Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple, TX, USA.
EMBO Mol Med. 2012 May;4(5):435-48. doi: 10.1002/emmm.201200221. Epub 2012 Feb 22.
Sterile inflammation underlies many diseases of the cornea including serious chemical burns and the common dry eye syndrome. In search for therapeutic targets for corneal inflammation, we defined the kinetics of neutrophil infiltration in a model of sterile injury to the cornea and identified molecular and cellular mechanisms triggering inflammatory responses. Neutrophil infiltration occurred in two phases: a small initial phase (Phase I) that began within 15 min after injury, and a larger second phase (Phase II) that peaked at 24-48 h. Temporal analysis suggested that the neuropeptide secretoneurin initiated Phase I without involvement of resident macrophages. Phase II was initiated by the small heat shock protein HSPB4 that was released from injured keratocytes and that activated resident macrophages via the TLR2/NF-κB pathway. The Phase II inflammation was responsible for vision-threatening opacity and was markedly suppressed by different means of inhibition of the HSPB4/TLR2/NF-κB axis: in mice lacking HSPB4 or TLR2, by antibodies to HSPB4 or by TNF-α stimulated gene/protein 6 that CD44-dependently inhibits the TLR2/NF-κB pathway. Therefore, our data identified the HSPB4/TLR2/NF-κB axis in macrophages as an effective target for therapy of corneal inflammation.
无菌性炎症是许多角膜疾病的基础，包括严重的化学灼伤和常见的干眼症。为了寻找治疗角膜炎症的靶点，我们在角膜无菌性损伤模型中定义了中性粒细胞浸润的动力学，并确定了触发炎症反应的分子和细胞机制。中性粒细胞浸润发生在两个阶段：损伤后 15 分钟内开始的初始小阶段（I 期），以及在 24-48 小时达到峰值的较大的第二阶段（II 期）。时间分析表明，神经肽分泌素启动了 I 期，而不涉及驻留巨噬细胞。II 期由从小型热休克蛋白 HSPB4 开始，HSPB4 从受伤的角膜细胞释放，并通过 TLR2/NF-κB 途径激活驻留巨噬细胞。第二期炎症是导致威胁视力的混浊的原因，通过抑制 HSPB4/TLR2/NF-κB 轴的不同方法显著抑制：在缺乏 HSPB4 或 TLR2 的小鼠中，通过针对 HSPB4 的抗体或通过 TNF-α 刺激基因/蛋白 6，该蛋白 6 通过 CD44 依赖性抑制 TLR2/NF-κB 途径。因此，我们的数据确定了巨噬细胞中的 HSPB4/TLR2/NF-κB 轴是治疗角膜炎症的有效靶点。
