The Metabolic Cytokine Adiponectin Inhibits Inflammatory Lung Pathology in Invasive Aspergillosis
The Metabolic Cytokine Adiponectin Inhibits Inflammatory Lung Pathology in Invasive Aspergillosis
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脂联素抑制侵袭性肺曲霉菌病炎症性肺病变的研究
DOI：
10.4049/jimmunol.1900174
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发表时间：
2019-08-15
影响因子：
4.4
通讯作者：
Templeton, Steven P.
中科院分区：
文献类型：
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作者：
Amarsaikhan, Nansalmaa;Tsoggerel, Angar;Templeton, Steven P.
系统免疫和代谢受到多种可溶性因素的共同调节，其中包括胰岛素调节脂肪组织细胞因子脂联素。这些因素如何在真菌感染期间影响有害的炎症反应仍不清楚。在这项研究中，我们观察到，在中性粒细胞减少的侵袭性曲霉病模型中，脂联素缺陷小鼠的死亡率、真菌负担和组织病理学增加。肺RNA测序、定量RT-PCR和随后的途径分析显示，在脂联素缺陷小鼠中，炎症细胞因子途径被激活，并受到IL-1和肿瘤坏死因子的上游调控，抗炎基因/途径减少/被抑制，这表明广泛的细胞因子介导的病理伴随着无效的真菌清除。定量RT-PCR分析证实，脂联素缺陷小鼠感染后早期IL-1a、IL-6、IL-12b、IL-17A/F和肿瘤坏死因子的转录增加，肺泡巨噬细胞内的肿瘤坏死因子特异性增加。尽管脂联素缺乏的小鼠的嗜酸性粒细胞募集和激活增加，但在脂联素和嗜酸性粒细胞缺乏的小鼠中，死亡率延迟，但并未降低。有趣的是，脂联素缺陷小鼠对膨胀/固定的分生孢子的反应是中性粒细胞耗尽导致炎症增加，这表明免疫抑制增强了有害的炎症，而侵袭性真菌的生长是可有可无的。我们的结果表明，脂联素可以抑制侵袭性曲霉病患者过度的肺部炎症。因此，我们的研究确定脂联素途径是免疫功能低下、对侵袭性真菌感染免疫不良的患者的新疗法的潜在来源。
Systemic immunity and metabolism are coregulated by soluble factors, including the insulin-regulating adipose tissue cytokine adiponectin. How these factors impact detrimental inflammatory responses during fungal infection remains unknown. In this study, we observed that mortality, fungal burden, and tissue histopathology were increased in adiponectin-deficient mice in a neutropenic model of invasive aspergillosis. Lung RNA sequencing, quantitative RT-PCR, and subsequent pathway analysis demonstrated activation of inflammatory cytokine pathways with upstream regulation by IL-1 and TNF in adiponectin-deficient mice with decreased/inhibited anti-inflammatory genes/pathways, suggesting broad cytokine-mediated pathology along with ineffective fungal clearance. Quantitative RT-PCR analysis confirmed increased transcription of IL-1a, IL-6, IL-12b, IL-17A/F, and TNF in adiponectin-deficient mice at early time points postinfection, with a specific increase in intracellular TNF in alveolar macrophages. Although eosinophil recruitment and activation were increased in adiponectin-deficient mice, mortality was delayed, but not decreased, in mice deficient in both adiponectin and eosinophils. Interestingly, neutrophil depletion was required for increased inflammation in adiponectin-deficient mice in response to swollen/fixed conidia, suggesting that immune suppression enhances detrimental inflammation, whereas invasive fungal growth is dispensable. Our results suggest that adiponectin inhibits excessive lung inflammation in invasive aspergillosis. Our study has therefore identified the adiponectin pathway as a potential source for novel therapeutics in immune-compromised patients with detrimental immunity to invasive fungal infection.