Németh Tamás, Futosi Krisztina, Sitaru Cassian, Ruland Jürgen, Mócsai Attila
Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary.
MTA-SE 'Lendület' Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, 1094 Budapest, Hungary.
Nat Commun. 2016 Apr 1;7:11004. doi: 10.1038/ncomms11004.
Neutrophils are terminally differentiated cells with limited transcriptional activity. The biological function of their gene expression changes is poorly understood. CARD9 regulates transcription during antifungal immunity but its role in sterile inflammation is unclear. Here we show that neutrophil CARD9 mediates pro-inflammatory chemokine/cytokine but not lipid mediator release during non-infectious inflammation. Genetic deficiency of CARD9 suppresses autoantibody-induced arthritis and dermatitis in mice. Neutrophil-specific deletion of CARD9 is sufficient to induce that phenotype. Card9(-/-) neutrophils show defective immune complex-induced gene expression changes and pro-inflammatory chemokine/cytokine release but normal LTB4 production and other short-term responses. In vivo deletion of CARD9 reduces tissue levels of pro-inflammatory chemokines and cytokines but not LTB4. The CARD9-mediated signalling pathway involves Src-family kinases, Syk, PLCγ2, Bcl10/Malt1 and NFκB. Collectively, CARD9-mediated gene expression changes within neutrophils play important roles during non-infectious inflammation in vivo and CARD9 acts as a divergence point between chemokine/cytokine and lipid mediator release.
中性粒细胞是终末分化细胞，转录活性有限。其基因表达变化的生物学功能尚不清楚。CARD9在抗真菌免疫过程中调节转录，但其在无菌性炎症中的作用尚不清楚。在这里，我们表明中性粒细胞CARD9在非感染性炎症期间介导促炎趋化因子/细胞因子的释放，但不介导脂质介质的释放。CARD9基因缺陷可抑制小鼠自身抗体诱导的关节炎和皮炎。中性粒细胞特异性缺失CARD9足以诱导该表型。Card9(-/-)中性粒细胞在免疫复合物诱导的基因表达变化和促炎趋化因子/细胞因子释放方面存在缺陷，但白三烯B4（LTB4）产生和其他短期反应正常。体内缺失CARD9可降低促炎趋化因子和细胞因子的组织水平，但不影响LTB4。CARD9介导的信号通路涉及Src家族激酶、Syk、PLCγ2、Bcl10/Malt1和NFκB。总的来说，中性粒细胞内CARD9介导的基因表达变化在体内非感染性炎症过程中起重要作用，并且CARD9是趋化因子/细胞因子释放和脂质介质释放之间的分歧点。
