Honey bee (Apis mellifera) venom induces AIM2 inflammasome activation in human keratinocytes
Honey bee (Apis mellifera) venom induces AIM2 inflammasome activation in human keratinocytes
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DOI：
10.1111/all.12022
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发表时间：
2012-11-01
期刊：
影响因子：
12.4
通讯作者：
Schauber, J.
中科院分区：
文献类型：
--
作者：
Dombrowski, Y.;Peric, M.;Schauber, J.
在过敏原暴露后，细胞因子和其他促炎信号在导致过敏致敏的免疫级联反应中起重要作用。炎性小体感知外源性和内源性危险信号并触发IL-1 β和IL-18激活，进而形成Th2反应。蜂毒（BV）过敏是很常见的；然而，导致过敏性致敏的局部炎症级联反应尚不清楚。在本研究中，研究了暴露于BV后皮肤的局部炎症级联反应。方法采用ELISA、Western blot、流式细胞术、siRNA技术和免疫荧光等方法分析BV暴露后人皮肤和体外培养角质形成细胞炎症小体活化的机制。结果在离体蜜蜂蜇伤模型中，BV诱导IL-1 β释放，提示炎症小体激活。事实上，在培养的角化细胞中，BV成分蜂化素通过AIM2炎性体触发IL-1 β和IL-18的释放。AIM2是一种细胞质DNA受体，在蜂毒素处理的角质形成细胞的细胞质中检测到线粒体和基因组DNA作为炎性体激活的触发器。作为一种机制，蜂毒素介导的线粒体膜破坏导致线粒体DNA渗漏到细胞质室。这些数据表明，在BV暴露后，角质形成细胞通过激活AIM2炎性体和随后由内源性DNA触发的IL-1 β和IL-18释放参与先天免疫反应。由于IL-1 β和IL-18参与了Th2和ige介导的免疫反应，这些结果可能有助于理解组织微环境在随后的过敏反应中的作用。
Background Following allergen exposure, cytokines and other pro-inflammatory signals play an important role in the immunological cascade leading to allergic sensitization. Inflammasomes sense exogenous and endogenous danger signals and trigger IL-1 beta and IL-18 activation which in turn shape Th2 responses. Honey bee venom (BV) allergies are very common; however, the local inflammatory cascade leading to the initiation of allergic sensitization is poorly understood. In this study, the local inflammatory cascades in skin after exposure to BV were investigated. Methods The mechanisms of inflammasome activation in human skin and in cultured keratinocytes upon BV exposure were analyzed by ELISA, Western blot, flow cytometry, siRNA techniques, and immunofluorescence. Results In an ex vivo bee sting model, BV induced IL-1 beta release suggesting the activation of inflammasomes. Indeed, in cultured keratinocytes, the BV component melittin triggered IL-1 beta and IL-18 release via the AIM2 inflammasome. AIM2 is a cytosolic DNA receptor, and mitochondrial as well as genomic DNA was detected in the cytosol of melittin-treated keratinocytes as triggers of inflammasome activation. As a mechanism, melittin mediated destruction of mitochondrial membranes leading to the leakage of mitochondrial DNA into the cytosolic compartment. Conclusion These data suggest that upon BV exposure, keratinocytes are involved in an innate immune response by the activation of the AIM2 inflammasome and subsequent IL-1 beta and IL-18 release triggered by endogenous DNA. As IL-1 beta and IL-18 are involved in Th2- and IgE-mediated immune reactions, these results could add to the understanding of the role of the tissue microenvironment to subsequent allergic responses.