Signalling mechanisms controlling neutrophil apoptosis
An important mechanism which limits neutrophil-mediated tissue damage during inflammation is their short life-time at the inflammatory site. We have found that as part of the progress towards apoptosis, neutrophils also become non-responsive to certain stimuli.
This is an early event and occurs before they undergo morphological apoptosis and that there is a selective shutting down of receptor-stimulated Ca2+ influx (and possibly other) signalling mechanisms. This signalling shut-down may be critical for reducing unwanted toxic effects of large numbers of activated neutrophils. In any case, the existence of a endogenous mechanism for switch-off signalling in neutrophils gives the possibly that it could be “hi-jacked” as a therapy to switch-off unwanted neutrophil activity in inflammatory conditions.
The two major aims for this project are to fully characterise the nature of signalling shutdown during progression towards apoptosis by neutrophils and to investigate the molecular mechanism for this signalling shutdown with the aim of establishing the key (driving or rate limiting) molecular event.
Nuclear morphology changes during neutrophil apoptosis - Each image is a 3D reconstruction from confocal optical sections.
Ayub K. and M. B. Hallett (2004) Signalling shutdown strategies in aging immune cells. Aging Cell 145-149
Ayub K. and M.B. Hallett (2004) Ca2+ influx shutdown during neutrophil apoptosis: importance and possible mechanism. Immunology111 8-12
Ayub, K. and M. B. Hallett (2004) The mitochondrial ADPR link between Ca2+ store release and Ca2+ influx channel opening in immune cells. FASEB J 18 1335-1338