The Flavonoid Luteolin Inhibits Fcγ-Dependent Respiratory Burst in Granulocytes, but Not Skin Blistering in a New Model of Pemphigoid in Adult Mice
The Flavonoid Luteolin Inhibits Fcγ-Dependent Respiratory Burst in Granulocytes, but Not Skin Blistering in a New Model of Pemphigoid in Adult Mice
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DOI：
10.1371/journal.pone.0031066
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发表时间：
2012-02-06
期刊：
影响因子：
3.7
通讯作者：
Sitaru, Cassian
中科院分区：
文献类型：
--
作者：
Oswald, Eva;Sesarman, Alina;Sitaru, Cassian
大疱性类天疱疮是一种自身免疫性起泡性皮肤病，与对抗真皮-表皮交界处的自身抗体相关。将抗BP180/胶原(C) XVII（一种主要的半半粒体类天疱疮抗原）的抗体被动转移到新生小鼠体内，在对其皮肤施加轻微压力后，会导致真皮-表皮分离，但不会导致自发性皮肤起泡。此外，这种新生小鼠模型禁止对患病动物进行2-3天以上的治疗和观察。因此，在本研究中，我们在小鼠身上建立了一种新的疾病模型，再现了人类疾病的自发性起泡和慢性病程特征。用兔IgG预免疫成年小鼠，再注射BP180/CXVII兔IgG。预先免疫兔IgG后，每2天注射6次BP180/ cxviii特异性抗体（n = 35），小鼠皮肤出现自发性持续性水泡，而预先免疫后再注射正常兔IgG (n = 5)，小鼠皮肤未出现自发性持续性水泡。起泡与IgG和补体C3在表皮基底膜的沉积和炎症细胞的募集有关，部分依赖于ly - 6g阳性细胞。我们进一步利用这个新的实验模型来研究木犀草素（一种具有有效抗炎和抗氧化特性和良好安全性的植物类黄酮）对实验性BP的治疗潜力。木犀草素抑制免疫复合物刺激的粒细胞Fc γ依赖性呼吸爆发和自身抗体诱导的皮肤冷冻中真皮-表皮分离，但在体内对皮肤起泡无明显抑制作用。这些研究建立了一个强大的动物模型，将是解剖水疱形成机制的有用工具，并将促进开发更有效的治疗策略来管理类天疱疮疾病。
Bullous pemphigoid is an autoimmune blistering skin disease associated with autoantibodies against the dermal-epidermal junction. Passive transfer of antibodies against BP180/collagen (C) XVII, a major hemidesmosomal pemphigoid antigen, into neonatal mice results in dermal-epidermal separation upon applying gentle pressure to their skin, but not in spontaneous skin blistering. In addition, this neonatal mouse model precludes treatment and observation of diseased animals beyond 2-3 days. Therefore, in the present study we have developed a new disease model in mice reproducing the spontaneous blistering and the chronic course characteristic of the human condition. Adult mice were pre-immunized with rabbit IgG followed by injection of BP180/CXVII rabbit IgG. Mice pre-immunized against rabbit IgG and injected 6 times every second day with the BP180/CXVII-specific antibodies (n = 35) developed spontaneous sustained blistering of the skin, while mice pre-immunized and then treated with normal rabbit IgG (n = 5) did not. Blistering was associated with IgG and complement C3 deposits at the epidermal basement membrane and recruitment of inflammatory cells, and was partly dependent on Ly-6G-positive cells. We further used this new experimental model to investigate the therapeutic potential of luteolin, a plant flavonoid with potent anti-inflammatory and anti-oxidative properties and good safety profile, in experimental BP. Luteolin inhibited the Fc gamma-dependent respiratory burst in immune complex-stimulated granulocytes and the autoantibody-induced dermal-epidermal separation in skin cryosections, but was not effective in suppressing the skin blistering in vivo. These studies establish a robust animal model that will be a useful tool for dissecting the mechanisms of blister formation and will facilitate the development of more effective therapeutic strategies for managing pemphigoid diseases.