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Published on: April 29, 2015
VSIG4-Expressing Macrophages Contribute to Antiparasitic and Antimetastatic Responses in the Peritoneal Cavity
Els Lebegge1,2, Daliya Kancheva1,2,3, Jolien Van Craenenbroeck1,2
1Laboratory of Cellular and Molecular Immunology, Brussels Center for Immunology (BCIM), Vrije Universiteit Brussel, Brussels, Belgium.
Abstract:
Large peritoneal macrophages (LPMs) play a role as gatekeepers of peritoneal homeostasis by providing a first line of defense against pathogens. A third of the LPMs express the surface receptor VSIG4, but it is unclear whether these cells differ from their VSIG4-negative counterparts and perform dedicated functions. We demonstrate that VSIG4+, but not VSIG4-, LPMs are in the majority derived from embryonal precursors, and their occurrence is largely independent of sex and microbiota but increases with age. Although their transcriptome and surface proteome are indistinguishable from VSIG4- LPMs at steady-state, VSIG4+ LPMs are superior in phagocytosing S. aureus bioparticles and colorectal carcinoma (CRC) cells. Anti-VSIG4 nanobody constructs that are ADCC-enabled allowed a selective elimination of the VSIG4+ LPM subset without affecting overall LPM abundance. This strategy uncovered a role for VSIG4+ LPMs in lowering the first peak of parasitemia in a Trypanosoma brucei brucei infection model and in reducing CRC outgrowth in the peritoneal cavity, a prime metastatic site in CRC patients. Altogether, our data uncover a protective role for VSIG4+ LPMs in infectious and oncological diseases in the peritoneal cavity.
Insights
Large peritoneal macrophages (LPMs) expressing VSIG4 are derived from embryonic precursors and protect against infections and cancer. Eliminating these VSIG4+ LPMs revealed their crucial role in controlling pathogens and colorectal cancer growth.
Area of Science:
- Immunology
- Cell Biology
- Oncology
Background:
- Large peritoneal macrophages (LPMs) are key immune cells in the peritoneum.
- A subset of LPMs expresses the surface receptor VSIG4, but their specific function is unknown.
Purpose of the Study:
- To investigate the distinct functions of VSIG4-positive (VSIG4+) LPMs compared to VSIG4-negative (VSIG4-) LPMs.
- To explore the role of VSIG4+ LPMs in infectious and oncological diseases.
Main Methods:
- Flow cytometry and single-cell RNA sequencing to characterize LPM subsets.
- Phagocytosis assays using S. aureus bioparticles and colorectal cancer (CRC) cells.
- Development of ADCC-enabled anti-VSIG4 nanobodies for selective cell depletion.
- Infection models (Trypanosoma brucei brucei) and CRC peritoneal metastasis models.
Main Results:
- VSIG4+ LPMs originate predominantly from embryonic precursors and increase with age.
- Despite similar transcriptomes, VSIG4+ LPMs exhibit enhanced phagocytosis of bacteria and CRC cells.
- Selective elimination of VSIG4+ LPMs impaired control of T. brucei brucei infection and promoted CRC outgrowth.
- VSIG4+ LPMs play a protective role in peritoneal infections and CRC metastasis.
Conclusions:
- VSIG4+ LPMs represent a distinct, functionally specialized subset of peritoneal macrophages.
- These cells are crucial for defense against peritoneal infections and limiting colorectal cancer progression.
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