title: Fas death receptor signaling represses monocyte numbers and macrophage activation in vivo.
abstract: Over 1 billion monocytes are produced daily, with a small percentage differentiating into macrophages, suggesting that excess monocytes are deleted through a tightly regulated process. Although the in vivo mechanism governing monocyte/macrophage homeostasis is unknown, deletion of monocytes in culture is mediated by the Fas death pathway and is blocked by M-CSF. To determine the in vivo significance of Fas in monocyte development, mice lacking Fas (lpr/lpr) and mice deficient in Fas and M-CSF were examined. Compared with congenic control C57BL/6 (B6) mice, lpr/lpr mice displayed increased numbers of circulating monocytes. The lack of Fas in M-CSF-deficient mice resulted in an enhanced percentage, but not total numbers, of monocytes. Fas deficiency led to an increase in myeloid bone marrow progenitor potential only in M-CSF-intact mice. Although lpr/lpr and B6 mice had similar numbers of tissue macrophages, the loss of Fas in M-CSF-deficient mice was sufficient to increase the number of macrophages in a subset of tissues. Additionally, after stimulation with thioglycolate, lpr/lpr and B6 mice showed equivalent numbers of peritoneal macrophages. However, Fas-deficient peritoneal macrophages displayed a marked increase in spontaneous and LPS-induced proinflammatory molecule production. Moreover, Fas-deficient mice showed enhanced systemic inflammatory arthritis associated with up-regulation of IL-1beta and CCL2 secretion, elevated numbers of inflammatory monocytes, and increased numbers of tissue macrophages. Collectively, these data suggest that Fas may be required for maintaining circulating monocytes and for suppressing macrophage activation and recruitment that are stimulus dependent.
authors.affiliation: Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Jack
authors.initials: J
authors.lastname: Hutcheson
authors.forename: Emily
authors.initials: E
authors.lastname: Bickel
authors.forename: John C
authors.initials: JC
authors.lastname: Scatizzi
authors.forename: Lee D
authors.initials: LD
authors.lastname: Albee
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.forename: Joy
authors.initials: J
authors.lastname: Eslick
authors.forename: Kathleen
authors.initials: K
authors.lastname: Bradley
authors.forename: Elsa
authors.initials: E
authors.lastname: Taricone
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006131:Growth Inhibitors / Q000097:blood / Q000235:genetics / Q000502:physiology*; D007958:Leukocyte Count; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000097:blood / Q000235:genetics / Q000502:physiology*
chemical_list: D006131:Growth Inhibitors; D019014:fas Receptor; D016173:Macrophage Colony-Stimulating Factor