title: Requirement of myeloid cell-specific Fas expression for prevention of systemic autoimmunity in mice.
abstract: OBJECTIVE
  The death receptor Fas is a critical mediator of the extrinsic apoptotic pathway, and its role in mediating lymphoproliferation has been extensively examined. The present study was undertaken to investigate the impact of myeloid cell-specific loss of Fas.
  
  
  METHODS
  Mice with Fas flanked by loxP sites (Fas(flox/flox) ) were crossed with mice expressing Cre under control of the murine lysozyme M gene promoter (Cre(LysM) ), which functions in mature lysozyme-expressing cells of the myelomonocytic lineage. The genotype for Cre(LysM) Fas(flox/flox)  mice was verified by polymerase chain reaction and flow cytometric analysis. Flow cytometric analysis was also used to characterize myeloid, dendritic, and lymphoid cell distribution and activation in bone marrow, blood, and spleen. Luminex-based assays and enzyme-linked immunosorbent assays were used to measure serum cytokine/chemokine and immunoglobulin levels. Renal damage or dysfunction was examined by immunohistochemical and immunofluorescence analysis.
  
  
  RESULTS
  Cre(LysM) Fas(flox/flox)  mice exhibited a systemic lupus erythematosus (SLE)-like disease that included leukocytosis, splenomegaly, hypergammaglobulinemia, antinuclear autoantibody and proinflammatory cytokine production, and glomerulonephritis. Loss of Fas in myeloid cells increased levels of both Gr-1(low)  and Gr-1(intermediate)  blood monocytes and splenic macrophages and, in a paracrine manner, incited activation of conventional dendritic cells and lymphocytes in Cre(LysM) Fas(flox/flox)  mice.
  
  
  CONCLUSIONS
  Taken together, these results suggest that loss of Fas in myeloid cells is sufficient to induce inflammatory phenotypes in mice, reminiscent of an SLE-like disease. Thus, Fas in myeloid cells may be considered a suppressor of systemic autoimmunity.
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Cuda
authors.forename: Hemant
authors.initials: H
authors.lastname: Agrawal
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Misharin
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.forename: Jack
authors.initials: J
authors.lastname: Hutcheson
authors.forename: Evan
authors.initials: E
authors.lastname: Weber
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Schoenfeldt
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015551:Autoimmunity; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; C491899:Fas protein, mouse; D019014:fas Receptor