Bacterial DNA promoting inflammation via the Sgk1/Nedd4L/Syk pathway in mast cells contributes to antihistamine-nonresponsive CSU

作者全名："Chen, Bangtao; Song, Yao; Yang, Xiongbo; Yang, Jing; Hao, Fei"

作者地址："[Chen, Bangtao; Yang, Xiongbo; Yang, Jing] Chong Univ, Sch Med, Gorges Hosp 3, Dept Dermatol, 165 Xincheng Rd, Chongqing 400030, Peoples R China; [Song, Yao; Hao, Fei] Chongqing Med Univ, Affiliated Hosp 3, Dept Pediat, 1 Shuanghu Rd, Chongqing 401120, Peoples R China; [Song, Yao] Chongqing Med Univ, Affiliated Hosp 3, Dept Dermatol, 1 Shuanghu Rd, Chongqing 401120, Peoples R China"

通信作者："Yang, J (通讯作者)，Chong Univ, Sch Med, Gorges Hosp 3, Dept Dermatol, 165 Xincheng Rd, Chongqing 400030, Peoples R China.; Hao, F (通讯作者)，Chongqing Med Univ, Affiliated Hosp 3, Dept Pediat, 1 Shuanghu Rd, Chongqing 401120, Peoples R China."

来源：JOURNAL OF LEUKOCYTE BIOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000981684700005

JCR分区：Q2

影响因子：3.6

年份：2023

卷号：113

期号：5

开始页：461

结束页：470

文献类型：Article

关键词：bacterial DNA; chronic spontaneous urticaria; inflammation; mast cell; spleen tyrosine kinase; serum and glucocorticoid-induced protein kinase 1; neuronally expressed developmentally downregulated 4L

摘要："Bacterial DNA/Tlr9 mediates proinflammation in mast cells involving the Sgk1/Nedd4L/Syk pathway, which is also present in IgE/Fc epsilon RI-induced degranulation. Inflammation centered on non-IgE-mediated mast cell activation characterizes chronic spontaneous urticaria resistant to nonsedating H1-antihistamines. We recently uncovered a strong positive association between inflammation and the fecal Escherichia. To further explore the actions of bacterial DNA derived from Escherichia on mast cells, intestinal permeability of patients with chronic spontaneous urticaria with or without nonsedating H1-antihistamine resistance and healthy controls were determined, and LAD2 cells with knockdown of Syk, Nedd4L, or Sgk1 or with incubation of inhibitors GS9973, GSK650394, and MG132 were posttreated with btDNA. We found that (i) serum intestinal permeability indices and bacterial DNA markedly increased in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance compared with those without (all P < 0.001), and bacterial DNA positively correlated with the degree of inflammation; (ii) IL-6 and TNF-alpha levels were time- and dose-dependently upregulated in bacterial DNA-stimulated LAD2 cells, which relied on unmethylated CpG in bacterial DNA and Toll-like receptor 9 protein in cells; (iii) Syk knockdown or inhibition of Syk Tyr525/526 phosphorylation blocked bacterial DNA-initiated cytokine production; (iv) Nedd4L interacted with Tyr525/526-phosphorylated Syk, and inhibition of Nedd4L Ser448 phosphorylation induced by bacterial DNA-activated Sgk1 was mandatory for bacterial DNA's proinflammatory property; and (v) Sgk1 suppression showed an inhibitory effect on bacterial DNA-induced inflammation by ensuring Nedd4L-mediated ubiquitination of Tyr525/526-phosphorylated Syk. Collectively, we identified previously unknown contributory roles of bacterial translocation and serum bacterial DNA on the inflammation phenotype in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance and further uncovered a vital negative regulatory role for the Sgk1/Nedd4L/Syk pathway in bacterial DNA-induced inflammation in LAD2 cells."

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