TLR7-MyD88-DC-CXCL16 axis results neutrophil activation to elicit inflammatory response in pustular psoriasis.
TLR7-MyD88-DC-CXCL16 axis results neutrophil activation to elicit inflammatory response in pustular psoriasis.
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DOI：
10.1038/s41419-023-05815-y
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发表时间：
2023-05-09
影响因子：
9
通讯作者：
Shi, Yuling
中科院分区：
文献类型：
--
作者：
Lu, Jiajing;Zhong, Xiaoyuan;Guo, Chunyuan;Tang, Li;Yu, Ning;Peng, Chen;Ding, Yangfeng;Bao, Xunxia;Zhou, Jing;Shi, Yuling
脓疱性银屑病（PP）是一种慢性炎症性疾病，伴有多种并发症，常伴有高热和低蛋白血症，其持续进展可危及生命。Toll样受体7（TLR 7）诱导树突状细胞（DC）产生炎症因子，加剧PP中的炎症反应。一种在DC上表达的膜结合趋化因子，CXC基序趋化因子配体16（CXCL 16）在PP病变中过表达，并且中性粒细胞表达其受体CXC趋化因子受体6（CXCR 6）。关于PP免疫微环境的研究很少，目前还不清楚TLR 7和CXCL 16是否可以用作PP治疗的靶点。从PP和健康正常对照组收集皮肤组织（n = 5）和血液（n = 20）样品。分析皮肤组织转录组以获得差异表达的基因，并使用途径富集来解密免疫微环境。组织测序分析表明，TLR 7，CXCL 16，DC和中性粒细胞参与PP过程。酶联免疫吸附试验、逆转录-PCR和评分表结果表明，TLR 7诱导DC分泌CXCL 16，这使得中性粒细胞激活炎症因子白细胞介素-8（IL-8）和肿瘤坏死因子α（TNF-α）的分泌。中性粒细胞与用TLR 7抑制剂或TLR 7激动剂处理的DC的共培养证明TLR 7调节中性粒细胞活化、迁移和凋亡。我们在野生型、Cd 11 c-Cre Myd 88 f/f和Mrp 8-Cre Cxcr 6 f/f小鼠中构建了咪喹莫特诱导的银屑病样皮肤病变。小鼠模型提示TLR 7可能通过干扰髓系分化初级反应基因88（MyD 88）信号通路影响DC释放CXCL 16和中性粒细胞促炎作用。总之，TLR 7-MyD 88-DC-CXCL 16轴是促进中性粒细胞迁移到PP皮肤病变并刺激炎症反应的重要机制。
Pustular psoriasis (PP) is a chronic inflammatory disease associated with multiple complications, often with hyperthermia and hypoproteinemia, and its continued progression can be life-threatening. Toll-like receptor 7 (TLR7) induces dendritic cell (DC) production of inflammatory factors that exacerbate the inflammatory response in PP. A membrane-bound chemokine expressed on DCs, CXC motif chemokine ligand 16 (CXCL16) is overexpressed in PP lesions, and neutrophils express its receptor CXC chemokine receptor 6 (CXCR6). There are few studies on the PP immune microenvironment and it is unclear whether TLR7 and CXCL16 can be used as targets in PP therapy. Skin tissue (n = 5) and blood (n = 20) samples were collected from PP and healthy normal controls. The skin tissue transcriptome was analyzed to obtain the differentially expressed genes, and the immune microenvironment was deciphered using pathway enrichment. Tissue sequencing analysis indicated that TLR7, CXCL16, DCs, and neutrophils were involved in the PP process. The enzyme-linked immunosorbent assay, reverse transcription–PCR, and scoring table results demonstrated that TLR7 induced DC secretion of CXCL16, which enabled neutrophil activation of the secretion of the inflammatory factors interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α). The co-culture of neutrophils with DCs treated with TLR7 inhibitor or TLR7 agonist demonstrated that TLR7 regulated neutrophil activation, migration, and apoptosis. We constructed imiquimod-induced psoriasis-like skin lesions in wild-type, Cd11c-Cre Myd88f/f, and Mrp8-Cre Cxcr6f/f mice. The mouse models suggested that TLR7 might influence DC release of CXCL16 and neutrophil proinflammatory effects by interfering with the myeloid differentiation primary response gene 88 (MyD88) signaling pathway. In conclusion, the TLR7–MyD88–DC–CXCL16 axis is an important mechanism that promotes neutrophil migration to PP skin lesions and stimulates the inflammatory response.
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影响因子：
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作者：
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