House dust mite allergen directly activates ILC2 cells via the TLR4 signaling pathway in allergic airway diseases

IF 3.7 4区 医学 Q2 CELL BIOLOGY Cellular immunology Pub Date : 2024-10-18 DOI:10.1016/j.cellimm.2024.104884
Yan Li , Zhennan Qu , Xue Wang , Qiqi Wang , Zhe Lv , Wei Wang , Sun Ying , Luo Zhang , Feng Lan
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.
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在过敏性气道疾病中,屋尘螨过敏原通过 TLR4 信号通路直接激活 ILC2 细胞。
背景:与 T 细胞和 B 细胞不同,第 2 组先天性淋巴细胞(ILC2s)的活化过程主要由上皮细胞衍生的细胞因子驱动,而非特异性抗原识别。抗原在激活 ILC2s 的过程中是否起直接作用,目前还不十分清楚:方法:在刺激后,评估了家尘螨(HDM)刺激的 ILC2 的 2 型细胞因子分泌和细胞死亡情况。为了研究其潜在机制,对受HDM刺激的ILC2s进行了RNA测序(RNA-seq)。利用针对受体和信号通路相关蛋白的特异性抑制剂,通过体外刺激试验和HDM诱导的哮喘小鼠模型进行了验证实验:结果:HDM刺激增加了ILC2分泌IL-5和IL-13细胞因子,抑制了ILC2的凋亡,促进了ILC2的增殖。RNA-seq证实,HDM刺激上调了ILC2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。ILC2上的toll样受体(TLR)1和TLR4都是组成型表达的,但在HDM刺激下,只有TLR4主要上调。TLR4特异性抑制剂TAK242能显著阻止HDM对ILC2的影响,包括2型细胞因子的分泌和细胞死亡。通过使用通路中的特异性抑制剂,我们证实了HDM通过TLR4-ERK、p38和NF-κB信号通路促进了ILC2s的活化:结论:过敏原 HDM 可通过 TLR4 介导的 ERK/p38/NF-κB 信号通路直接激活 ILC2。这些发现为了解抗原如何通过 ILC2s 传播 2 型免疫反应、导致过敏性气道疾病中的慢性炎症提供了新的视角。
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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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