Diaz-Nicieza Celia, Sahyoun Laura, Michalaki Christina, Johansson Cecilia, Culley Fiona J
National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Norfolk Place, London, W2 1PG, UK.
Immun Ageing. 2024 Sep 12;21(1):62. doi: 10.1186/s12979-024-00467-8.
Ageing is associated with an increased risk of lung infection and chronic inflammatory lung disease. Innate immune responses are the first line of defence in the respiratory tract, however, age-related changes to innate immunity in the lung are not fully described. Both resident haematopoietic cells, such as alveolar macrophages, and non-haematopoeitic cells, such as epithelial and endothelial cells can contribute to inflammatory and immune responses in the lung. In this study we aimed to determine the impact of ageing on early innate responses of resident cells in the lung.
Aged and young mice were inoculated intranasally with lipopolysaccharide (LPS). After 4 h, aged mice recruited higher numbers of neutrophils to the airways and lung. This exacerbated inflammatory response was associated with higher concentrations of chemokines CXCL1, CXCL2 and CCL2 in the airways. Next, precision cut lung slices (PCLS) were stimulated ex vivo with LPS for 16 h. Gene expression of Cxcl2, Tnf and Il1b were all higher in PCLS from aged than young mice and higher levels of secretion of CXCL2 and TNF were detected. To determine which lung cells were altered by age, LPS was intranasally administered to aged and young mice and individual populations of cells isolated by FACS. RT-PCR on sorted cell populations demonstrated higher expression of inflammatory cytokines Cxcl2, Ccl2 and Tnf in epithelial cells and alveolar macrophages and higher expression of Cxcl2 by endothelial cells of aged mice compared to young. These differences in expression of pro-inflammatory cytokines did not correspond to higher levels of Tlr4 expression.
Ageing leads to a heightened neutrophilic inflammatory response in the lung after LPS exposure, and higher expression and production of pro-inflammatory cytokines by resident lung cells, including alveolar macrophages, epithelial cells and endothelial cells. The responses of multiple resident lung cell populations are altered by aging and contribute to the exacerbated inflammation in the lung following LPS challenge. This has implications for our understanding of respiratory infections and inflammation in older people.
衰老与肺部感染和慢性炎症性肺病风险增加相关。固有免疫反应是呼吸道的第一道防线，然而，肺部固有免疫与年龄相关的变化尚未完全阐明。驻留造血细胞，如肺泡巨噬细胞，以及非造血细胞，如上皮细胞和内皮细胞，均可参与肺部的炎症和免疫反应。在本研究中，我们旨在确定衰老对肺部驻留细胞早期固有反应的影响。
将老年和年轻小鼠经鼻接种脂多糖（LPS）。4小时后，老年小鼠气道和肺中募集的中性粒细胞数量更多。这种加剧的炎症反应与气道中趋化因子CXCL1、CXCL2和CCL2的浓度升高有关。接下来，将精密切割肺片（PCLS）用LPS进行体外刺激16小时。老年小鼠的PCLS中Cxcl2、Tnf和Il1b的基因表达均高于年轻小鼠，并且检测到CXCL2和TNF的分泌水平更高。为了确定哪些肺细胞因年龄而发生改变，将LPS经鼻给予老年和年轻小鼠，并通过荧光激活细胞分选术（FACS）分离单个细胞群体。对分选的细胞群体进行逆转录-聚合酶链反应（RT-PCR）显示，与年轻小鼠相比，老年小鼠的上皮细胞和肺泡巨噬细胞中炎症细胞因子Cxcl2、Ccl2和Tnf的表达更高，内皮细胞中Cxcl2的表达更高。促炎细胞因子表达的这些差异与Tlr4表达水平升高无关。
衰老导致LPS暴露后肺部中性粒细胞炎症反应增强，以及包括肺泡巨噬细胞、上皮细胞和内皮细胞在内的肺部驻留细胞促炎细胞因子的表达和产生增加。多个肺部驻留细胞群体的反应因衰老而改变，并导致LPS攻击后肺部炎症加剧。这对我们理解老年人的呼吸道感染和炎症具有重要意义。
