title: Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis.
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.forename: Albert
authors.initials: A
authors.lastname: Dahdah
authors.forename: Gregory
authors.initials: G
authors.lastname: Gautier
authors.forename: Tarik
authors.initials: T
authors.lastname: Attout
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fiore
authors.forename: Emeline
authors.initials: E
authors.lastname: Lebourdais
authors.forename: Rasha
authors.initials: R
authors.lastname: Msallam
authors.forename: Marc
authors.initials: M
authors.lastname: Daëron
authors.forename: Renato C
authors.initials: RC
authors.lastname: Monteiro
authors.forename: Marc
authors.initials: M
authors.lastname: Benhamou
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charles
authors.forename: Jean
authors.initials: J
authors.lastname: Davoust
authors.forename: Ulrich
authors.initials: U
authors.lastname: Blank
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: Pierre
authors.initials: P
authors.lastname: Launay
mesh_terms: D000818:Animals; D001424:Bacterial Infections; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D002469:Cell Separation; D005434:Flow Cytometry; D007249:Inflammation / Q000276:immunology*; D015847:Interleukin-4 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D017737:Macrophages, Peritoneal / Q000166:cytology*; D008297:Male; D008407:Mast Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D010538:Peritonitis / Q000473:pathology; D010587:Phagocytosis; D018805:Sepsis / Q000276:immunology*
chemical_list: D015847:Interleukin-4