Neutrophil phenotypes in health and disease

Abstract

Neutrophils are one of the most important effector cells of the innate immune response (1). They are traditionally seen as a homogenous population of short‐lived cells mainly involved in the defence against extracellular microorganisms by phagocytosis and intracellular killing (1,2). The cells contain a large armamentarium that aids in this function and ranges from the production of reactive oxygen species by a membrane‐bound NADPH oxidase to cytotoxic proteins and peptides residing in the different granules present in the cytoplasm (3). Recently, the view of neutrophils belonging to a homogenous population of cells has been challenged, and several neutrophil phenotypes have been described that exhibit specialized functions, such as involvement in tissue repair, tumour killing and immune regulation (4). It is not clear whether these cells belong to separate parallel lineages originating from the bone marrow or that neutrophils become instructed in the distant tissues, thus changing their phenotypes. In addition, functional heterogeneity in a phenotypically homogenous population of neutrophils adds to the complexity of neutrophil phenotypes(5). This article will review the current literature describing the heterogeneity within the neutrophil compartment with respect to both phenotype and function in health and disease.

Neutrophil Diversity in Health and Disease

“…Currently, there is renewed interest in better understanding the sequential steps of neutrophil maturation [33,34], as well as the transcriptomic and epigenomic programs they carry [35], and through which these granulocytes progressively acquire specific functional abilities. Further complicating our understanding of neutrophil identities, the phenotype of circulating mature neutrophils appears to vary over the course of their lifespan [3,6,8,9]. Similarly to what has been consistently published in papers utilizing mouse models (see below), diurnal oscillations of C-X-C chemokine receptor type 4 (CXCR4) expression have been found in circulating neutrophils from healthy subjects, and these were proposed to correlate with neutrophil maturation and aging [36,37].…”

“…Heterogeneous populations of circulating neutrophils have been described based on discrete parameters (e.g., cell-surface markers, buoyancy, maturity, functions, localization) both in healthy and pathological conditions including cancer, infections, and autoimmune and inflammatory disorders [3][4][5][6][7][8][9]. In addition, the number of studies describing the existence of tissue-based populations of neutrophils, which can be either resident or newly infiltrated, and which acquire specialized phenotypes/functions depending on the tissue microenvironment, is continuously growing [3][4][5][6][7][8][9]. The question of neutrophil heterogeneity is of significant interest; however, no consensus criteria and/or molecular evidence have been demonstrated to unequivocally and reproducibly define clinically relevant distinct neutrophil subsets.…”

“…Humans Several publications have reported that, in healthy individuals, 45-65% of circulating neutrophils are CD177 + [5,6,8,14], with variability of CD177 expression reflecting control by epigenetic mechanisms [15] (Figure 1). CD177 (also known as human neutrophil antigen NB1) is a glycoprotein Neutrophils are the primary responders to infections and tissue damage, but a growing body of evidence suggests that distinct subpopulations of these cells are immunoregulatory and are associated with cancer and other inflammatory diseases.…”

“…Under resting conditions, only terminally differentiated neutrophils are released into the circulation and recovered as normal-density neutrophils (NDNs) (Box 1) [54]. Current evidence suggests that different neutrophil subpopulations, defined by the indicated markers, are present in human blood under homeostatic conditions [5,6,8,21,30,36,37]. Under resting conditions, neutrophils are also marginated in pools within the lungs, spleen, and liver, but the phenotypes and functions of these cells remain poorly defined [5,6,9].…”

“…Neutrophil ontogeny is currently recognized as a major contributor to heterogeneity [3,8,9]. Because of its rapid homeostatic turnover, the size of the circulating mature neutrophil pool is maintained by a fine balance between granulopoiesis, neutrophil release from the bone marrow (BM) into the circulation, and ultimately return to the BM for final clearance by resident macrophages [31] (Figure 1).…”