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 acutely induced by diverse cytokine stimuli in many tissues, 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 the gene encoding 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. Last, Cish-deficient, bone marrow–derived macrophages showed increased Gata2 expression and accumulated more lipid 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.

中文翻译：

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CISH 减弱稳态细胞因子信号以促进肺特异性巨噬细胞编程和功能。

组织特异性细胞因子刺激协调驻留巨噬细胞的特殊稳态功能。在肺中，细胞因子 GM-CSF 的稳态信号传导对肺泡巨噬细胞 (AM) 的发育和功能至关重要。在这里，我们发现 CISH 是一种细胞因子信号 (SOCS) 家族成员的抑制因子，它在许多组织中由多种细胞因子刺激急性诱导，在 AMs 中组成性表达以响应稳态 GM-CSF 信号。Cish 缺乏导致泡沫状 AMs 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 的激活增强以及编码转录因子 GATA2 的基因表达增加有关。Cish-/- AMs 的 RNA-seq 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 缺陷型骨髓来源的巨噬细胞在与支气管肺泡灌洗液孵育时显示 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和 Gata2 表达以维持 AM 身份和功能的反馈回路的一部分。