Age-related functional and metabolic alterations in lung resident innate immune cells
File(s)
Author(s)
Diaz Nicieza, Celia
Type
Thesis
Abstract
Older adults are at a higher risk of developing severe respiratory infections. As the global population ages, there is an urgent necessity to characterise how the lung immune system changes with age. The ageing of the lung innate immune response has been under-studied. We tested the hypotheses that aged mice exhibit age-associated functional alterations in the lung innate immune response and that age-associated metabolic alterations in alveolar macrophages (AMs), key in the initiation of the immune response in the lung, can affect AM function.
To characterise the lung innate immune response, young (2-5 months old) and aged (17-22 months old) male C57BL/6 mice were challenged intranasally with TLR ligands. Aged mice exhibited significantly enhanced recruitment of inflammatory cells into the lungs. Lung resident AMs, epithelial, endothelial and all other stromal cells of aged mice expressed higher levels of pro-inflammatory mediators in response to LPS compared to the young. AMs of aged mice also exhibited higher expression and production of pro-inflammatory mediators following stimulation with LPS, poly(I:C), IL-4 and live RSV ex vivo. To understand the potential mechanisms leading to altered function, age-associated changes to AM metabolism were characterised. AMs of aged mice were more glycolytic. This phenotype and elevated Il1b expression is likely the result of an increased accumulation of HIF-1α, which may be stabilised by mitochondrial ROS. AMs of aged mice demonstrated dysfunctional mitochondria with a lower membrane potential. NAD+ levels can influence cellular metabolism and mitochondrial function, and blocking the activity of the main NADases lead to a reduced expression of Il1b in LPS-stimulated AMs of aged mice, which was not seen in the young, suggesting a role of NAD+ metabolism in the age-associated exacerbated expression of Il1b. This understanding may aid the development of therapeutics to improve quality of life in old age.
To characterise the lung innate immune response, young (2-5 months old) and aged (17-22 months old) male C57BL/6 mice were challenged intranasally with TLR ligands. Aged mice exhibited significantly enhanced recruitment of inflammatory cells into the lungs. Lung resident AMs, epithelial, endothelial and all other stromal cells of aged mice expressed higher levels of pro-inflammatory mediators in response to LPS compared to the young. AMs of aged mice also exhibited higher expression and production of pro-inflammatory mediators following stimulation with LPS, poly(I:C), IL-4 and live RSV ex vivo. To understand the potential mechanisms leading to altered function, age-associated changes to AM metabolism were characterised. AMs of aged mice were more glycolytic. This phenotype and elevated Il1b expression is likely the result of an increased accumulation of HIF-1α, which may be stabilised by mitochondrial ROS. AMs of aged mice demonstrated dysfunctional mitochondria with a lower membrane potential. NAD+ levels can influence cellular metabolism and mitochondrial function, and blocking the activity of the main NADases lead to a reduced expression of Il1b in LPS-stimulated AMs of aged mice, which was not seen in the young, suggesting a role of NAD+ metabolism in the age-associated exacerbated expression of Il1b. This understanding may aid the development of therapeutics to improve quality of life in old age.
Version
Open Access
Date Issued
2023-02-25
Date Awarded
01/10/2023
License URL
Advisor
Culley, Fiona J
Sponsor
Wellcome Trust (London, England)
Grant Number
102126/B/13/Z
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)