Expanding Neutrophil Horizons: New Concepts in Inflammation

Abstract

Research into neutrophil biology in the last 10 years has uncovered a number of unexpected aspects of this still mysterious innate immune cell. Advances in technology have allowed visualisation of neutrophil trafficking to sites of inflammation, and, remarkably, neutrophils have been observed to depart from the scene in what has been termed reverse migration. There has also been increasing appreciation of the heterogeneity of neutrophils with ongoing categorisation of neutrophil subsets, including myeloid-derived suppressor cells and low-density granulocytes. Newly recognised neutrophil functions include the ability to release novel immune mediators such as extracellular DNA and microvesicles. Finally, studies of neutrophil cell death, both apoptotic and non-apoptotic, have revealed remarkable differences compared to other cell types. This review will highlight important discoveries in these facets of neutrophil biology and how the new findings will inform treatment of diseases where neutrophils are implicated.

Keywords: Apoptosis; Host defence; Inflammation; Neutrophil.

Fig. 1

Schematic overview of neutrophils. (1) Neutrophil heterogeneity: in inflammatory or pathological conditions, neutrophil subsets have been characterised as including immature neutrophils, hypersegmented neutrophils, low-density granulocytes and granulocyte myeloid-derived suppressor cells. (2) Neutrophil diapedesis: transendothelial migration (rolling, adhesion, crawling and migration to inflamed sites) and reverse migration (returning to the circulation after having migrated into tissues). (3) Effector mechanisms of neutrophils: oxidative burst with production of superoxides, hydrogen peroxide (reactive oxygen species [ROS]) and hypochlorous acid; release of anti-pathogen proteases, defensins, cytokines and chemokines; release of specialised pro-resolving molecules, neutrophil extracellular traps (NETs) and neutrophil microvesicles; and phagocytic clearance of bacterial and cell debris. Neutrophils interact with dendritic cells (DCs), B lymphocytes, natural killer cells, T lymphocytes and endothelial cells and thus influence both the innate and adaptive immune responses. (4) Resolution of inflammation: the modality of cell death (e.g., phagocytosis-induced cell death [PICD], necroptosis and apoptosis) may influence the response of surrounding tissue cells and either perpetuate inflammation or promote resolution. Macrophage efferocytosis of apoptotic neutrophils favours the resolution of inflammation. Recirculation of neutrophils shuttling antigens in lymphatics shapes the adaptive immune response. Interference with or defects in these pro-resolving mechanisms may promote inflammation and autoimmunity.

Fig. 2

Neutrophil apoptotic pathways. A simplified schematic of the intrinsic and extrinsic pathways of apoptosis with specific emphasis on the main factors involved in neutrophil apoptosis. Novel mediators of neutrophil apoptosis are: (A) cyclin-dependent kinases (CDKs) that inhibit Mcl-1 degradation and reduce apoptosis; (B) proliferating cell nuclear antigen (PCNA), which sequesters pro-caspases to prevent their activation; (C) myeloid cell nuclear differentiation antigen (MNDA), which is cleaved by caspase-3 and the cleaved product promotes Mcl-1 proteasomal degradation; and (D) proteinase 3, which leaks from the granules of aging neutrophils to directly cleave caspase-3 and activate the apoptotic programme.

Fig. 3

Neutrophil death with DNA release and decondensation triggered by monosodium urate crystals. Healthy control neutrophils incubated with monosodium urate crystals (0.2 mg/mL) for 4 h. Maximum-intensity projection of a z-stack. The fluorescent image is a merge of blue (DAPI), green (neutrophil elastase) and red (myeloperoxidase). DNA colocalised with neutrophil granule proteins aggregates the crystals.