Loss of c-REL but not NF-{kappa}B2 prevents autoimmune disease driven by FasL mutation

Lorraine A O'Reilly, Peter D Hughes, Ann Lin, Paul M Waring, Ulrich Siebenlist, Rajan Jain, Daniel Herbert Donald Gray, Steven Demetrious Gerondakis, Andreas Strasser

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11 Citations (Scopus)


FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL (FasL ?m/?m), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasL ?m/?m mice contain abnormally high numbers of leukocytes displaying activated and elevated NF-?B-regulated cytokine levels, indicating that NF-?B-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-?B signaling in FasL ?m/?m mice by deleting the c-Rel or NF-?B2 genes, respectively. Although the loss of NF-?B2 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 FasL ?m/?m c-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-?B inhibition.
Original languageEnglish
Pages (from-to)767 - 778
Number of pages12
JournalCell Death and Differentiation
Issue number5
Publication statusPublished - 2015

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