Neutrophil and Macrophage NADPH Oxidase 2 Differentially Control Responses to Inflammation and to Aspergillus fumigatus in Mice.
Neutrophil and Macrophage NADPH Oxidase 2 Differentially Control Responses to Inflammation and to Aspergillus fumigatus in Mice.
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DOI：
10.4049/jimmunol.2200543
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发表时间：
2022-11-15
期刊：
影响因子：
--
通讯作者：
Dinauer MC
中科院分区：
文献类型：
--
作者：
Idol RA;Bhattacharya S;Huang G;Song Z;Huttenlocher A;Keller NP;Dinauer MC
烟曲霉（Aspergillusfumigatus，AF）是一种重要的机会致病真菌，在先天性抗真菌免疫力低下的情况下可引起侵袭性肺曲霉病，包括慢性肉芽肿病，后者是由产生超氧化物的白细胞NADPH氧化酶2（NOX 2）的遗传缺陷引起的。衍生氧化剂具有抗微生物和免疫调节活性，并且在AF的情况下，有助于杀死真菌和抑制由真菌细胞壁诱导的炎症。由于巨噬细胞与中性粒细胞NOX 2在宿主对AF的反应中的相对作用尚不完全清楚，我们研究了NOX 2条件性缺失的小鼠。当由于LysM-Cre介导的缺失而导致肺泡巨噬细胞（AM）中不存在NOX 2时，吸入AF分生孢子的萌发增加。通过S100 a8（MRP 8）-Cre特异性地降低中性粒细胞中的N 0X 2活性也增加了真菌负荷，这与中性粒细胞N 0X 2活性水平成反比。此外，减少的NOX 2在中性粒细胞协同皮质类固醇免疫抑制损害肺清除AF。中性粒细胞特异性减少NOX 2活性也增强了急性炎症诱导的吸入无菌真菌细胞壁。这些结果推进理解到细胞特异性作用的NOX 2在主机响应AF。我们表明，肺泡巨噬细胞NOX 2是一个非冗余的效应器，限制了吸入AF分生孢子的萌发。相比之下，仅在中性粒细胞中降低NOX 2活性足以增强真菌细胞壁的炎症以及促进侵袭性AF。这可能与由于基础疾病导致的NOX 2活性获得性缺陷的临床环境相关，这些疾病与侵袭性曲霉病的风险因素重叠。
Aspergillus fumigatus (AF) is an important opportunistic fungal pathogen and causes invasive pulmonary aspergillosis in conditions with compromised innate antifungal immunity, including chronic granulomatous disease, which results from inherited deficiency of the superoxide-generating leukocyte NADPH oxidase 2 (NOX2). Derivative oxidants have both anti-microbial and immunoregulatory activity, and in the context of AF, contribute to both fungal killing and dampening inflammation induced by fungal cell walls. As the relative roles of macrophage vs neutrophil NOX2 in the host response to AF are incompletely understood, we studied mice with conditional deletion of NOX2. When NOX2 was absent in alveolar macrophages (AM) as a result of LysM-Cre-mediated deletion, germination of inhaled AF conidia was increased. Reducing NOX2 activity specifically in neutrophils via S100a8 (MRP8)-Cre also increased fungal burden, which was inversely proportional to the level of neutrophil NOX2 activity. Moreover, diminished NOX2 in neutrophils synergized with corticosteroid immunosuppression to impair lung clearance of AF. Neutrophil-specific reduction in NOX2 activity also enhanced acute inflammation induced by inhaled sterile fungal cell walls. These results advance understanding into cell-specific roles of NOX2 in the host response to AF. We show that alveolar macrophage NOX2 is a non-redundant effector that limits germination of inhaled AF conidia. In contrast, reducing NOX2 activity only in neutrophils is sufficient to enhance inflammation to fungal cell walls as well as to promote invasive AF. This may be relevant in clinical settings with acquired defects in NOX2 activity due to underlying conditions, which overlap risk factors for invasive aspergillosis.
感知曲霉菌感染带来的威胁。
影响因子：
5.4
作者：
Obar JJ
通讯作者：
Obar JJ
影响因子：
3.7
作者：
Amarsaikhan N;O'Dea EM;Tsoggerel A;Owegi H;Gillenwater J;Templeton SP
通讯作者：
Templeton SP