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Regulation of early peritoneal neutrophil migration by macrophage inflammatory protein-2 and mast cells in
M A Mercer-Jones1, M S Shrotri, M Heinzelmann
1Veterans Affairs Medical Center, and Department of Surgery, University of Louisville School of Medicine, Kentucky, USA.
Abstract:
Neutrophil (PMN) migration into the peritoneal cavity in response to fecal peritonitis is an important mechanism of host defense against bacterial invasion. We show that the murine C-X-C (PMN-specific) chemokine, macrophage inflammatory protein-2 (MIP-2), on intraperitoneal injection in mice, causes PMN migration into the peritoneum. MIP-2 mRNA and protein were expressed by peritoneal leukocytes after cecal ligation and puncture (CLP) in mice and neutralization of MIP-2 reduced peritoneal PMN migration. A prerequisite for neutrophil-endothelial adhesion and subsequent migration from the circulation is selectin-mediated rolling. Pretreatment of mice with an anti-P-selectin antibody before intraperitoneal injection of MIP-2 significantly reduced peritoneal PMN migration. However, there are no reports that a C-X-C chemokine can up-regulate endothelial selectins. We postulated that MIP-2, when injected intraperitoneally, interacts with a cell that is known to release factors that up-regulate endothelial selectins. A likely candidate is the mast cell, which contains histamine and tumor necrosis factor alpha (TNF-alpha), and both of these factors induce selectins. Intraperitoneally injected MIP-2 caused an early significant increase in peritoneal TNF-alpha, whereas histamine levels were unaffected. In a subsequent experiment, mast cell-deficient mice and their normal controls were then injected intraperitoneally with MIP-2 or underwent CLP. Significantly fewer PMNs migrated into the peritoneal cavity in the mast cell-deficient mice after MIP-2 injection or CLP. Thus, our findings indicate that mast cells and MIP-2 are necessary for PMN migration into the peritoneum in response to intra-abdominal infection, and that MIP-2 appears to facilitate this through an increase in TNF-alpha release.
Insights
Macrophage inflammatory protein-2 (MIP-2) drives neutrophil migration during abdominal infection by activating mast cells, which release TNF-alpha to facilitate this crucial immune response.
Area of Science:
- Immunology
- Cell Biology
- Infectious Disease
Background:
- Neutrophil (PMN) migration into the peritoneum is vital for combating bacterial invasion during fecal peritonitis.
- The C-X-C chemokine macrophage inflammatory protein-2 (MIP-2) is implicated in PMN recruitment.
Purpose of the Study:
- To elucidate the role of MIP-2 in PMN migration during abdominal infection.
- To investigate the cellular mechanisms by which MIP-2 induces PMN recruitment.
Main Methods:
- Intraperitoneal injection of MIP-2 in mice to assess PMN migration.
- Cecal ligation and puncture (CLP) model of fecal peritonitis.
- Neutralization of MIP-2 and P-selectin blockade.
- Measurement of TNF-alpha and histamine levels.
- Experiments using mast cell-deficient mice.
Main Results:
- MIP-2 injection induced significant PMN migration into the peritoneum.
- MIP-2 neutralization reduced PMN recruitment post-CLP.
- Anti-P-selectin antibody treatment diminished MIP-2-induced PMN migration.
- MIP-2 increased peritoneal TNF-alpha levels but not histamine.
- Mast cell-deficient mice showed significantly reduced PMN migration after MIP-2 administration or CLP.
Conclusions:
- Mast cells and MIP-2 are essential for PMN migration into the peritoneum during intra-abdominal infection.
- MIP-2 likely facilitates PMN migration via mast cell activation and subsequent TNF-alpha release, which up-regulates endothelial selectins.