well as when induced by TLR9 in vivo. Microarray and RT-PCR analysis of Ly-6D− CLPs point to HOXa9 and EBF-1 as transcription factors altered by TLR9 induced inflammation. Our work demonstrates both cellular and molecular targets that lead to diminished B-cell lymphopoiesis in sustained TLR9 and IFN-γ driven inflammation that may be relevant in a number of infectious and autoimmune/inflammatory settings.