Neutrophils in Physiology and Pathology

Abstract

Infections, cardiovascular disease, and cancer are major causes of disease and death worldwide. Neutrophils are inescapably associated with each of these health concerns, by either protecting from, instigating, or aggravating their impact on the host. However, each of these disorders has a very different etiology, and understanding how neutrophils contribute to each of them requires understanding the intricacies of this immune cell type, including their immune and nonimmune contributions to physiology and pathology. Here, we review some of these intricacies, from basic concepts in neutrophil biology, such as their production and acquisition of functional diversity, to the variety of mechanisms by which they contribute to preventing or aggravating infections, cardiovascular events, and cancer. We also review poorly explored aspects of how neutrophils promote health by favoring tissue repair and discuss how discoveries about their basic biology inform the development of new therapeutic strategies.

Keywords: cancer; cardiovascular disease; infection; inflammation; neutrophil.

Figure 1.. Origin and Diversity of Neutrophils.

A. Granulopoiesis is a stepwise process during which neutrophils acquire transcriptomic, proteomic, structural and functional properties. There are several features that allow categorizing neutrophil development, namely their precursors, proliferative capacity, transcriptional program driven by master transcription factors, nuclear morphology, granule formation, acquisition of effector functions, the cell surface proteome and type of granules. B. During normal granulopoiesis (1) precursors and mature neutrophils acquire diversity during development. Transcriptomic and phenotypic heterogeneity starts in the bone marrow but becomes prominent once in the periphery. It is likely that the exposure of neutrophils to inflammatory and microbial molecules and biochemical cues in the micro-circulation, might initiate this diversification. In tissues, neutrophils are reprogrammed and acquire tissue-tailored signatures. Neutrophils precursors may also egress into blood and migrate to the spleen to continue their differentiation (2). In some settings of infection or inflammation, neutrophil precursors are recruited and can differentiate in situ to generate a local pool of mature cells (3). Finally, neutrophil diversification may rely on the varying composition of the hematopoietic niches found in different bones. (4).

Figure 2.. Pathogenic mediators of neutrophils.

The effector functions of neutrophils may cause disease in different scenarios, from metabolic disorders and atherosclerosis to clonal hematopoiesis and organismal aging. For example, NETs have been shown to contribute to most, if not all, cardiovascular events and in chronic inflammation, whereas interactions with other cells have been reported mostly in the context of stroke, autoimmune disease and cancer. Please refer to the text for details about the multiple mechanisms by which neutrophils cause disease.

Figure 3.. Strategies to target neutrophils.

Many strategies have been used to interfere with the pathogenic function of neutrophils, from their production in and release from the bone marrow, to cytotoxic functions in tissues. Please refer to Section 5 for more details. Red and green boxes indicate strategies to block or to promote the associated process.