Mechanisms underlying innate immunesenescence

Hazeldine, Jon (2013). Mechanisms underlying innate immunesenescence. University of Birmingham. Ph.D.

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Abstract

Although it is evident that physiological ageing is accompanied by marked alterations in the function of innate immune cells, little is known regarding the underlying mechanism(s). Furthermore, the effect of age on many novel aspects of innate immunity is unknown. This thesis has identified the mechanism(s) behind the well-documented age-related decline in natural killer (NK) cytotoxicity (NKCC) and demonstrated for the first time that human ageing is accompanied by a significant reduction in the generation of neutrophil extracellular traps (NETs).

Following target cell recognition, it was found that NK cells from older adults secreted into the immunological synapse (IS) significantly lower levels of perforin, a pore-forming protein that plays a non-redundant role in NKCC. This impairment led to reduced perforin binding to the target cell surface, an event that correlated strongly with NKCC. Underlying the reduction in perforin secretion was defective polarisation of lytic granules to the IS, which was associated with delayed activation of extracellular signal-regulated kinase 1/2.

Whilst no age-related difference was observed in NET production triggered by phorbol 12-myristate 13-acetate (PMA), neutrophils from older adults generated significantly fewer NETs when challenged with interleukin-8 or lipopolysaccharide, which was accompanied by a reduction in reactive oxygen species generation. As PMA activates cells independent of membrane receptors, aberrant intracellular signalling proximal to the neutrophil membrane may underlie the age-related impairment in NET production.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):