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Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis
Albert Dahdah, … , Bernard Malissen, Pierre Launay
Albert Dahdah, … , Bernard Malissen, Pierre Launay
Published October 1, 2014; First published September 2, 2014
Citation Information: J Clin Invest. 2014;124(10):4577-4589. https://doi.org/10.1172/JCI75212.
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Categories: Research Article Immunology

Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis

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Abstract

Controlling the overwhelming inflammatory reaction associated with polymicrobial sepsis remains a prevalent clinical challenge with few treatment options. In septic peritonitis, blood neutrophils and monocytes are rapidly recruited into the peritoneal cavity to control infection, but the role of resident sentinel cells during the early phase of infection is less clear. In particular, the influence of mast cells on other tissue-resident cells remains poorly understood. Here, we developed a mouse model that allows both visualization and conditional ablation of mast cells and basophils to investigate the role of mast cells in severe septic peritonitis. Specific depletion of mast cells led to increased survival rates in mice with acute sepsis. Furthermore, we determined that mast cells impair the phagocytic action of resident macrophages, thereby allowing local and systemic bacterial proliferation. Mast cells did not influence local recruitment of neutrophils and monocytes or the release of inflammatory cytokines. Phagocytosis inhibition by mast cells involved their ability to release prestored IL-4 within 15 minutes after bacterial encounter, and treatment with an IL-4–neutralizing antibody prevented this inhibitory effect and improved survival of septic mice. Our study uncovers a local crosstalk between mast cells and macrophages during the early phase of sepsis development that aggravates the outcome of severe bacterial infection.

Authors

Albert Dahdah, Gregory Gautier, Tarik Attout, Frédéric Fiore, Emeline Lebourdais, Rasha Msallam, Marc Daëron, Renato C. Monteiro, Marc Benhamou, Nicolas Charles, Jean Davoust, Ulrich Blank, Bernard Malissen, Pierre Launay

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Figure 1

Visualization and efficient depletion of mast cells and basophils in RMB mice.

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Visualization and efficient depletion of mast cells and basophils in RMB...
(A) Detection of mast cells (FcεRI+tdT+CD117+) by flow cytometry in the peritoneal cavity (left panel) and dermis (right panel) of RMB mice before and after 2 i.p. DT injections. (B) Detection of basophils (FcεRI+tdT+CD49b+) in the blood (left panel) and in the spleen (right panel) of RMB mice before and after DT treatment. Dotted lines represent isotype control antibodies. Numbers in each panel represent the percentage of mast cells and basophils among CD45+ gated cells. (C) Flow cytometric analysis of blood leukocytes in B6 and untreated RMB mice. Data represent the mean ± SEM. (D) Percentage of blood lymphocytes, neutrophils, and monocytes in B6 and untreated RMB mice and in RMB mice 1 week or 3 weeks after DT treatment, as determined by a hematological analyzer (n = 9 mice/group). Data are representative of 5 independent experiments (A–C).
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