Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific.
Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific.
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DOI：
10.3389/fimmu.2021.749504
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发表时间：
2021
影响因子：
7.3
通讯作者：
Kale SD
中科院分区：
文献类型：
--
作者：
Kastelberg B;Ayubi T;Tubau-Juni N;Leber A;Hontecillas R;Bassaganya-Riera J;Kale SD
Nlr家族成员X1 （Nlrx1）是一个免疫代谢中枢，参与介导对病毒、细菌、真菌、癌症和自身免疫性疾病的有效反应。我们之前已经证明Nlrx1是使用临床相关真菌烟曲霉感染的几种肺部真菌感染模型中免疫信号和死亡率的关键调节因子。在缺乏Nlrx1的情况下，宿主主要通过CD103+树突状细胞群产生增强的Th2应答，从而通过免疫发病机制和真菌负荷增加导致死亡率增加。在这里，我们展示了我们随后的研究成果，表明Nlrx1的缺失导致宿主细胞以细胞类型特异性的方式通过BEAS-2B气道上皮细胞、肺泡巨噬细胞、骨髓源性巨噬细胞（但不是骨髓源性中性粒细胞）处理烟状芽孢杆菌的能力下降。此外，Nlrx1的缺失导致在对真菌PAMPs、分生孢子和菌丝的特定反应中产生超氧化物和/或一般活性氧的能力下降。糖酵解和线粒体功能分析表明，在BEAS-2B细胞中，Nlrx1需要适当地关闭烟曲霉分生孢子的糖酵解，并增加对菌丝的糖酵解。通过葡萄糖-6-磷酸脱氢酶抑制剂阻断糖酵解和戊糖磷酸途径（PPP），通过2-DG和NADPH产生，导致野生型BEAS-2B细胞分生孢子加工显著减少至nlrx1缺陷的BEAS-2B细胞水平。我们的研究结果表明，气道上皮细胞需要通过PPP产生NADPH来响应分生孢子产生活性氧。在真菌肺部感染的背景下，我们的研究结果表明Nlrx1在宿主防御中发挥重要作用，通过PPP调节代谢的几个方面，特别是糖酵解，促进分生孢子加工，除了在调节免疫信号传导方面发挥关键作用。
The Nlr family member X1 (Nlrx1) is an immuno-metabolic hub involved in mediating effective responses to virus, bacteria, fungi, cancer, and auto-immune diseases. We have previously shown that Nlrx1 is a critical regulator of immune signaling and mortality in several models of pulmonary fungal infection using the clinically relevant fungus Aspergillus fumigatus. In the absence of Nlrx1, hosts produce an enhanced Th2 response primarily by CD103+ dendritic cell populations resulting in enhanced mortality via immunopathogenesis as well as enhanced fungal burden. Here, we present our subsequent efforts showcasing loss of Nlrx1 resulting in a decreased ability of host cells to process A. fumigatus conidia in a cell-type-specific manner by BEAS-2B airway epithelial cells, alveolar macrophages, bone marrow-derived macrophages, but not bone marrow-derived neutrophils. Furthermore, loss of Nlrx1 results in a diminished ability to generate superoxide and/or generic reactive oxygen species during specific responses to fungal PAMPs, conidia, and hyphae. Analysis of glycolysis and mitochondrial function suggests that Nlrx1 is needed to appropriately shut down glycolysis in response to A. fumigatus conidia and increase glycolysis in response to hyphae in BEAS-2B cells. Blocking glycolysis and pentose phosphate pathway (PPP) via 2-DG and NADPH production through glucose-6-phosphate dehydrogenase inhibitor resulted in significantly diminished conidial processing in wild-type BEAS-2B cells to the levels of Nlrx1-deficient BEAS-2B cells. Our findings suggest a need for airway epithelial cells to generate NADPH for reactive oxygen species production in response to conidia via PPP. In context to fungal pulmonary infections, our results show that Nlrx1 plays significant roles in host defense via PPP modulation of several aspects of metabolism, particularly glycolysis, to facilitate conidia processing in addition to its critical role in regulating immune signaling.