Sezin Tanya, Krajewski Matthias, Wutkowski Adam, Mousavi Sadegh, Chakievska Lenche, Bieber Katja, Ludwig Ralf J, Dahlke Markus, Rades Dirk, Schulze Franziska S, Schmidt Enno, Kalies Kathrin, Gupta Yask, Schilf Paul, Ibrahim Saleh M, König Peter, Schwudke Dominik, Zillikens Detlef, Sadik Christian D
Department of Dermatology, Allergy, and Venereology, University of Lübeck, 23538 Lübeck, Germany.
Division of Bioanalytical Chemistry, Research Center Borstel- Leibniz-Center for Medicine and Biosciences, 23845 Borstel, Germany.
J Invest Dermatol. 2017 May;137(5):1104-1113. doi: 10.1016/j.jid.2016.12.021. Epub 2017 Jan 17.
Recruitment of neutrophils and eosinophils into the skin is a hallmark of pemphigoid diseases. The molecular cues regulating granulocyte recruitment into the skin and the individual contributions of neutrophils and eosinophils to pemphigoid diseases are, however, poorly understood. The lipid mediator leukotriene B (LTB) is a potent granulocyte chemoattractant and is abundant in the skin blister fluid of bullous pemphigoid (BP) patients, but its pathogenic significance is unknown. Using mouse models of BP-like epidermolysis bullosa acquisita and of BP, we show that LTB and its receptor BLT1 act as critical drivers of neutrophil entry into the skin upon antibody deposition at the dermal-epidermal junction. Mice deficient in 5-lipoxygenase, a key enzyme in LTB biosynthesis, or in BLT1 exhibited dramatic resistance to neutrophil recruitment and, consequently, skin inflammation. Accordingly, liquid chromatography-mass spectrometry, used to comprehensively profile lipid mediator generation in the first 48 hours after antibody deposition, showed a pronounced parallel increase in LTB and in neutrophils in the skin. Subsequent mechanistic studies in BP-like epidermolysis bullosa acquisita uncovered that neutrophils are necessary for skin inflammation, whereas eosinophils are dispensable, thus identifying neutrophils as major culprits of blister formation. Our results highlight LTB/BLT1 as absolutely critical drivers of murine pemphigoid disease-like skin inflammation.
嗜中性粒细胞和嗜酸性粒细胞向皮肤的募集是类天疱疮疾病的一个标志。然而，调节粒细胞向皮肤募集的分子信号以及嗜中性粒细胞和嗜酸性粒细胞在类天疱疮疾病中的各自作用尚不清楚。脂质介质白三烯B4（LTB4）是一种有效的粒细胞趋化因子，在大疱性类天疱疮（BP）患者的皮肤疱液中含量丰富，但其致病意义尚不清楚。利用类BP样获得性大疱性表皮松解症和BP的小鼠模型，我们发现LTB4及其受体BLT1在抗体沉积于真皮-表皮交界处时，作为嗜中性粒细胞进入皮肤的关键驱动因素。缺乏5-脂氧合酶（LTB4生物合成中的一种关键酶）或BLT1的小鼠对嗜中性粒细胞募集和皮肤炎症表现出显著抗性。因此，用于全面分析抗体沉积后最初48小时内脂质介质生成情况的液相色谱-质谱分析显示，皮肤中LTB4和嗜中性粒细胞明显同时增加。随后对类BP样获得性大疱性表皮松解症的机制研究发现，嗜中性粒细胞是皮肤炎症所必需的，而嗜酸性粒细胞则是可有可无的，从而确定嗜中性粒细胞是水疱形成的主要元凶。我们的结果突出了LTB4/BLT1作为小鼠类天疱疮样皮肤炎症的绝对关键驱动因素。
