Conditional Macrophage Ablation Demonstrates That Resident Macrophages Initiate Acute Peritoneal Inflammation

Abstract

The role played by resident macrophages (Mφ) in the initiation of peritoneal inflammation is currently unclear. We have used a conditional Mφ ablation strategy to determine the role of resident peritoneal Mφ in the regulation of neutrophil (PMN) recruitment in experimental peritonitis. We developed a novel conditional Mφ ablation transgenic mouse (designated CD11bDTR) based upon CD11b promoter-mediated expression of the human diphtheria toxin (DT) receptor. The murine DT receptor binds DT poorly such that expression of the human receptor confers toxin sensitivity. Intraperitoneal injection of minute (nanogram) doses of DT results in rapid and marked ablation of F4/80-positive Mφ populations in the peritoneum as well as the kidney, and ovary. In experimental peritonitis, resident Mφ ablation resulted in a dramatic attenuation of PMN infiltration that was rescued by the adoptive transfer of resident nontransgenic Mφ. Attenuation of PMN infiltration was associated with diminished CXC chemokine production at 1 h. These studies indicate a key role for resident peritoneal Mφ in sensing perturbation to the peritoneal microenvironment and regulating PMN infiltration.

Macrophage heterogeneity and acute inflammation

“…It is likely that the contribution of tissue-resident macrophages to the overall coordinated tissue response varies with the nature and dose of the noxious challenge and the capacity of other tissue-resident cells to respond appropriately. For example, depletion of tissueresident macrophages was found to markedly affect the production of chemokines and subsequent recruitment of neutrophils in an experimental peritonitis model [20]. This parallels observations from our own laboratory that indicate an important role for resident cells in establishing immediate responses (B) At the outset of inflammation, after injury or infection, inflammatory cells are rapidly recruited to the inflammatory lesion.…”

Plasmin Induces In Vivo Monocyte Recruitment through Protease-Activated Receptor-1–, MEK/ERK-, and CCR2-Mediated Signaling

“…However, the drop in levels of KC and MCP-1 was not so intense after macrophage ablation, suggesting that there was a source other than residential macrophages, such as mesothelial cells, in MCP-1 production in vivo and subsequent mononuclear cell recruitment (40). Although we did not perform experiments to identify the cell population responsible for the detected cytokine production in our model, we think that the findings on the carrageenan-induced pleurisy can be applied in the Pla-induced pleurisy as well, leading to the conclusion that residential macrophages are responsible for the production of IL-6 and mesothelial cells for the MCP-1 release (40). It was previously stated that Pla activates macrophages via the annexin A2 heterotetramer (composed of annexin A2 and S100A10) and the following signaling pathways lead to IL-6 production (31).…”

“…Of note, Pla-activated monocyte-derived dendritic cells did not release these proinflammatory cytokines (33). Cailhier et al (40) showed that the ablation of resident pleural macrophages in a model of carrageenan-induced pleurisy had marked effects on the production of several cytokines and chemokines, such as CXCL2, TNF-a, IL-6, and IL-10. However, the drop in levels of KC and MCP-1 was not so intense after macrophage ablation, suggesting that there was a source other than residential macrophages, such as mesothelial cells, in MCP-1 production in vivo and subsequent mononuclear cell recruitment (40).…”

“…Cailhier et al (40) showed that the ablation of resident pleural macrophages in a model of carrageenan-induced pleurisy had marked effects on the production of several cytokines and chemokines, such as CXCL2, TNF-a, IL-6, and IL-10. However, the drop in levels of KC and MCP-1 was not so intense after macrophage ablation, suggesting that there was a source other than residential macrophages, such as mesothelial cells, in MCP-1 production in vivo and subsequent mononuclear cell recruitment (40). Although we did not perform experiments to identify the cell population responsible for the detected cytokine production in our model, we think that the findings on the carrageenan-induced pleurisy can be applied in the Pla-induced pleurisy as well, leading to the conclusion that residential macrophages are responsible for the production of IL-6 and mesothelial cells for the MCP-1 release (40).…”

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

“…Thus, in the i.p. 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).…”