title: Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus.
abstract: Loss-of-function mutations in the Fas death receptor or its ligand result in a lymphoproliferative syndrome and exacerbate clinical disease in most lupus-prone strains of mice. One exception is mice injected with 2,6,10,14-tetramethylpentadecane (TMPD), a hydrocarbon oil commonly known as pristane, which induces systemic lupus erythematosus-like disease. Although Fas/Fas ligand (FasL) interactions have been strongly implicated in the activation-induced cell death of both lymphocytes and other APCs, FasL can also trigger the production of proinflammatory cytokines. FasL is a transmembrane protein with a matrix metalloproteinase cleavage site in the ectodomain. Matrix metalloproteinase cleavage inactivates membrane-bound FasL and releases a soluble form reported to have both antagonist and agonist activity. To better understand the impact of FasL cleavage on both the proapoptotic and proinflammatory activity of FasL, its cleavage site was deleted through targeted mutation to produce the deleted cleavage site (ΔCS) mouse line. ΔCS mice express higher levels of membrane-bound FasL than do wild-type mice and fail to release soluble FasL. To determine to what extent FasL promotes inflammation in lupus mice, TMPD-injected FasL-deficient and ΔCS BALB/c mice were compared with control TMPD-injected BALB/c mice. We found that FasL deficiency significantly reduced the early inflammatory exudate induced by TMPD injection. In contrast, ΔCS mice developed a markedly exacerbated disease profile associated with a higher frequency of splenic neutrophils and macrophages, a profound change in anti-nuclear Ab specificity, and markedly increased proteinuria and kidney pathology compared with controls. These results demonstrate that FasL promotes inflammation in TMPD-induced autoimmunity, and its cleavage limits FasL proinflammatory activity.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bossaller
authors.forename: Vijay A K
authors.initials: VA
authors.lastname: Rathinam
authors.forename: Ramon
authors.initials: R
authors.lastname: Bonegio
authors.forename: Ping-I
authors.initials: PI
authors.lastname: Chiang
authors.forename: Patricia
authors.initials: P
authors.lastname: Busto
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wespiser
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Caffrey
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D041702:BALB 3T3 Cells; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000633:toxicity; D007674:Kidney Diseases / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013729:Terpenes / Q000633:toxicity; D059467:Transcriptome
chemical_list: D053222:Fas Ligand Protein; D007166:Immunosuppressive Agents; D013729:Terpenes; C009042:pristane
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