A Stromal Niche Defined by Expression of the Transcription Factor WT1 Mediates Programming and Homeostasis of Cavity-Resident Macrophages
A Stromal Niche Defined by Expression of the Transcription Factor WT1 Mediates Programming and Homeostasis of Cavity-Resident Macrophages
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DOI：
10.1016/j.immuni.2019.05.010
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发表时间：
2019-07-16
期刊：
影响因子：
32.4
通讯作者：
Turley, Shannon J.
中科院分区：
文献类型：
--
作者：
Buechler, Matthew B.;Kim, Ki-Wook;Turley, Shannon J.
组织驻留巨噬细胞需要特定的环境来维持定义的基因表达程序。转录因子GATA6的表达是腹膜腔驻留巨噬细胞的稳态、功能和定位所必需的。Gata 6表达以非细胞自主方式维持，并由维生素A代谢物视黄酸引起。在这里，我们发现GATA 6转录程序是所有内脏体腔中巨噬细胞的共同特征。GATA 6（+）巨噬细胞的视黄酸依赖性和非依赖性标志基因由表达转录因子Wilms' Tumor 1（WT 1）的间皮细胞和成纤维细胞基质细胞诱导，其驱动视黄醇代谢中两种限速酶的表达。Wt1（+）基质细胞的耗竭降低了腹膜、胸膜和心包腔中GATA 6（+）巨噬细胞的频率。因此，Wt1（+）间皮细胞和成纤维细胞基质细胞构成了支持组织特异性转录景观和腔驻留巨噬细胞稳态的基本生态位组分。
Tissue-resident macrophages require specific milieus for the maintenance of defining gene-expression programs. Expression of the transcription factor GATA6 is required for the homeostasis, function and localization of peritoneal cavity-resident macrophages. Gata6 expression is maintained in a non-cell autonomous manner and is elicited by the vitamin A metabolite, retinoic acid. Here, we found that the GATA6 transcriptional program is a common feature of macrophages residing in all visceral body cavities. Retinoic acid-dependent and -independent hallmark genes of GATA6(+) macrophages were induced by mesothelial and fibroblastic stromal cells that express the transcription factor Wilms' Tumor 1 (WT1), which drives the expression of two rate-limiting enzymes in retinol metabolism. Depletion of Wt1(+) stromal cells reduced the frequency of GATA6(+) macrophages in the peritoneal, pleural and pericardial cavities. Thus, Wt1(+) mesothelial and fibroblastic stromal cells constitute essential niche components supporting the tissue-specifying transcriptional landscape and homeostasis of cavity-resident macrophages.