The role of neutrophils in immune dysfunction during severe inflammation

Abstract

Critically ill post-surgical, post-trauma and/or septic patients are characterised by severe inflammation. This immune response consists of both a pro- and an anti-inflammatory component. The pro-inflammatory component contributes to (multiple) organ failure whereas occurrence of immune paralysis predisposes to infections. Strikingly, infectious complications arise in these patients despite the presence of a clear neutrophilia. We propose that dysfunction of neutrophils potentially increases the susceptibility to infections or can result in the inability to clear existing infections. Under homeostatic conditions these effector cells of the innate immune system circulate in a quiescent state and serve as the first line of defence against invading pathogens. In severe inflammation, however, neutrophils are rapidly activated, which affects their functional capacities, such as chemotaxis, phagocytosis, intra-cellular killing, NETosis, and their capacity to modulate adaptive immunity. This review provides an overview of the current understanding of neutrophil dysfunction in severe inflammation. We will discuss the possible mechanisms of downregulation of anti-microbial function, suppression of adaptive immunity by neutrophils and the contribution of neutrophil subsets to immune paralysis.

Fig. 1

Downregulation of immune receptors by serine proteases from degranulated neutrophils and desensitisation by pattern recognition receptors. a Schematic representation of downregulation of receptors on neutrophils, monocytes and lymphocytes during inflammation due to cleavage by neutrophil serine proteases after degranulation. Binding of C5a to neutrophils results in internalisation of C5aR. Decreased expression of these receptors impairs neutrophil effector functions during subsequent challenges. b Biological mimicry between DAMPs and MAMPs. Danger signals derived from necrotic tissue cells ("First hit") bind to pattern recognition receptors (PRRs) and limit subsequent responses to microbial signals ("Second hit") through homo- and heterologous desensitisation. DAMP damage-associated molecular pattern, IL interleukin, MAMP microbe-associated molecular pattern

Fig. 2

Circulating neutrophil subsets in severe inflammation. At least four types of neutrophils circulate in the bloodstream of patients during severe inflammation: immature, competent and suppressive neutrophils and myeloid-derived suppressor cells. Mechanisms contributing to immune dysfunction are displayed for neutrophils from different subsets. ROS reactive oxygen species