HPV16 activates the AIM2 inflammasome in keratinocytes
HPV16 activates the AIM2 inflammasome in keratinocytes
复制标题
DOI：
10.1007/s00403-013-1375-0
复制
发表时间：
2013-10-01
影响因子：
3
通讯作者：
Schauber, J.
中科院分区：
文献类型：
--
作者：
Reinholz, M.;Kawakami, Y.;Schauber, J.
人乳头瘤病毒（HPV）是一种双链DNA病毒，它选择性地感染复层上皮中的角质形成细胞。初次感染后，许多患者清除HPV。然而，在一些患者中，HPV持续存在，并且对HPV感染的先天免疫应答功能障碍可能与这些病毒的无效清除有关。在这项研究中，HPV诱导的角质形成细胞的免疫反应的机制进行了研究。病毒DNA的结合导致AIM 2炎性体活化和IL-1 β释放，而IFI 16活化导致IFN-β释放。使用免疫组织化学，AIM 2和IFI 16-最近确定的细胞溶质DNA传感器-也检测到HPV阳性皮肤病变。CISH染色进一步证实了活检样品中胞浆HPV 16 DNA的存在。此外，在HPV感染的皮肤中检测到活性IL-1 β和裂解的半胱天冬酶-1，表明病毒DNA激活了炎性小体。在随后的功能研究中，HPV 16 DNA通过正常人角质形成细胞中的AIM 2炎性小体触发IL-1 β和IL-18释放。虽然HPV DNA在角质形成细胞中不诱导IFN-β，但当AIM 2被阻断时观察到IFN-β分泌。同时，阻断IFI 16可增加HPV 16 DNA诱导的IL-1 β分泌，但不增加IL-18分泌。这些发现表明在对HPV DNA的免疫应答中IFI 16和AIM 2之间存在串扰。总之，鉴定了关于HPV诱导的先天免疫应答的新方面。最终，了解HPV诱导的炎性小体激活的机制可能会导致预防和治疗HPV感染的新策略的发展。
Human papillomaviruses (HPV) are double-stranded DNA viruses, which selectively infect keratinocytes in stratified epithelia. After an initial infection, many patients clear HPV. In some patients, however, HPV persist, and dysfunctional innate immune responses to HPV infection could be involved in the ineffective clearing of these viruses. In this study, the mechanisms of HPV-induced immune responses in keratinocytes were investigated. Binding of viral DNA leads to AIM2 inflammasome activation and IL-1 beta release, while IFI16 activation results in IFN-beta release. Using immunohistochemistry, AIM2 and IFI16-two recently identified sensors for cytosolic DNA-were also detected in HPV positive skin lesions. CISH stainings further confirmed the presence of cytosolic HPV16 DNA in biopsy samples. Moreover, active IL-1 beta and cleaved caspase-1 were detected in HPV infected skin, suggesting inflammasome activation by viral DNA. In subsequent functional studies, HPV16 DNA triggered IL-1 beta and IL-18 release via the AIM2 inflammasome in normal human keratinocytes. Although HPV DNA did not induce IFN-beta in keratinocytes, IFN-beta secretion was observed when AIM2 was blocked. Meanwhile, blocking of IFI16 increased HPV16 DNA-induced IL-1 beta, but not IL-18, secretion. These findings suggest crosstalk between IFI16 and AIM2 in the immune response to HPV DNA. In sum, novel aspects concerning HPV-induced innate immune responses were identified. Eventually, understanding the mechanisms of HPV-induced inflammasome activation could lead to the development of novel strategies for the prevention and treatment of HPV infections.