A Stromal Niche Defined by Expression of the Transcription Factor WT1 Mediates Programming and Homeostasis of Cavity-Resident Macrophages.

Immunity. 2019 Jul 16;51(1):119-130.e5. doi: 10.1016/j.immuni.2019.05.010. | PubMed

Matthew B Buechler¹, Ki-Wook Kim², Emily J Onufer³, Jesse W Williams², Christine C Little¹, Claudia X Dominguez¹, Qingling Li⁴, Wendy Sandoval⁴, Jonathan E Cooper⁵, Charles A Harris⁶, Melissa R Junttila⁵, Gwendalyn J Randolph², Shannon J Turley⁷

1. Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
3. Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
4. Microchemistry and Proteomics, Genentech, South San Francisco, CA 94080, USA.
5. Translational Oncology, Genentech, South San Francisco, CA 94080, USA.
6. Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
7. Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA. Electronic address: turley.shannon@gene.com.

Abstract

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.

Presented By Matthew Buechler