Longistatin in tick saliva blocks advanced glycation end-product receptor activation
Longistatin in tick saliva blocks advanced glycation end-product receptor activation
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DOI：
10.1172/jci74917
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发表时间：
2014-10-01
影响因子：
15.9
通讯作者：
Tsuji, Naotoshi
中科院分区：
文献类型：
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作者：
Anisuzzaman;Hatta, Takeshi;Tsuji, Naotoshi
蜱虫是臭名昭著的噬血体外寄生虫和许多致命病原体的载体。作为一种有效的媒介，蜱虫必须在进食过程中打破宿主皮肤提供的强大屏障，它们的唾液含有一种复杂的生物活性分子混合物，可以瘫痪宿主的防御系统。晚期糖基化终产物受体（RAGE）介导炎症部位的免疫细胞激活，并在皮肤中组成性和高表达。在这里，我们证明了长角血蜱唾液分泌的长角他汀与RAGE结合并调节宿主免疫反应。与其他RAGE配体类似，长司他汀特异性结合RAGE V结构域，刺激培养的HUVECs粘附在长司他汀包被的表面；这种结合被可溶性RAGE或RAGE siRNA显著抑制。在刺激之前用长司他汀治疗HUVECs，可以显著减弱细胞氧化应激，防止NF-kappa B易位，从而减少粘附分子和细胞因子的产生。重组龙司他汀抑制rage介导的小鼠腹膜常驻细胞（mPRCs）迁移，改善小鼠足垫水肿和肺炎模型的炎症。重要的是，蜱叮咬上调了皮肤中的RAGE配体，内源性长睾酮可以减轻蜱食过程中RAGE介导的炎症。我们的研究结果表明，龙司他汀是一种RAGE拮抗剂，可以抑制蜱虫叮咬相关的炎症，使宿主能够成功地获得血粉。
Ticks are notorious hematophagous ectoparasites and vectors of many deadly pathogens. As an effective vector, ticks must break the strong barrier provided by the skin of their host during feeding, and their saliva contains a complex mixture of bioactive molecules that paralyze host defenses. The receptor for advanced glycation end products (RAGE) mediates immune cell activation at inflammatory sites and is constitutively and highly expressed in skin. Here, we demonstrate that longistatin secreted with saliva of the tick Haemaphysalis longicornis binds RAGE and modulates the host immune response. Similar to other RAGE ligands, longistatin specifically bound the RAGE V domain, and stimulated cultured HUVECs adhered to a longistatin-coated surface; this binding was dramatically inhibited by soluble RAGE or RAGE siRNA. Treatment of HUVECs with longistatin prior to stimulation substantially attenuated cellular oxidative stress and prevented NF-kappa B translocation, thereby reducing adhesion molecule and cytokine production. Recombinant longistatin inhibited RAGE-mediated migration of mouse peritoneal resident cells (mPRCs) and ameliorated inflammation in mouse footpad edema and pneumonia models. Importantly, tick bite upregulated RAGE ligands in skin, and endogenous longistatin attenuated RAGE-mediated inflammation during tick feeding. Our results suggest that longistatin is a RAGE antagonist that suppresses tick bite-associated inflammation, allowing successful blood-meal acquisition from hosts.