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Title: The effect of ageing on the acute inflammatory response
Author: De Maeyer, Roel P. H.
ISNI:       0000 0004 7231 1641
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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The elderly present with a state of low-level chronic inflammation termed inflamm-ageing. The aetiology of this phenotype is unknown. Most efforts have focused on the mechanisms by which inflammation starts, whereas little is known regarding the processes that switch off inflammation – resolution – in this context. I therefore investigated the inflammatory response in healthy young and aged individuals using the cantharidin skin blister model of acute, sterile inflammation. Inflammatory onset was unchanged, but neutrophil clearance – a key step in resolution – was impaired in the aged. I observed no defects in neutrophil apoptosis. However, the clearance defect coincided with increased prevalence of HLA-DR+/CD14hi/CD16lo/CD163+ mononuclear phagocytes (MP) in aged compared to young volunteers. Ex vivo incubation of blister MPs with autologous apoptotic neutrophils revealed significantly impaired efferocytosis in aged compared to young individuals. Comparison of key cell surface proteins that mediate efferocytosis revealed that while MerTK, CD14 and CD36 expression was unchanged with age, TIM-4, a key phosphatidylserine receptor, exhibited significantly lower expression on MPs from aged individuals. I also observed a failure of MPs to undergo pro-resolution signaling resulting in a failure to upregulate CCR7, produce TGF-β and release pro-resolving cytochrome P450-derived lipid mediators by resolution in the aged; all known consequences of successful apoptotic cell clearance by MPs. Contrary to a plethora of published literature, inflammatory onset in the skin of aged humans was unimpaired. However, resolution pathways revolving around efferocytosis are severely inhibited resulting in chronic inflammation. This could underpin the aetiology of inflamm-ageing and provide a pharmacologically tractable target to improve immune responses in the elderly.
Supervisor: Gilroy, D. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available