He Meng, Borlak Jürgen
Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Immun Ageing. 2023 Nov 6;20(1):58. doi: 10.1186/s12979-023-00373-5.
The aging lung is a complex process and influenced by various stressors, especially airborne pathogens and xenobiotics. Additionally, a lifetime exposure to antigens results in structural and functional changes of the lung; yet an understanding of the cell type specific responses remains elusive. To gain insight into age-related changes in lung function and inflammaging, we evaluated 89 mouse and 414 individual human lung genomic data sets with a focus on genes mechanistically linked to extracellular matrix (ECM), cellular senescence, immune response and pulmonary surfactant, and we interrogated single cell RNAseq data to fingerprint cell type specific changes.
We identified 117 and 68 mouse and human genes linked to ECM remodeling which accounted for 46% and 27%, respectively of all ECM coding genes. Furthermore, we identified 73 and 31 mouse and human genes linked to cellular senescence, and the majority code for the senescence associated secretory phenotype. These cytokines, chemokines and growth factors are primarily secreted by macrophages and fibroblasts. Single-cell RNAseq data confirmed age-related induced expression of marker genes of macrophages, neutrophil, eosinophil, dendritic, NK-, CD4, CD8-T and B cells in the lung of aged mice. This included the highly significant regulation of 20 genes coding for the CD3-T-cell receptor complex. Conversely, for the human lung we primarily observed macrophage and CD4 and CD8 marker genes as changed with age. Additionally, we noted an age-related induced expression of marker genes for mouse basal, ciliated, club and goblet cells, while for the human lung, fibroblasts and myofibroblasts marker genes increased with age. Therefore, we infer a change in cellular activity of these cell types with age. Furthermore, we identified predominantly repressed expression of surfactant coding genes, especially the surfactant transporter Abca3, thus highlighting remodeling of surfactant lipids with implications for the production of inflammatory lipids and immune response.
We report the genomic landscape of the aging lung and provide a rationale for its growing stiffness and age-related inflammation. By comparing the mouse and human pulmonary genome, we identified important differences between the two species and highlight the complex interplay of inflammaging, senescence and the link to ECM remodeling in healthy but aged individuals.
肺老化是一个复杂的过程，受多种应激源影响，尤其是空气传播的病原体和外源性物质。此外，终生暴露于抗原会导致肺的结构和功能发生变化；然而，对细胞类型特异性反应的了解仍然有限。为了深入了解肺功能与炎症衰老的年龄相关变化，我们评估了89个小鼠和414个人类肺基因组数据集，重点关注与细胞外基质（ECM）、细胞衰老、免疫反应和肺表面活性物质有机制联系的基因，并对单细胞RNA测序数据进行分析，以明确细胞类型特异性变化。
我们鉴定出117个和68个与ECM重塑相关的小鼠和人类基因，分别占所有ECM编码基因的46%和27%。此外，我们鉴定出73个和31个与细胞衰老相关的小鼠和人类基因，其中大多数编码衰老相关分泌表型。这些细胞因子、趋化因子和生长因子主要由巨噬细胞和成纤维细胞分泌。单细胞RNA测序数据证实了老年小鼠肺中巨噬细胞、中性粒细胞、嗜酸性粒细胞、树突状细胞、NK细胞、CD4、CD8 - T细胞和B细胞标记基因的年龄相关诱导表达。这包括20个编码CD3 - T细胞受体复合物基因的高度显著调控。相反，对于人类肺，我们主要观察到巨噬细胞以及CD4和CD8标记基因随年龄变化。此外，我们注意到小鼠基底细胞、纤毛细胞、棒状细胞和杯状细胞标记基因的年龄相关诱导表达，而对于人类肺，成纤维细胞和肌成纤维细胞标记基因随年龄增加。因此，我们推断这些细胞类型的细胞活性随年龄变化。此外，我们主要鉴定出表面活性物质编码基因的表达受抑制，尤其是表面活性物质转运蛋白Abca3，从而突出了表面活性物质脂质的重塑，这对炎症脂质的产生和免疫反应有影响。
我们报告了老化肺的基因组概况，并为其不断增加的僵硬度和年龄相关炎症提供了理论依据。通过比较小鼠和人类肺基因组，我们确定了两个物种之间的重要差异，并强调了健康但衰老个体中炎症衰老、衰老与ECM重塑之间的复杂相互作用。
