TREM-2介导的中耳胆脂瘤骨质破坏作用及分子调控机制研究

The middle ear cholesteatoma is an inflammatory deafness disease characterized by progressie bone destruction. Preliminary study confirmed that the pathogen infection of the middle ear cholesteatoma can activate the TLR4 signaling pathway, release pro-inflammatory factor, promote osteoclast activation, causing bone destruction. Triggering receptor (TREM) -2, a newly discovered pattern recognition receptors, could inhibits or activates TLRs signal. However, there is no report about the role of TREM-2 in middle ear cholesteatoma. Preliminary experiments found that expression of TREM-2 in cholesteatoma were significantly up-regulated, and positively related to the bone destruction; After the knockout of TREM-2, volume of cholesteatoma and bone destruction in mice were downregulated. In addition, the TREM-2 inhibits the expression of negative regulatory factors of TLRs such as PAAR-δ, C1q, and upregulates expression of TLR4 and proinflammatory factor, promoting osteoclast activation. Thus, we first make a hypothesis that through inhibiting activation of PAAR-δ/C1q, TREM-2 upregulates TLR signaling pathways and enhances the mediated inflammatory reaction, promoting the bony destruction in cholesteatoma. This research will reveal the role of TREM-2 in cholesteatoma through experiments in vivo and in vitro. Further, we will provide the experimental basis to make clear the molecular mechanism of bone destruction in cholestetoma, and open up new ideas for its prevention and treatment.

中耳胆脂瘤是以进行性骨质破坏为特征的炎性致聋性疾病。前期研究证实病原菌感染中耳胆脂瘤可激活TLR4信号通路，通过释放促炎因子，促破骨细胞激活而促进骨质破坏。诱发受体（TREM）-2是新近发现的模式识别受体，可抑制或活化TLRs信号。然而，目前尚无TREM-2在中耳胆脂瘤中作用的报道。预实验发现：TREM-2在人胆脂瘤中表达均显著上调，并且与骨质破坏程度正相关；其敲除后，显著减轻小鼠胆脂瘤体积、骨质破坏程度。此外，TREM-2抑制TLRs的负性调控因子PAAR-δ、C1q表达，上调TLR4及促炎因子表达，促破骨细胞激活。由此，我们首次提出TREM-2通过抑制PAAR-δ/C1q激活而发挥正调控TLR信号通路并放大其介导的炎症反应，促胆脂瘤骨质破坏作用”的假说。本课题将通过体内、外实验揭示TREM-2在胆脂瘤骨质破坏中的作用，为明确中耳胆脂瘤骨质破坏的分子机制提供实验依据，并为其防治开辟新思路

中耳胆脂瘤是一种以鳞状上皮过度增生、角化上皮脱屑堆积和骨质破坏为主要特征的最常见的慢性致聋性疾病。我们的前期研究发现细菌感染及其激活的免疫炎症反应启动中耳胆脂瘤骨质破坏，且证实TLR4在胆脂瘤骨质破坏中起关键作用。那么，TLR4介导胆脂瘤骨质破坏的具体机制是什么？我们进一步研究发现髓样诱发受体（Triggering receptor－2 expressed on myeloid cells，TREM-2）主要表达于树突状细胞，且在人及小鼠胆脂瘤中表达均显著上调，并与骨破坏程度呈正相关。沉默TREM-2后，小鼠骨质破坏程度减轻。此外，通过体内、体外实验证明TREM2与MMPs、TLR4及TLR4下游的炎症因子（IL-1β、TNF-α、IL-6）呈正相关。因此，我们的研究证实了TREM-2通过放大TLR4信号通路介导的炎症反应，促进MMPs分泌，破骨细胞活化,而介导胆脂瘤的骨质破坏。本课题将通过体内、外实验揭示TREM-2在胆脂瘤骨质破坏中的作用，为明确中耳胆脂瘤骨质破坏的分子机制提供实验依据，并为其防治开辟新思路。