Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging.
Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging.
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DOI：
10.1152/ajplung.00315.2021
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发表时间：
2022-01-01
期刊：
影响因子：
--
通讯作者：
Mishra A
中科院分区：
文献类型：
--
作者：
Jaiswal AK;Yadav J;Makhija S;Sandey M;Suryawanshi A;Mitra AK;Mishra A
哮喘及其异质性随年龄而变化。空域中性粒细胞数量增加导致老年人严重的激素抵抗性哮喘加重，这与成人哮喘患者的变化相关。然而，这是否类似于老年人和成年人的相同疾病机制和病理生理学尚不清楚。在这里，我们试图解决老年小鼠类固醇耐药气道炎症发展和对皮质类固醇（Dex）治疗反应的潜在分子机制。为了研究炎症机制的变化，我们使用了一个临床相关的治疗模型，屋尘螨（HDM）诱导的过敏性哮喘，并研究了肺适应性免疫反应的成年（20-22周龄）和老年（80-82周龄）小鼠。我们的研究结果表明，年龄依赖性增加的气道高反应性（AHR），混合肉芽肿性气道炎症，包括嗜酸性粒细胞和中性粒细胞，和Th 1/Th 17免疫反应的频率和数量的HDM轴承树突状细胞（DC）积累在老年小鼠的引流淋巴结（DLn）与成年小鼠相比，进行性下降。老年肺的RNA-Seq实验揭示了短腭、肺和鼻上皮克隆1（SPLUNC 1）作为类固醇响应基因之一，其随着年龄的增长而逐渐下降，并进一步通过HDM诱导的炎症而下降。此外，我们发现重组SPLUNC 1（rSPLUNC 1）处理增加了糖酵解重编程、DC的成熟/活化、OT-II细胞的增殖和Th 2细胞因子分泌。我们的研究结果表明SPLUNC 1调节DC的代谢适应/成熟的新的免疫调节作用。SPLUNC 1水平的年龄依赖性下降可能与类固醇抵抗性气道炎症和哮喘异质性的发展有关。
Asthma and its heterogeneity change with age. Increased airspace neutrophil numbers contribute to severe steroid-resistant asthma exacerbation in the elderly, which correlates with the changes seen in adults with asthma. However, whether that resembles the same disease mechanism and pathophysiology in aged and adults is poorly understood. Here, we sought to address the underlying molecular mechanism of steroid-resistant airway inflammation development and response to corticosteroid (Dex) therapy in aged mice. To study the changes in inflammatory mechanism, we used a clinically relevant treatment model of house-dust mite (HDM)-induced allergic asthma and investigated lung adaptive immune response in adult (20–22 wk old) and aged (80–82 wk old) mice. Our result indicates an age-dependent increase in airway hyperresponsiveness (AHR), mixed granulomatous airway inflammation comprising eosinophils and neutrophils, and Th1/Th17 immune response with progressive decrease in frequencies and numbers of HDM-bearing dendritic cells (DC) accumulation in the draining lymph node (DLn) of aged mice as compared with adult mice. RNA-Seq experiments of the aged lung revealed short palate, lung, and nasal epithelial clone 1 (SPLUNC1) as one of the steroid-responsive genes, which progressively declined with age and further by HDM-induced inflammation. Moreover, we found increased glycolytic reprogramming, maturation/activation of DCs, the proliferation of OT-II cells, and Th2 cytokine secretion with recombinant SPLUNC1 (rSPLUNC1) treatment. Our results indicate a novel immunomodulatory role of SPLUNC1 regulating metabolic adaptation/maturation of DC. An age-dependent decline in the SPLUNC1 level may be involved in developing steroid-resistant airway inflammation and asthma heterogeneity.
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DOI：
10.18632/aging.100973
发表时间：
2016-06
期刊：
Aging
影响因子：
--
作者：
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通讯作者：
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DOI：
10.1165/rcmb.2003-0142oc
发表时间：
2004-02-01
影响因子：
6.4
作者：
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