Requirement of myeloid cell-specific Fas expression for prevention of systemic autoimmunity in mice

Carla M. Cuda, Hemant Agrawal, Alexander V. Misharin, G. Kenneth Haines, Jack Hutcheson, Evan Weber, Joseph A. Schoenfeldt, Chandra Mohan, Richard M. Pope, Harris Perlman*

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

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 LysMFas 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 LysMFas 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 LysMFas flox/flox mice. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)808-820
Number of pages13
JournalArthritis and rheumatism
Volume64
Issue number3
DOIs
StatePublished - Mar 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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