Abstract
FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL (FasLΔm/Δm), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasLΔm/Δm mice contain abnormally high numbers of leukocytes displaying activated and elevated NF-κB-regulated cytokine levels, indicating that NF-κB-dependent inflammation may be a key pathological driver in this multifaceted autoimmune disease. We tested this hypothesis by genetically impairing canonical or non-canonical NF-κB signaling in FasLΔm/Δm mice by deleting the c-Rel or NF-κB2 genes, respectively. Although the loss of NF-κB2 reduced the levels of inflammatory cytokines and autoantibodies, the impact on animal survival was minor due to substantially accelerated and exacerbated lymphoproliferative disease. In contrast, a marked increase in lifespan resulting from the loss of c-REL coincided with a striking reduction in classical parameters of autoimmune pathology, including the levels of cytokines and antinuclear autoantibodies. Notably, the decrease in regulatory T-cell numbers associated with loss of c-REL did not exacerbate autoimmunity in FasLΔm/Δmc-rel−/− mice. These findings indicate that selective inhibition of c-REL may be an attractive strategy for the treatment of autoimmune pathologies driven by defects in FASL/FAS signaling that would be expected to circumvent many of the complications caused by pan-NF-κB inhibition.
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Abbreviations
- ANA:
-
antinuclear autoantibodies
- GN:
-
glomerulonephritis
- sFASL:
-
soluble FASL
- mFASL:
-
membrane-bound FASL
- mTEC:
-
medullary thymic epithelial cells
- AIRE:
-
autoimmune regulator
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Acknowledgements
We thank G Siciliano, K Hughes, J Coughlin, K McKenzie and F Dabrowski, for animal care; J Corbin for automated blood analysis; B Helbert and C Young for genotyping; and E Tsui, V Babo, K Weston and all histology staff for preparation of histological sections. This work was supported by fellowships and grants from the NHMRC (Canberra; programs #461221 and #1016701, fellowship; (DG) #637353 and project grants #1009145 (LOR), #637332 (DG) and an NHMRC infrastructure grant, Independent Research Institutes Infrastructure Support Scheme Grant #361646, the Victorian State Government (OIS grant), the Leukemia and Lymphoma Society (SCOR grant #7413 and #7001-13) and the JDRF/NHMRC #466658 (AS). This research was also supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (US).
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O'Reilly, L., Hughes, P., Lin, A. et al. Loss of c-REL but not NF-κB2 prevents autoimmune disease driven by FasL mutation. Cell Death Differ 22, 767–778 (2015). https://doi.org/10.1038/cdd.2014.168
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DOI: https://doi.org/10.1038/cdd.2014.168
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