Department of Otorhinolaryngology Head and Neck Surgery, Department of Allergy, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China; Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing 100005, China; Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing 100005, China.
Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Cell Immunol. 2024 Nov-Dec;405-406:104884. doi: 10.1016/j.cellimm.2024.104884. Epub 2024 Oct 18.
Unlike T cells and B cells, the activation process of group 2 innate lymphoid cells (ILC2s) is mainly driven by epithelial cell derived cytokines rather than specific antigen recognition. Whether antigens have a direct role in activating ILC2s remains poorly understood.
Following stimulation, type 2 cytokine secretions and cell death were assessed in house dust mite (HDM)-stimulated ILC2s. To investigate the underlying mechanisms, RNA-sequencing (RNA-seq) was performed on HDM-stimulated ILC2s. The validation experiments were done through in vitro stimulation assays and an HDM-induced asthmatic murine model, using specific inhibitors targeting receptor and relevant proteins of signaling pathways.
HDM stimulation increased the secretion of IL-5 and IL-13 cytokines from ILC2s, inhibited apoptosis of ILC2, and promoted the proliferation of ILC2s. As confirmed by RNA-seq, HDM stimulation upregulated genes in ILC2s, including those responsible for type 2 cytokines, ILC2s-specific transcriptional factors, and related receptors. Both toll-like receptor (TLR) 1 and TLR4 were constitutively expressed on ILC2s, however, only TLR4 was predominantly upregulated upon HDM stimulation. TAK242, a specific TLR4 inhibitor, significantly blocked the effect of HDM on ILC2s, in terms of type 2 cytokine secretions and cell death. Using specific inhibitors in pathways, we confirmed that HDM promoted ILC2s activation via TLR4-ERK, p38, and NF-κB signaling pathways.
Allergen HDM directly activates ILC2s through TLR4 mediated-ERK/p38/NF-κB signaling pathway. These findings provide new insights into how antigens propagate type 2 immune response via ILC2s, contributing to chronic inflammations in allergic airway diseases.
与 T 细胞和 B 细胞不同，2 型固有淋巴细胞（ILC2）的激活过程主要由上皮细胞衍生的细胞因子驱动，而不是由特定抗原识别驱动。抗原是否直接在激活 ILC2 中起作用尚不清楚。
用屋尘螨（HDM）刺激 ILC2 后，评估 2 型细胞因子的分泌和细胞死亡。为了研究潜在的机制，对 HDM 刺激的 ILC2 进行了 RNA 测序（RNA-seq）。通过体外刺激试验和 HDM 诱导的哮喘小鼠模型，使用针对信号通路受体和相关蛋白的特异性抑制剂，对验证实验进行了验证。
HDM 刺激增加了 ILC2 细胞分泌 IL-5 和 IL-13 细胞因子，抑制了 ILC2 细胞的凋亡，并促进了 ILC2 细胞的增殖。正如 RNA-seq 所证实的那样，HDM 刺激上调了 ILC2 中的基因，包括负责 2 型细胞因子、ILC2 特异性转录因子和相关受体的基因。TLR1 和 TLR4 都在 ILC2 上持续表达，但只有 TLR4 在受到 HDM 刺激后明显上调。TLR4 特异性抑制剂 TAK242 显著阻断了 HDM 对 ILC2 细胞 2 型细胞因子分泌和细胞死亡的影响。通过在途径中使用特异性抑制剂，我们证实 HDM 通过 TLR4-ERK、p38 和 NF-κB 信号通路促进 ILC2 激活。
过敏原 HDM 通过 TLR4 介导的 ERK/p38/NF-κB 信号通路直接激活 ILC2。这些发现为抗原如何通过 ILC2 引发 2 型免疫反应提供了新的见解，有助于过敏性气道疾病的慢性炎症。
