CISH attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function.
CISH attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function.
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DOI：
10.1126/scisignal.abe5137
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发表时间：
2021-08-31
影响因子：
7.3
通讯作者：
Gottschalk RA
中科院分区：
文献类型：
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作者：
Shoger KE;Cheemalavagu N;Cao YM;Michalides BA;Chaudhri VK;Cohen JA;Singh H;Gottschalk RA
组织特异性细胞因子刺激协调常驻巨噬细胞的专门稳态功能。在肺部，细胞因子 GM-CSF 的稳态信号传导对于肺泡巨噬细胞 (AM) 的发育和功能至关重要。在这里，我们发现 CISH 是细胞因子信号传导抑制因子 (SOCS) 家族成员，由多种细胞因子刺激急性诱导，在 AM 中组成型表达，以响应稳态 GM-CSF 信号传导。 Cish 缺乏导致泡沫状 AM 的产生和肺表面活性物质的积累。这些表型变化与 STAT5、AKT 和 ERK 激活增强以及编码转录因子 GATA2 的 Gata2 表达增加相关。 Cish−/− AM 的 RNA 序列分析揭示了一组失调的免疫和脂质过程模块，包括富含 GATA2 结合基序的基因表达增加。最后，与 Cish 充足的细胞相比，Cish 缺陷的骨髓来源巨噬细胞在与支气管肺泡灌洗液一起孵育后，Gata2 表达增加，并积累更多脂质。因此，CISH 是限制稳态细胞因子信号传导和 Gata2 表达以维持 AM 身份和功能的反馈环路的一部分。
Tissue-specific cytokine stimuli orchestrate specialized homeostatic functions of resident macrophages. In the lung, steady-state signaling by the cytokine GM-CSF is critical for alveolar macrophage (AM) development and function. Here, we showed that CISH, a suppressor of cytokine signaling (SOCS) family member that is induced acutely by diverse cytokine stimuli, was expressed constitutively in AMs in response to steady-state GM-CSF signaling. Cish deficiency led to the generation of foamy AMs and the accumulation of pulmonary surfactant. These phenotypic changes were associated with enhanced activation of STAT5, AKT, and ERK, and increased expression of Gata2, which encodes the transcription factor GATA2. RNA-seq analysis of Cish−/− AMs revealed a set of dysregulated immune and lipid-process modules, including the increased expression of genes enriched for GATA2-binding motifs. Finally, Cish-deficient, bone marrow–derived macrophages showed increased Gata2 expression and accumulated more lipids upon incubation with bronchoalveolar lavage fluid compared with Cish-sufficient cells. Thus, CISH is part of a feedback loop that constrains homeostatic cytokine signaling and Gata2 expression to maintain AM identity and function.
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影响因子：
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作者：
Chia, Dennis J.;Rotwein, Peter
通讯作者：
Rotwein, Peter
急性髓样白血病细胞中的GATA因子依赖性阳性反馈回路。
影响因子：
8.8
作者：
Katsumura KR;Ong IM;DeVilbiss AW;Sanalkumar R;Bresnick EH
通讯作者：
Bresnick EH
影响因子：
4.8
作者：
Baldan, Angel;Tarr, Paul;Edwards, Peter A.
通讯作者：
Edwards, Peter A.
影响因子：
6.5
作者：
Baker, Anna D.;Malur, Anagha;Thomassen, Mary Jane
通讯作者：
Thomassen, Mary Jane
影响因子：
30.5
作者：
通讯作者：
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