Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus

Lukas Bossaller, Vijay A K Rathinam, Ramon Bonegio, Ping I. Chiang, Patricia Busto, Adam R. Wespiser, Daniel R. Caffrey, Quan Zhen Li, Chandra Mohan, Katherine A. Fitzgerald, Eicke Latz, Ann Marshak-Rothstein

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2104-2114
Number of pages11
JournalJournal of Immunology
Volume191
Issue number5
DOIs
StatePublished - Sep 1 2013

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Fas Ligand Protein
Autoimmune Diseases
Pathology
Kidney
Membranes
Matrix Metalloproteinases
pristane
Inflammation
CD95 Antigens
Mineral Oil
Death Domain Receptors
Mutation
Exudates and Transudates
Autoimmunity
Proteinuria
Systemic Lupus Erythematosus
Neutrophils
Cell Death

ASJC Scopus subject areas

  • Immunology

Cite this

Bossaller, L., Rathinam, V. A. K., Bonegio, R., Chiang, P. I., Busto, P., Wespiser, A. R., ... Marshak-Rothstein, A. (2013). Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus. Journal of Immunology, 191(5), 2104-2114. https://doi.org/10.4049/jimmunol.1300341

Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus. / Bossaller, Lukas; Rathinam, Vijay A K; Bonegio, Ramon; Chiang, Ping I.; Busto, Patricia; Wespiser, Adam R.; Caffrey, Daniel R.; Li, Quan Zhen; Mohan, Chandra; Fitzgerald, Katherine A.; Latz, Eicke; Marshak-Rothstein, Ann.

In: Journal of Immunology, Vol. 191, No. 5, 01.09.2013, p. 2104-2114.

Research output: Contribution to journalArticle

Bossaller, L, Rathinam, VAK, Bonegio, R, Chiang, PI, Busto, P, Wespiser, AR, Caffrey, DR, Li, QZ, Mohan, C, Fitzgerald, KA, Latz, E & Marshak-Rothstein, A 2013, 'Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus', Journal of Immunology, vol. 191, no. 5, pp. 2104-2114. https://doi.org/10.4049/jimmunol.1300341
Bossaller, Lukas ; Rathinam, Vijay A K ; Bonegio, Ramon ; Chiang, Ping I. ; Busto, Patricia ; Wespiser, Adam R. ; Caffrey, Daniel R. ; Li, Quan Zhen ; Mohan, Chandra ; Fitzgerald, Katherine A. ; Latz, Eicke ; Marshak-Rothstein, Ann. / Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus. In: Journal of Immunology. 2013 ; Vol. 191, No. 5. pp. 2104-2114.
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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.",
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