Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation
Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation
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DOI：
10.1073/pnas.1300617110
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发表时间：
2013-08-27
影响因子：
11.1
通讯作者：
Lowell, Clifford A.
中科院分区：
文献类型：
--
作者：
Lamagna, Chrystelle;Scapini, Patrizia;Lowell, Clifford A.
林恩是一种由B细胞、髓样细胞和树突状细胞（DCs）表达的Src家族酪氨酸激酶，其缺失在小鼠中触发狼疮样疾病，其特征在于自身抗体产生和肾免疫复合物沉积，导致慢性肾小球肾炎。这些小鼠的B细胞由于林恩激酶介导的抑制性信号传导的丧失而对抗原受体刺激过度活跃。过度活跃的B细胞反应被认为是该模型中自身免疫发展的基础。Lyn-deficient小鼠也表现出显著的骨髓扩张。为了测试在该模型中不同免疫细胞类型对狼疮样疾病的贡献，我们产生了林恩（flox/flox）转基因小鼠品系。令我们惊讶的是，当我们将这些小鼠与Cd 11 c-cre动物杂交，产生DC特异性林恩缺失时，这些动物出现自发性B和T细胞活化，随后产生自身抗体和严重肾炎。值得注意的是，DC特异性Lyn缺陷小鼠也发生了严重的组织炎症性疾病，这在全球林恩（-/-）菌株中不存在。Lyn-deficient DCs对Toll样受体激动剂和IL-1 β过度活化和过度反应。为了检测DCs中这些信号通路的失调是否导致炎症/自身免疫表型，我们将lyn（f/f）Cd 11 c-cre（+）小鼠与myd 88（f/f）小鼠杂交，产生了DCs中既缺乏林恩又缺乏衔接蛋白髓样分化因子88（MyD 88）的双突变小鼠。在DC中单独缺失MyD 88完全逆转了DC特异性Lyn-mutant小鼠中的炎性自身免疫。因此，我们证明了在DC中MyD 88依赖性信号传导的超活化足以驱动狼疮样疾病的发病机制，阐明了先天免疫细胞的失调单独可导致自身免疫的事实。
Deletion of lyn, a Src-family tyrosine kinase expressed by B, myeloid, and dendritic cells (DCs), triggers lupus-like disease in mice, characterized by autoantibody production and renal immune complex deposition leading to chronic glomerulonephritis. B cells from these mice are hyperactive to antigen-receptor stimulation owing to a loss of inhibitory signaling mediated by Lyn kinase. The hyperactive B-cell responses are thought to underlie the development of autoimmunity in this model. Lyn-deficient mice also manifest significant myeloexpansion. To test the contribution of different immune cell types to the lupus-like disease in this model, we generated a lyn(flox/flox) transgenic mouse strain. To our surprise, when we crossed these mice to Cd11c-cre animals, generating DC-specific deletion of Lyn, the animals developed spontaneous B- and T-cell activation and subsequent production of autoantibodies and severe nephritis. Remarkably, the DC-specific Lyn-deficient mice also developed severe tissue inflammatory disease, which was not present in the global lyn(-/-) strain. Lyn-deficient DCs were hyperactivated and hyperresponsive to Toll-like receptor agonists and IL-1 beta. To test whether dysregulation of these signaling pathways in DCs contributed to the inflammatory/autoimmune phenotype, we crossed the lyn(f/f) Cd11c-cre(+) mice to myd88(f/f) animals, generating double-mutant mice lacking both Lyn and the adaptor protein myeloid differentiation factor 88 (MyD88) in DCs, specifically. Deletion of MyD88 in DCs alone completely reversed the inflammatory autoimmunity in the DC-specific Lyn-mutant mice. Thus, we demonstrate that hyperactivation of MyD88-dependent signaling in DCs is sufficient to drive pathogenesis of lupus-like disease, illuminating the fact that dysregulation in innate immune cells alone can lead to autoimmunity.