Tracing LYVE1⁺ peritoneal fluid macrophages unveils two paths to resident macrophage repopulation with differing...

Area of Science:

• Immunology
• Cell Biology
• Tissue Regeneration

Background:

• Mouse resident peritoneal macrophages, known as large cavity macrophages (LCMs), originate from embryonic progenitors.
• Mature LCMs express CD73 and Gata6 (CD73+Gata6+).
• Monocytes are traditionally thought to replenish LCMs post-injury via a CD73-LYVE1+ intermediate.

Purpose of the Study:

• To investigate the mechanisms and pathways involved in replenishing resident peritoneal macrophages (LCMs) after injury.
• To clarify the role of CD73-LYVE1+ LCMs in the repopulation of the peritoneum.

Main Methods:

• Fate mapping studies in mice.
• Analysis of macrophage populations (CD73, Gata6, LYVE1) after irradiation and inflammation.
• Monocyte depletion experiments.
• Assessment of integrin-mediated interactions with mesothelial cells.

Main Results:

• CD73-LYVE1+ LCMs can differentiate into Gata6+CD73+ LCMs through interactions with mesothelial surfaces.
• Peritoneal repopulation by CD73-LYVE1+ LCMs is dependent on and proportional to monocyte recruitment.
• Unexpectedly, only ~10% of Gata6-dependent LCMs after injury relied on the LYVE1+ intermediate stage.
• Gata6+CD73+ LCMs rebounded efficiently after irradiation even in monocyte-poor conditions, suggesting an alternative pathway.

Conclusions:

• Two parallel pathways contribute to the replenishment of resident peritoneal macrophages after inflammatory insult.
• These pathways involve distinct differentiation intermediates with varying reliance on monocytes.
• The findings challenge the singular model of monocyte-derived CD73-LYVE1+ intermediates being the sole source for LCM regeneration.