Loss of c-REL but not NF-κB2 prevents autoimmune disease driven by FasL mutation.
Loss of c-REL but not NF-κB2 prevents autoimmune disease driven by FasL mutation.
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失去 c-REL 而不是 NF-κB2 可以预防由 FasL 突变驱动的自身免疫性疾病。
DOI：
10.1038/cdd.2014.168
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发表时间：
2015
影响因子：
12.4
通讯作者：
Strasser,A
中科院分区：
文献类型：
--
作者：
O'Reilly,LA;Hughes,P;Lin,A;Waring,P;Siebenlist,U;Jain,R;Gray,DHD;Gerondakis,S;Strasser,A
FASL/FAS信号传导对自身免疫性疾病和淋巴结病施加关键屏障。不能产生膜结合FASL（FasL Δm/Δm）的突变小鼠（其是FAS诱导的细胞凋亡的先决条件）发生淋巴结病和全身性自身免疫性疾病，伴有免疫复合物介导的肾小球肾炎。在疾病发作之前，FasL Δm/Δm小鼠含有异常高数量的白细胞，显示出活化和升高的NF-κ B调节的细胞因子水平，表明NF-κ B依赖性炎症可能是这种多方面自身免疫性疾病的关键病理驱动因素。我们通过分别删除c-Rel或NF-κB2基因，在FasL Δm/Δm小鼠中遗传性地损害经典或非经典NF-κB信号传导来验证这一假设。尽管NF-κB2的缺失降低了炎性细胞因子和自身抗体的水平，但由于淋巴组织增生性疾病的显著加速和加重，对动物生存的影响很小。相比之下，c-REL的缺失导致寿命显着增加，同时自身免疫病理学的经典参数（包括细胞因子和抗核自身抗体水平）显着降低。值得注意的是，与c-REL缺失相关的调节性T细胞数量减少不会加剧FasL Δm/Δm c-rel−/−小鼠的自身免疫。这些发现表明，c-REL的选择性抑制可能是治疗由FASL/FAS信号传导缺陷驱动的自身免疫性病理的有吸引力的策略，预期可避免泛NF-κB抑制引起的许多并发症。
FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL (FasL Δm/Δm), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasL Δm/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 FasL Δm/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 FasL Δm/Δm 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-κB inhibition.