Misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, a hallmark of various pathologies. Cells combat this via the unfolded protein response (UPR) which facilitates correct protein folding. With age protein misfolding increases, independent of disease, indicating a diminished UPR as a part of the natural aging process. The UPR and aging has been explored in neurodegenerative disorders, however, its impact on respiratory epithelial cells (RECs) and their role in infection responses remains unexplored. We hypothesise that age-related UPR senescence contributes to increased susceptibility and severity of respiratory infections in the elderly.
C57BL/6 mice (4- to 80-weeks old) served as an aging model. RECs were isolated and the expression of UPR genes was assessed via qRT-PCR. Additionally, lung organoids from mice of various ages were established to explore ER stress responses and their role in infection management across aging.
Our results revealed significant downregulation of various key UPR factors throughout aging in murine RECs. Lung organoids from 8- and 60-week-old mice were treated with tunicamycin or IFNy+TNFa which displayed a reduced ability to activate the UPR to manage ER stress in the aging. Additionally, IFNy treatment in RECs increased intracellular MHC-II expression, however, surface expression required both IFNy and TNFa. Using DQ-Ova (model antigen), we observed that RECs can uptake, process, and transfer antigen to immune cells, in human cell lines and murine lung organoids. Lung organoids from aged mice had an elevated uptake and processing of DQ-Ova which was mediated by ER stress and the UPR.
Our findings reveal that aging diminishes the capacity of RECs to activate the UPR and effectively present antigen. Given their ability to process and transfer antigens, RECs present as key players in immunity, and their impairment with age may contribute to the increased infection susceptibility and severity in older individuals.