Regulation of early peritoneal neutrophil migration by macrophage inflammatory protein-2 and mast cells in experimental peritonitis

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.

The P2 receptor antagonist PPADS abrogates LPS-induced neutrophil migration in the murine air pouch via inhibition of MIP-2 and KC production

“…As neutrophil MIP-2 production was not affected by PPADS, a potential explanation for this observation would be that extracellular nucleotides control the extravasation of early migrating neutrophils and that the reduced MIP-2 production in the pouches would have been the direct extension of this effect. In further support for the role of early neutrophil migration in chemokine production and in contrast to previous reports proposing a major role for resident cells in this process (Kopydlowski et al, 1999;Mercer-Jones et al, 1999;Schramm et al, 2000;Tessier et al, 1997), PPADS did not inhibit MIP-2 and KC production by air pouch resident cells in vitro and in vivo. Thus, this work puts forward a potential novel role of early migrated neutrophils in the development of the acute inflammatory response in the air pouch.…”

TLR3-, TLR7-, and TLR9-Mediated Production of Proinflammatory Cytokines and Chemokines from Murine Connective Tissue Type Skin-Derived Mast Cells but Not from Bone Marrow-Derived Mast Cells

“…Similarly, mast cell-derived MIP-2 has been reportedly produced in infected sites and caused the infiltration of neutrophils (58). Thus, mast cell-derived cytokines and chemokines are important mediators in host defense against bacteria.…”

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

“…infection models used in this study, resident peritoneal macrophages were likely one of the cell types responsible for the IDR-1002-induced chemokine production, as peritoneal macrophages are known to be an important source of chemokines for leukocyte recruitment during peritoneal infections (53)(54)(55). However, a contribution of other cell types to the IDR-1002-stimulated chemokine production cannot be ruled out, and these cell types may include mast cells and peritoneal mesothelial cells, which are also known to be important chemokine producers in some models of peritonitis (55)(56)(57)(58). The elevated levels of IFN-g in the peptide-treated animals during S. aureus infection were interesting and unexpected (Fig.…”