Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China.
Department of Ophthalmology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, China.
Int Immunopharmacol. 2024 Aug 20;137:112428. doi: 10.1016/j.intimp.2024.112428. Epub 2024 Jun 21.
Herpes simplex keratitis (HSK) is a blinding disease caused by herpes simplex virus type 1 (HSV-1) infection, and rapid eradication of the virus from the affected cornea is imperative. Nod-like receptors (NLRs) are intracellular innate immune sensors closely associated with cell death, inflammation and immune responses. In this study, we investigated the role of NLRP12 in the antiviral immunology in HSK and the underlying mechanisms. We found that NLRP12 expression was significantly decreased in HSV-1-infected human corneal epithelial cells (HCE-Ts) and HSK mouse corneas. Overexpression of NLRP12 significantly reduced viral replication in infected HCE-Ts and functioned through inflammasome-mediated pyroptosis and downstream IL-18-IFN-γ axis. In HSK mouse models, overexpression of NLRP12 reduced viral replication in the cornea and alleviated HSK symptoms. This resulted from enhanced antiviral immune responses including the activation of specific immune cells in both the cornea and the draining lymph nodes. Specifically, the NLRP12-IL-18-IFN-γ axis regulated the interaction between infected corneal epithelial cells and macrophages. In conclusion, our study identified a role of NLRP12 in mediating pyroptosis and regulating antiviral immune responses. This novel finding opens the possibilities of NLRP12 as a viable target in the therapeutic strategies for HSV-1 infection.
单纯疱疹性角膜炎（HSK）是由单纯疱疹病毒 1 型（HSV-1）感染引起的致盲性疾病，必须迅速从受影响的角膜中清除病毒。核苷酸结合寡聚化结构域样受体（NLRs）是与细胞死亡、炎症和免疫反应密切相关的细胞内固有免疫传感器。在这项研究中，我们研究了 NLRP12 在 HSK 中的抗病毒免疫学作用及其潜在机制。我们发现 NLRP12 在 HSV-1 感染的人角膜上皮细胞（HCE-Ts）和 HSK 小鼠角膜中的表达显著降低。NLRP12 的过表达可显著减少感染的 HCE-Ts 中的病毒复制，并通过炎性小体介导的细胞焦亡和下游 IL-18-IFN-γ 轴发挥作用。在 HSK 小鼠模型中，NLRP12 的过表达减少了角膜中的病毒复制并缓解了 HSK 症状。这是由于增强了抗病毒免疫反应，包括在角膜和引流淋巴结中特异性免疫细胞的激活。具体而言，NLRP12-IL-18-IFN-γ 轴调节受感染的角膜上皮细胞和巨噬细胞之间的相互作用。总之，我们的研究确定了 NLRP12 在介导细胞焦亡和调节抗病毒免疫反应中的作用。这一新发现为 NLRP12 作为 HSV-1 感染治疗策略的一个可行靶点提供了可能性。
