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

Matthew B. Buechler, Ki Wook Kim, Emily J. Onufer, Jesse W. Williams, Christine C. Little, Claudia X. Dominguez, Qingling Li, Wendy Sandoval, Jonathan E. Cooper, Charles A. Harris, Melissa R. Junttila, Gwendalyn J. Randolph, Shannon J. Turley

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)119-130.e5
JournalImmunity
Volume51
Issue number1
DOIs
StatePublished - Jul 16 2019
Externally publishedYes

Bibliographical note

Funding Information:
We acknowledge members of the Turley and Randolph labs for their useful discussions and assistance in the laboratory. We thank facility staff at Genentech and Washington University in St. Louis for vivarium maintenance and core facility assistance and N.W. Lounsbury and S. Lianoglou for management of sequencing files. We express gratitude to A.M. Berkley for her careful review of this manuscript. We also acknowledge technical support from BioRender for the graphical abstract. This work was supported by Genentech, NIH grants R37 AI049653 and DP1DK109668 to G.J.R., K99 HL138163 to J.W.W., and T32 DK077653 to E.J.O.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • Fibroblasts
  • Macrophages
  • Mesothelial cells
  • Retinoic acid
  • WT1
  • Mice, Inbred C57BL
  • Cells, Cultured
  • Homeostasis
  • Pleural Cavity/immunology
  • Mice, Transgenic
  • Peritoneal Cavity/physiology
  • GATA6 Transcription Factor/genetics
  • Stromal Cells/physiology
  • Repressor Proteins/genetics
  • Pericardium/immunology
  • Animals
  • Cell Differentiation
  • Mice
  • Macrophages/physiology
  • Tretinoin/metabolism

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural

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