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Isolation of Murine Peritoneal Macrophages to Carry Out Gene Expression Analysis Upon Toll-like Receptors Stimulation
Published on: April 29, 2015
MMP8 mediates CD115 cleavage-dependent elimination of large peritoneal macrophages in response to microbial exposure
Shilpi Giri1, Andrew T Martin1, Alexandra Safronova1
1Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.
Abstract:
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.
Insights
Bacterial infections cause macrophages to lose cell surface CD115 (M-CSFR) via MMP8 enzyme activity, leading to macrophage disappearance. This mechanism explains the macrophage disappearance reaction (MDR) and impacts immune responses.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Macrophages are crucial for tissue homeostasis and immune regulation.
- Microbial infections and inflammation can trigger macrophage loss via the macrophage disappearance reaction (MDR).
- The mechanisms underlying MDR and its impact on immune responses require further elucidation.
Purpose of the Study:
- To investigate the molecular mechanisms driving macrophage disappearance during infection.
- To identify the specific molecules involved in the loss of macrophages during the MDR.
- To understand how this process affects macrophage signaling and inflammatory responses.
Main Methods:
- Utilized bacterial infection and Toll-like receptor (TLR) stimulation models in vivo.
- Quantified changes in cell surface CD115 (M-CSFR) expression on macrophages.
- Assessed the role of matrix metalloproteinase 8 (MMP8) in CD115 cleavage and shedding.
- Investigated the functional consequences of CD115 loss on M-CSF signaling and macrophage survival.
Main Results:
- Bacterial presence or TLR stimulation led to the loss of cell surface CD115 (M-CSFR) on macrophages.
- This CD115 loss rendered macrophages unresponsive to M-CSF signaling, inducing their disappearance.
- MMP8, released by macrophages upon LPS stimulation, was identified as the enzyme responsible for CD115 cleavage and shedding during MDR.
- The findings were corroborated in human cells, confirming MMP8's role in CD115 shedding.
Conclusions:
- MMP8-mediated cleavage and shedding of CD115 (M-CSFR) is a key mechanism initiating the macrophage disappearance reaction (MDR).
- This process limits M-CSF signaling, contributing to macrophage loss during infection and inflammation.
- The study provides novel insights into the regulation of inflammatory responses by controlling essential growth factor signaling.
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