Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
Inflamm Res. 2023 Jan;72(1):27-41. doi: 10.1007/s00011-022-01638-3. Epub 2022 Oct 31.
Dendritic cells (DCs) are one of the key immune cells in bridging innate and adaptive immune response against Mycobacterium tuberculosis (Mtb) infection. Interferons (IFNs) play important roles in regulating DC activation and function. Virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible (Viperin) is one of the important IFN-stimulated genes (ISGs), and elicits host defense against infection.
We investigated the effects and mechanisms of Viperin on DC activation and function using Viperin deficient bone marrow-derived dendritic cells (BMDCs) during Mtb infection.
Viperin deficiency enhanced phagocytic activity and increased clearance of Mtb in DCs, produced higher abundance of NO, cytokine including interleukin-12 (IL-12), Tumor necrosis factor-α (TNF-α), IL-1β, IL-6 and chemokine including CXCL1, CXCL2 and CXCL10, elevated MHC I, MHC II and co-stimulatory molecules expression, and enhanced CD4 and CD8 T cell responses. Mechanistically, Viperin deficiency promoted DC activation and function through NF-κB p65 activation. NF-κB p65 inhibitor prevented cytokine and chemokine production, and co-stimulatory molecules expression promoted by Viperin deficiency.
These results suggest that Mtb induced Viperin expression could impair the activation of host defense function of DCs and DC-T cell cross talk during Mtb infection. This research may provide a potential target for future HDT in TB therapy.
树突状细胞（DC）是连接先天免疫和适应性免疫对抗结核分枝杆菌（Mtb）感染的关键免疫细胞之一。干扰素（IFN）在调节 DC 激活和功能方面发挥着重要作用。病毒抑制蛋白、内质网相关、干扰素诱导（Viperin）是重要的干扰素刺激基因（ISGs）之一，可引发宿主对感染的防御。
我们研究了 Viperin 在 Mtb 感染期间对 DC 激活和功能的影响及其机制，使用 Viperin 缺陷型骨髓来源的树突状细胞（BMDCs）进行研究。
Viperin 缺陷增强了 DC 中的吞噬活性和 Mtb 的清除，产生了更高水平的 NO、细胞因子（包括白细胞介素-12（IL-12）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和趋化因子（包括 CXCL1、CXCL2 和 CXCL10），上调 MHC I、MHC II 和共刺激分子的表达，并增强 CD4 和 CD8 T 细胞反应。在机制上，Viperin 缺陷通过 NF-κB p65 激活促进 DC 的激活和功能。NF-κB p65 抑制剂可防止由 Viperin 缺陷引起的细胞因子和趋化因子产生以及共刺激分子表达。
这些结果表明，Mtb 诱导的 Viperin 表达可能会损害 DC 在 Mtb 感染期间激活宿主防御功能和 DC-T 细胞相互作用。这项研究可能为未来结核病治疗中的高密度治疗提供一个潜在的靶点。
