MMP8 mediates CD115 cleavage-dependent elimination of large peritoneal macrophages in response to microbial exposure

Macrophages, critical for tissue homeostasis and immune regulation, undergo significant changes during microbial infections. Certain inflammatory conditions can trigger the loss of these macrophages through a process called macrophage disappearance reaction (MDR), which, in turn, affects the ongoing immune response. Here, we show that the presence of bacteria in the peritoneal cavity, which can be mimicked by Toll-like receptor (TLR) stimulation, leads to loss of cell surface CD115, also known as macrophage colony-stimulating factor receptor (M-CSFR). This loss renders macrophages unresponsive to M-CSF signaling and induces their disappearance. MMP8, an enzyme released by macrophages in response to LPS, was responsible for CD115 cleavage and its subsequent loss from the cell surface during MDR, establishing a biochemical mechanism for this phenomenon. Our findings extended to human cells, highlighting the role of MMP8 in CD115 shedding. This study enhances our understanding of MDR initiation and proposes a regulatory mechanism for inflammatory responses by restricting essential growth factors.