Division of Clinical and Translational Research, House Research Institute, Los Angeles, CA 90057, USA.
J Immunol. 2012 Apr 1;188(7):3496-505. doi: 10.4049/jimmunol.1103182. Epub 2012 Feb 29.
The inner ear, composed of the cochlea and the vestibule, is a specialized sensory organ for hearing and balance. Although the inner ear has been known as an immune-privileged organ, there is emerging evidence indicating an active immune reaction of the inner ear. Inner ear inflammation can be induced by the entry of proinflammatory molecules derived from middle ear infection. Because middle ear infection is highly prevalent in children, middle ear infection-induced inner ear inflammation can impact the normal development of language and motor coordination. Previously, we have demonstrated that the inner ear fibrocytes (spiral ligament fibrocytes) are able to recognize nontypeable Haemophilus influenzae, a major pathogen of middle ear infection, and upregulate a monocyte-attracting chemokine through TLR2-dependent NF-κB activation. In this study, we aimed to determine the molecular mechanism involved in nontypeable H. influenzae-induced cochlear infiltration of polymorphonuclear cells. The rat spiral ligament fibrocytes were found to release CXCL2 in response to nontypeable H. influenzae via activation of c-Jun, leading to the recruitment of polymorphonuclear cells to the cochlea. We also demonstrate that MEK1/ERK2 signaling pathway is required for nontypeable H. influenzae-induced CXCL2 upregulation in the rat spiral ligament fibrocytes. Two AP-1 motifs in the 5'-flanking region of CXCL2 appeared to function as a nontypeable H. influenzae-responsive element, and the proximal AP-1 motif was found to have a higher binding affinity to nontypeable H. influenzae-activated c-Jun than that of the distal one. Our results will enable us better to understand the molecular pathogenesis of middle ear infection-induced inner ear inflammation.
内耳由耳蜗和前庭组成，是听觉和平衡的专门感觉器官。尽管内耳被认为是免疫特惠器官，但越来越多的证据表明内耳存在活跃的免疫反应。内耳炎症可由来自中耳感染的促炎分子的进入引起。由于中耳感染在儿童中非常普遍，中耳感染引起的内耳炎症会影响语言和运动协调的正常发育。以前，我们已经证明内耳成纤维细胞（螺旋韧带成纤维细胞）能够识别非典型性流感嗜血杆菌，这是中耳感染的主要病原体，并通过 TLR2 依赖性 NF-κB 激活上调单核细胞趋化因子。在这项研究中，我们旨在确定非典型性流感嗜血杆菌诱导的耳蜗多形核细胞浸润涉及的分子机制。发现非典型性流感嗜血杆菌通过激活 c-Jun 使大鼠螺旋韧带成纤维细胞释放 CXCL2，导致多形核细胞募集到耳蜗。我们还证明 MEK1/ERK2 信号通路是大鼠螺旋韧带成纤维细胞中非典型性流感嗜血杆菌诱导 CXCL2 上调所必需的。CXCL2 5'-侧翼区的两个 AP-1 基序似乎作为非典型性流感嗜血杆菌反应元件起作用，并且近端 AP-1 基序与非典型性流感嗜血杆菌激活的 c-Jun 的结合亲和力高于远端 AP-1 基序。我们的研究结果将使我们能够更好地理解中耳感染引起的内耳炎症的分子发病机制。
