Diverse novel functions of neutrophils in immunity, inflammation, and beyond

Abstract

Neutrophils have long been considered simple suicide killers at the bottom of the hierarchy of the immune response. That view began to change 10-20 yr ago, when the sophisticated mechanisms behind how neutrophils locate and eliminate pathogens and regulate immunity and inflammation were discovered. The last few years witnessed a new wave of discoveries about additional novel and unexpected functions of these cells. Neutrophils have been proposed to participate in protection against intracellular pathogens such as viruses and mycobacteria. They have been shown to intimately shape the adaptive immune response at various levels, including marginal zone B cells, plasmacytoid dendritic cells and T cell populations, and even to control NK cell homeostasis. Neutrophils have been shown to mediate an alternative pathway of systemic anaphylaxis and to participate in allergic skin reactions. Finally, neutrophils were found to be involved in physiological and pathological processes beyond the immune system, such as diabetes, atherosclerosis, and thrombus formation. Many of those functions appear to be related to their unique ability to release neutrophil extracellular traps even in the absence of pathogens. This review summarizes those novel findings on versatile functions of neutrophils and how they change our view of neutrophil biology in health and disease.

Figure 1.

Neutrophil functions: state of the art in the early 2000s. After migrating to the site of inflammation, neutrophils (PMN) phagocytose and digest the invading microbes; release NETs, which likely trap bacteria; and produce cytokines, which contribute to the inflammatory reaction. Once infection is cleared, neutrophils die by apoptosis and trigger an active program to resolve inflammation. Inset, pathogen killing inside the phagosome occurs by ROS generated by the NADPH oxidase, as well as by granule enzymes released from intracellular granules. The NADPH oxidase also induces depolarization of the phagosomal membrane, which may be required for providing optimal environment inside the phagosome.

Figure 2.

Novel interactions of neutrophils with other immune cells. (A) Neutrophils (PMN) accumulate in the splenic marginal zone upon microbial challenge and facilitate the antibody production and maturation of marginal zone B cells (MZB) in response to T cell–independent (TI) antigens. (B) Neutrophils participate in a vicious cycle during autoimmune disease (e.g., SLE) pathogenesis by releasing NETs that trigger pDCs to release IFN-α, which then promotes antibody production by B cells (B). (C) Neutrophils may directly present antigens to T cells (T) and they also activate DCs and deliver antigens to them. (D) Neutrophils and DCs jointly activate NK cells (NK).

Figure 3.

Novel functions of neutrophils in vascular diseases. (A) Neutrophils (PMN) mediate an alternative pathway of anaphylactic reaction which is distinct from the classical pathway mediated by mast cells or basophils. (B) Sequential recruitment of platelets, neutrophils, and monocytes (Mono) participates in the pathogenesis of atherosclerosis. (C) Neutrophils contribute to coagulation and thrombosis by releasing tissue factor and inhibitors of the tissue factor pathway inhibitor (TFPI), as well as the procoagulant NETs.