How neutrophils detect and resolve infection and how this deteriorates with age

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Neutrophils play a key role in maintaining life long health and wellbeing. Neutrophils play a central role in maintaining human health. Patients with reduced neutrophil function die early and have severe symptoms following infection by minor pathogens. Neutrophils are adapted to contribute to the normal cycle of events that resolves infections. They migrate towards pro-inflammatory mediators released at sites of infection, they kill pathogens by phagocytosis, local production of reactive oxygen species (ROS) and release of proteases and they recruit further immune cells by release of pro-inflammatory mediators. In inflamed tissue neutrophils can be remodelled (“primed” to augment their functional responses) by the presence of cytokines like GM-CSF and TNFá which also delays their apoptotic death and thus increases their pathogen-killing capability. During recovery the levels of local cytokines return towards normal and neutrophils are lost by apoptosis. The molecules coordinating these activities are not fully understood although some key players have been clarified. GPCRs on neutrophils are key sensors of inflammation/infection and guide chemotaxis and stimulate ROS formation. A wide range of adhesive, pattern-recognition and antibody receptors allow neutrophils to generate some of the force needed for movement, stimulate ROS formation and allow pathogens to be recognised and phagocytosed. In past work we have found that class I PI3Ks heterodimers of catalytic and regulatory subunits that make the signalling lipid PIP3, and a number of RacGEFs (PRex1, Vav1 and Vav3; activators of the Rac-family of small GTPases, in neutrophils Rac1, Rac2, RhoG) are critical links between all of these receptors and physiological responses in isolated neutrophils and mouse models. However, the mechanisms that enable PIP3 and Rac signals to simultaneously or serially coordinate such complex behaviours remain unclear and depend on studying the different stages in the neutrophil response-to-infection cycle, defining molecular specificities and acquiring single cell and spatio-temporally-specific data. Our long-term aim is to understand, at a systems and molecular level, how class I PI3Ks and Rac GTPases coordinate neutrophil’s roles in host defence.

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