NADPH Oxidase Limits Collaborative Pattern-Recognition Receptor Signaling to Regulate Neutrophil Cytokine Production in Response to Fungal Pathogen-Associated Molecular Patterns.
NADPH Oxidase Limits Collaborative Pattern-Recognition Receptor Signaling to Regulate Neutrophil Cytokine Production in Response to Fungal Pathogen-Associated Molecular Patterns.
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DOI：
10.4049/jimmunol.2001298
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发表时间：
2021-08-01
期刊：
影响因子：
--
通讯作者：
Dinauer MC
中科院分区：
文献类型：
--
作者：
Yoo DG;Paracatu LC;Xu E;Lin X;Dinauer MC
慢性肉芽肿病（CGD）是由白细胞NADPH氧化酶基因缺陷引起的一种原发性免疫缺陷病，具有杀菌和免疫调节作用。因此，CGD的特征在于复发性细菌和真菌感染以及异常炎症。真菌细胞壁诱导CGD中的嗜酸性炎症，但其潜在机制尚未完全了解。本研究探讨了真菌细胞壁激活的CGD中性粒细胞中驱动异常促炎细胞因子产生的受体和信号通路。虽然细胞因子对β-葡聚糖颗粒的反应在NADPH氧化酶活性和NADPH氧化酶缺陷的小鼠和人类中性粒细胞中相似，但酵母聚糖（一种更复杂的真菌颗粒）的刺激可诱导NADPH氧化酶缺陷的中性粒细胞中细胞因子产生增加。识别β（1-3）-葡聚糖的dectin-1 C型凝集素受体和Toll样受体（TLR）介导野生型鼠中性粒细胞的细胞因子应答。在没有NADPH氧化酶的情况下，真菌PAMPs与Mac-1和TLR进行额外的协同信号传导，以显著增加细胞因子的产生。从机制上讲，这种细胞因子的过度产生是由酪氨酸磷酸酶SHP 2-Syk和下游Card 9依赖性NFkB和Card 9独立性JNK-c-Jun的增强近端激活介导的。外源性H2 O2处理，外源性H2 O2的酶促生成或Mac-1阻断显著降低了这种激活和放大的细胞因子产生。与酵母聚糖类似，烟曲霉分生孢子诱导CGD小鼠嗜中性粒细胞中增加的信号传导以激活促炎细胞因子产生，其也利用Mac-1并且是Card 9依赖性的。这项研究提供了新的见解如何NADPH氧化酶缺乏失调中性粒细胞细胞因子的生产，以应对真菌细胞壁。
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by genetic defects in leukocyte NADPH oxidase, which has both microbicidal and immunomodulatory roles. Hence, CGD is characterized by recurrent bacterial and fungal infections as well as aberrant inflammation. Fungal cell walls induce neutrophilic inflammation in CGD yet underlying mechanisms are incompletely understood. This study investigated the receptors and signaling pathways driving aberrant pro-inflammatory cytokine production in CGD neutrophils activated by fungal cell walls. While cytokine responses to β-glucan particles were similar in NADPH oxidase -competent and NADPH-oxidase deficient mouse and human neutrophils, stimulation with zymosan, a more complex fungal particle, induced elevated cytokine production in NADPH oxidase-deficient neutrophils. The dectin-1 C-type lectin receptor, which recognizes β(1–3)-glucans, and Toll-like receptors (TLRs) mediated cytokine responses by wild-type murine neutrophils. In the absence of NADPH oxidase, fungal PAMPs engaged additional collaborative signaling with Mac-1 and TLRs to markedly increase cytokine production. Mechanistically, this cytokine overproduction is mediated by enhanced proximal activation of tyrosine phosphatase SHP2-Syk and downstream Card9-dependent NFkB and Card9-independent JNK-c-Jun. This activation and amplified cytokine production were significantly decreased by exogenous H2O2 treatment, enzymatic generation of exogenous H2O2 or Mac-1 blockade. Similar to zymosan, Aspergillus fumigatus conidia induced increased signaling in CGD mouse neutrophils for activation of pro-inflammatory cytokine production, which also utilized Mac-1 and was Card9-dependent. This study provides new insights into how NADPH oxidase deficiency deregulates neutrophil cytokine production in response to fungal cell walls.
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