The role of neutrophil death in chronic inflammation and cancer

Abstract

The lifespan of a neutrophil is short and limited by programmed cell death, followed by efferocytosis. When activated or exposed to insult, neutrophil death may be delayed to support neutrophil effector functions such as phagocytosis, cytokine release, and pathogen destruction by degranulation. However, neutrophils may also alter the type of cell death and thereby affect inflammatory responses and tissue remodeling. This review briefly introduces the various forms of neutrophil death including apoptosis, necrosis/necroptosis, and the formation of so-called "neutrophil extracellular traps" (NETs), and it summarizes the clearance of dead cells by efferocytosis. Importantly, distinct types of neutrophil death have been found to drive chronic inflammatory disorders and cancer. Thus, the tumor and its microenvironment can delay neutrophil apoptosis to exploit their pro-angiogenic and pro-metastatic properties. Conversely, neutrophils may enter rapid and suicidal cell death by forming extracellular traps, which are expelled DNA strands with neutrophil proteins. Components of these DNA-protein complexes such as histones, high-mobility group protein B1, or neutrophil elastase have been found to promote cancer cell proliferation, adhesion, migration, invasion, and thereby tumor metastasis. In other settings of chronic inflammatory disease such as gout, NETs have been found protective rather than detrimental, as they promoted the local degradation of pro-inflammatory cytokines by neutrophil proteases. Thus, the interaction of neutrophils with the tissue environment extends beyond the stage of the living cell and the type of neutrophil death shapes immune responses and tissue remodeling in health and disease.

Keywords: Cancer microenvironment; Cell death and immune response; Granulocytes; Immune cell death.

Fig. 1. Neutrophil extracellular traps in cancer.

Neutrophils originating from bone marrow have a short lifespan in circulation, which is controlled by programmed cell death. When attracted by chemokines, they extravasate into tumor tissue where they are activated to delay apoptosis and engage in the inflammatory tumor microenvironment. A fraction of activated neutrophils may reverse migrate and home back to the bone marrow which shapes further neutrophil release. The tumor-invading neutrophils are exposed to hypoxia as well as cancer and stroma cell signals, which can trigger the formation of neutrophil extracellular traps (NETs). NET components such as oxidized DNA may stimulate an inflammatory response by macrophages or dendritic cells. NET-associated proteases alter the extracellular matrix and NET-derived HMGB1 molecules activate cancer cells to jointly promote tumor cell proliferation, migration, invasion, and metastasis.

Fig. 2. Neutrophil apoptosis and efferocytosis in cancer.

Tissue-infiltrating neutrophils that are attracted by tumor-derived signals are exposed to a variety of survival factors originating from tumor cells, stroma, hypoxia, or dying cells. They may propagate the inflammatory tumor microenvironment by recruiting and activating further leukocytes, such as cytotoxic T-cells. Tumor-associated neutrophils have the potential to reverse migrate into circulation, thereby facilitating metastasis of attached tumor cells. However, the majority of them is proposed to undergo local apoptosis and subsequent efferocytosis by macrophages, which drives an anti-inflammatory M2-like polarization, tumor proliferation, and vascularization. Conversely, neutrophils may remove apoptotic tumor cells by efferocytosis and thereby promote tissue remodeling and cancer growth.