Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa
Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa
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DOI：
10.1073/pnas.1709111115
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发表时间：
2018-01-23
影响因子：
11.1
通讯作者：
Bruckner-Tuderman, Leena
中科院分区：
文献类型：
--
作者：
Nystroem, Alexander;Bornert, Olivier;Bruckner-Tuderman, Leena
胶原蛋白VII的遗传丢失导致隐性营养不良性大疱性表皮病（RDEB），这是一种皮肤脆性疾病，其意外地还表现为肠道细菌的定植增加和频繁的伤口感染。在这里，我们描述了一个前所未有的全身功能的胶原蛋白VII作为一个独特的先天免疫支持多蛋白复合物在脾脏和淋巴结的成员。在这种复合物中，胶原蛋白VII特异性地结合并隔离淋巴管内腔中的先天免疫激活剂cochlin。在遗传小鼠模型中，胶原蛋白VII的丢失通过降低循环cochlin LCCL结构域的水平来增加细菌定植。腹膜内注射VII型胶原蛋白可恢复脾脏中的cochlin，但不能恢复皮肤中的cochlin，通过cochlin重新激活外周先天免疫细胞，并减少细菌在皮肤上的定植。单独的cochlin LCCL结构域的全身施用足以减少RDEB小鼠皮肤的细菌超定殖。人体验证表明，RDEB患者表现出较低水平的全身cochlin LCCL结构域，随后在感染伤口中受损的巨噬细胞反应。这项研究确定了RDEB的内在先天免疫功能障碍，并揭示了淋巴细胞外基质在系统防御细菌中的独特作用。
Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB), a skin fragility disorder that, unexpectedly, manifests also with elevated colonization of commensal bacteria and frequent wound infections. Here, we describe an unprecedented systemic function of collagen VII as a member of a unique innate immune-supporting multiprotein complex in spleen and lymph nodes. In this complex, collagen VII specifically binds and sequesters the innate immune activator cochlin in the lumen of lymphoid conduits. In genetic mouse models, loss of collagen VII increased bacterial colonization by diminishing levels of circulating cochlin LCCL domain. Intraperitoneal injection of collagen VII, which restored cochlin in the spleen, but not in the skin, reactivated peripheral innate immune cells via cochlin and reduced bacterial skin colonization. Systemic administration of the cochlin LCCL domain was alone sufficient to diminish bacterial supercolonization of RDEB mouse skin. Human validation demonstrated that RDEB patients displayed lower levels of systemic cochlin LCCL domain with subsequently impaired macrophage response in infected wounds. This study identifies an intrinsic innate immune dysfunction in RDEB and uncovers a unique role of the lymphoid extracellular matrix in systemic defense against bacteria.