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Mesothelium-Derived Factors Shape GATA6-Positive Large Cavity Macrophages
Chin-Wen Lai1, Prachi Bagadia1, Derek A G Barisas1
1Department of Pathology and Immunology, Washington University Medical School, St. Louis, MO.
Abstract:
The local microenvironment shapes macrophage differentiation in each tissue. We hypothesized that in the peritoneum, local factors in addition to retinoic acid can support GATA6-driven differentiation and function of peritoneal large cavity macrophages (LCMs). We found that soluble proteins produced by mesothelial cells lining the peritoneal cavity maintained GATA6 expression in cultured LCMs. Analysis of global gene expression of isolated mesothelial cells highlighted mesothelin (Msln) and its binding partner mucin 16 (Muc16) as candidate secreted ligands that potentially regulate GATA6 expression in peritoneal LCMs. Mice deficient for either of these molecules showed diminished GATA6 expression in peritoneal and pleural LCMs that was most prominent in aged mice. The more robust phenotype in older mice suggested that monocyte-derived macrophages were the target of Msln and Muc16. Cell transfer and bone marrow chimera experiments supported this hypothesis. We found that lethally irradiated Msln-/- and Muc16-/- mice reconstituted with wild-type bone marrow had lower levels of GATA6 expression in peritoneal and pleural LCMs. Similarly, during the resolution of zymosan-induced inflammation, repopulated peritoneal LCMs lacking expression of Msln or Muc16 expressed diminished GATA6. These data support a role for mesothelial cell-produced Msln and Muc16 in local macrophage differentiation within large cavity spaces such as the peritoneum. The effect appears to be most prominent on monocyte-derived macrophages that enter into this location as the host ages and also in response to infection.
Insights
Mesothelial cells produce mesothelin (Msln) and mucin 16 (Muc16), which are crucial for maintaining GATA6 expression in large cavity macrophages (LCMs). This interaction is particularly important in aging mice and during inflammation.
Area of Science:
- Immunology
- Cell Biology
- Microenvironment
Background:
- Tissue-specific microenvironments critically influence macrophage differentiation and function.
- Peritoneal macrophages (large cavity macrophages, LCMs) are influenced by local factors and retinoic acid.
- GATA6 is a key transcription factor in macrophage differentiation.
Purpose of the Study:
- To investigate the role of local factors, beyond retinoic acid, in supporting GATA6-driven differentiation of peritoneal LCMs.
- To identify specific secreted ligands from mesothelial cells that regulate GATA6 expression in LCMs.
Main Methods:
- Culturing LCMs with soluble proteins from mesothelial cells.
- Global gene expression analysis of mesothelial cells.
- Generating and analyzing mice deficient in mesothelin (Msln) and mucin 16 (Muc16).
- Bone marrow chimera experiments and adoptive cell transfers.
- Studying macrophage differentiation during zymosan-induced inflammation.
Main Results:
- Soluble mesothelial cell proteins maintained GATA6 expression in cultured LCMs.
- Mesothelin (Msln) and mucin 16 (Muc16) were identified as candidate secreted ligands.
- Mice lacking Msln or Muc16 exhibited reduced GATA6 expression in peritoneal and pleural LCMs, especially in aged mice.
- Cell transfer and chimera experiments confirmed Msln and Muc16 act on monocyte-derived macrophages.
- Reduced GATA6 expression was observed in LCMs lacking Msln or Muc16 during inflammation resolution.
Conclusions:
- Mesothelial cell-derived Msln and Muc16 play a significant role in regulating macrophage differentiation in large cavity spaces like the peritoneum.
- This regulation is particularly pronounced in monocyte-derived macrophages, especially in aging hosts and during inflammatory responses.
- Msln and Muc16 are key components of the peritoneal microenvironment that support LCM differentiation and function.
