Németh Tamás, Virtic Oana, Sitaru Cassian, Mócsai Attila
Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary; MTA-SE "Lendület" Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
Department of Dermatology, University Hospital Freiburg, Freiburg, Germany.
J Invest Dermatol. 2017 Oct;137(10):2131-2139. doi: 10.1016/j.jid.2017.05.017. Epub 2017 May 30.
The inflammatory form of epidermolysis bullosa acquisita is caused by autoantibodies against type VII collagen (C7), a component of the dermal-epidermal junction. We have previously shown that myeloid Src family kinases mediate skin inflammation triggered by anti-C7 antibodies. Here we identify the Syk tyrosine kinase as a critical component of autoantibody-induced skin inflammation downstream of Src family kinases. Immobilized C7-anti-C7 immune complexes triggered neutrophil activation and Syk phosphorylation in a Src family kinase-dependent manner. Bone marrow chimeric mice lacking Syk in their hematopoietic compartment were completely protected from skin inflammation triggered by anti-C7 antibodies despite normal circulating anti-C7 levels. Syk deficiency abrogated the accumulation of CXCL2, IL-1β, and leukotriene B at the site of inflammation and resulted in defective in vivo neutrophil recruitment. Syk neutrophils had a normal intrinsic migratory capacity but failed to release CXCL2 or leukotriene B upon activation by immobilized C7-anti-C7 immune complexes, indicating a role for Syk in the amplification of the inflammation process. These results identify Syk as a critical component of skin inflammation in a mouse model of epidermolysis bullosa acquisita and as a potential therapeutic target in epidermolysis bullosa acquisita and other mechanistically related inflammatory skin diseases such as bullous pemphigoid.
获得性大疱性表皮松解症的炎症形式是由针对VII型胶原蛋白（C7）的自身抗体引起的，C7是真皮-表皮交界处的一种成分。我们之前已经表明，髓系Src家族激酶介导抗C7抗体引发的皮肤炎症。在这里，我们确定Syk酪氨酸激酶是Src家族激酶下游自身抗体诱导的皮肤炎症的关键组成部分。固定化的C7-抗C7免疫复合物以Src家族激酶依赖性方式触发中性粒细胞活化和Syk磷酸化。造血区室中缺乏Syk的骨髓嵌合小鼠尽管循环抗C7水平正常，但完全免受抗C7抗体引发的皮肤炎症。Syk缺陷消除了炎症部位CXCL2、IL-1β和白三烯B的积累，并导致体内中性粒细胞募集缺陷。Syk缺陷的中性粒细胞具有正常的内在迁移能力，但在被固定化的C7-抗C7免疫复合物激活时未能释放CXCL2或白三烯B，这表明Syk在炎症过程的放大中起作用。这些结果确定Syk是获得性大疱性表皮松解症小鼠模型中皮肤炎症的关键组成部分，并且是获得性大疱性表皮松解症和其他机制相关的炎症性皮肤病如大疱性类天疱疮的潜在治疗靶点。
