Loss of c-REL but not NF-κB2 prevents autoimmune disease driven by FasL mutation

• Published in: Cell death and differentiation 2015-04, Vol.22 (5), p.767-778
• Main Authors: O'Reilly, L A, Hughes, P, Lin, A, Waring, P, Siebenlist, U, Jain, R, Gray, D H D, Gerondakis, S, Strasser, A
• Format: Article
• Language: English
• Subjects: 13/2; 64/110; 692/308/1426; Animals; Apoptosis; Autoimmune Diseases - genetics; Autoimmune Diseases - metabolism; Autoimmune Diseases - pathology; Autoimmune Diseases - prevention & control; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Fas Ligand Protein - genetics; Fas Ligand Protein - metabolism; fas Receptor - genetics; fas Receptor - metabolism; Life Sciences; Mice; Mice, Knockout; Mutation; NF-kappa B p52 Subunit - genetics; NF-kappa B p52 Subunit - metabolism; Original Paper; Proto-Oncogene Proteins c-rel - genetics; Proto-Oncogene Proteins c-rel - metabolism; Signal Transduction - genetics; Stem Cells
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2014.168

FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL ( FasL Δ m/ Δ m ), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasL Δ m/ Δ m mice contain abnormally high numbers of leukocytes displaying activated and elevated NF- κ B-regulated cytokine levels, indicating that NF- κ 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- κ B signaling in FasL Δ m/ Δ m mice by deleting the c-Rel or NF-κB2 genes, respectively. Although the loss of NF- κ 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 Δ m/ Δ 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- κ B inhibition.