Neutrophil heterogeneity: Bona fide subsets or polarization states?

Abstract

Neutrophils are key components of the innate immune system that play important roles during infection, injury, and chronic disease. In recent years, neutrophil heterogeneity has become an emerging focus with accumulating evidence of neutrophil populations with distinct functions under both steady-state and pathologic conditions. Despite these advances, it remains unclear whether these different populations represent bona fide subsets or simply activation/polarization states in response to local cues. In this review, we summarize the varied neutrophils populations that have been described under both basal and during inflammation. We discuss the evidence that supports the existence of neutrophils subsets. Finally, we identify potential gaps in our knowledge that may further advance our current understanding of neutrophil heterogeneity.

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].…”

“…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]. A unique population of human neutrophils was found in the marginal zone (MZ) of the spleen, and these were termed B cell helper neutrophils (N BH cells) owing to their robust B cell-activating properties [39].…”