Clearance of apoptotic cells by neutrophils in inflammation and cancer.

ABSTRACT

When a cell dies of apoptosis, it is eliminated either by neighbouring cells or by attracted professional phagocytes. Although it was generally believed that neutrophils also have the ability to perform efferocytosis, their contribution to the clearance of apoptotic cells was considered less important compared with macrophages. Therefore, this ability of neutrophils remained unexplored for a long time. Over the past decade, it has been shown that during inflammation, neutrophils contribute significantly to the clearance of apoptotic neutrophils that accumulate in large numbers at the site of tissue damage. This "neutrophil cannibalism" is accompanied by inhibition of pro-inflammatory activities of these cells, such as respiratory burst and formation of neutrophil extracellular traps (NETs). Furthermore, efferocytosing neutrophils secrete anti-inflammatory mediators and mitogens including hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF2), vascular endothelial growth factors (VEGF), and transforming growth factor beta (TGFß). Thus, efferocytosis by neutrophils is involved in resolution of inflammation. Recent research indicates that it plays also a role in cancer. Many different solid tumours contain aggregates of dead tumour cells that have undergone spontaneous apoptosis. Their extent correlates with poor clinical outcome in most cancer types. These clusters of apoptotic tumour cells are strongly infiltrated by tumour-associated neutrophils (TANs) that acquired an anti-inflammatory and pro-resolving polarization state. This review summarizes the potential consequences discussed in the current literature. Although the picture of the role of efferocytosis by neutrophils in inflammation and cancer is becoming clearer, many questions are still unexplored.