Lim King Hoo, Wang Lishi, Dotse Eunice, Wang Meijun, Tiu Cheuk Ying, Wijanarko Kevin Julio, Wang Xin, Chow Kwan T
Department of Biomedical Sciences, City University of Hong Kong, 83 Tat Chee Ave, Kowloon Tong, Kowloon, Hong Kong.
Department of Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
J Leukoc Biol. 2024 Jan 5;115(1):190-200. doi: 10.1093/jleuko/qiad111.
Plasmacytoid dendritic cells are a rare subset of dendritic cells that exhibit antiviral functions in response to toll-like receptor 7/8 stimulations. Alternative toll-like receptors such as TLR4 have been known to be active in plasmacytoid dendritic cells for immune regulatory functions. However, it is unclear whether these toll-like receptors differentially activate plasmacytoid dendritic cells as compared with canonical toll-like receptor 7/8 stimulation. Here, we assessed alternative plasmacytoid dendritic cell activation states mediated by toll-like receptors other than endosomal toll-like receptors via the RNA sequencing approach. We found that toll-like receptor 4 stimulation induced a high degree of similarity in gene expression pattern to toll-like receptor 7/8 stimulation in plasmacytoid dendritic cells. Despite high resemblance to toll-like receptor 7/8, we discovered unique genes that were activated under toll-like receptor 4 activation only, as well as genes that were induced at a higher magnitude in comparison to toll-like receptor 7/8 activation. In comparison between toll-like receptor 4-activated plasmacytoid dendritic cells and conventional dendritic cells, we revealed that plasmacytoid dendritic cells and conventional dendritic cells expressed distinct gene sets, whereby conventional dendritic cells mostly favored antigen presentation functions for adaptive immune response regulation while plasmacytoid dendritic cells leaned toward immune response against infectious diseases. Last, we determined that toll-like receptor 4 activation sensitized plasmacytoid dendritic cells against SARS-CoV-2 (COVID-19) single-stranded RNA by enhancing antiviral-related responses and type I interferon production. These findings provided greater insights into the toll-like receptor 4 activation state in plasmacytoid dendritic cells, which can be beneficial for alternative therapeutic interventions involving plasmacytoid dendritic cells for various diseases.
浆细胞样树突状细胞是树突状细胞的一个罕见亚群，在受到Toll样受体7/8刺激时表现出抗病毒功能。已知其他Toll样受体，如TLR4，在浆细胞样树突状细胞中具有免疫调节功能。然而，与经典的Toll样受体7/8刺激相比，这些Toll样受体是否会差异激活浆细胞样树突状细胞尚不清楚。在此，我们通过RNA测序方法评估了由内体Toll样受体以外的Toll样受体介导的浆细胞样树突状细胞的替代激活状态。我们发现，Toll样受体4刺激在浆细胞样树突状细胞中诱导的基因表达模式与Toll样受体7/8刺激高度相似。尽管与Toll样受体7/8高度相似，但我们发现了仅在Toll样受体4激活下被激活的独特基因，以及与Toll样受体7/8激活相比诱导程度更高的基因。在比较Toll样受体4激活的浆细胞样树突状细胞和传统树突状细胞时，我们发现浆细胞样树突状细胞和传统树突状细胞表达不同的基因集，其中传统树突状细胞大多倾向于抗原呈递功能以调节适应性免疫反应，而浆细胞样树突状细胞则倾向于针对传染病的免疫反应。最后，我们确定Toll样受体4激活通过增强抗病毒相关反应和I型干扰素产生，使浆细胞样树突状细胞对SARS-CoV-2（新冠病毒）单链RNA敏感。这些发现为浆细胞样树突状细胞中Toll样受体4的激活状态提供了更深入的见解，这可能有助于针对各种疾病的涉及浆细胞样树突状细胞的替代治疗干预。
