Low‐Density Neutrophils in Systemic Lupus Erythematosus

Abstract

Patients with systemic lupus erythematosus ( SLE ) display increased numbers of immature neutrophils in the blood, but the exact role of these immature neutrophils is unclear. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low‐density neutrophils ( LDN s). Far beyond antimicrobial functions, LDN s are emerging as decision‐shapers during innate and adaptive immune responses. Traditionally, neutrophils have been viewed as a homogeneous population. However, the various LDN populations identified in SLE to date are heterogeneously composed of mixed populations of activated mature neutrophils and immature neutrophils at various stages of differentiation. Controversy also surrounds the role of LDN s in SLE in terms of whether they are proinflammatory or polymorphonuclear myeloid‐derived suppressor cells. It is clear that LDN s in SLE can secrete increased levels of type I interferon ( IFN ) and that they contribute to the cycle of inflammation and tissue damage. They readily form neutrophil extracellular traps, exposing modified autoantigens and oxidized mitochondrial DNA , which contribute to autoantibody production and type I IFN signaling, respectively. Importantly, the ability of LDN s in SLE to perform canonical neutrophil functions is polarized, based on mature CD 10+ and immature CD 10− neutrophils. Although this field is still relatively new, multiomic approaches have advanced our understanding of the diverse origins, phenotype, and function of LDN s in SLE . This review updates the literature on the origin and nature of LDN s, their distinctive features, and their biologic roles in the immunopathogenesis and end‐organ damage in SLE .

Low-Density Neutrophils in Healthy Individuals Display a Mature Primed Phenotype

“…Since LDN seemed to be more reactive and it has been suggested that LDN in several pathological conditions are prone to release NET (32,47,48), the response of LDN to PMA to form NET was evaluated next. LDN are found among the more abundant MNC, thus in order to appreciate NET formation by LDN alone, these cells were first purified by cell sorting.…”

Neutrophil-to-Lymphocyte Ratio Predicts Development of Immune-Related Adverse Events and Outcomes from Immune Checkpoint Blockade: A Case-Control Study

“…The hallmark of PMN-MDSCs is their ability to suppress T lymphocyte function [ 14 ]. The most prominent factors implicated in MDSC suppressive activity include increased production of ROS and nitric oxide, upregulation of arginase I and production of prostaglandin E2 [ 15 , 16 ]. Importantly, Basu et al reported a significant correlation between NLR and MDSCs recently [ 17 ].…”

Cognitive Dysfunction in Systemic Lupus Erythematosus: Immunopathology, Clinical Manifestations, Neuroimaging and Management

“…Activated neutrophils undergo NETosis to release NETs, a unique form of cell death that is distinct to necrosis and apoptosis [18]. [83,84]. Another related protein is lipocalin-2, an acute phase reactant protein that is found in close association with MMP-9 in the granules of neutrophils [85].…”

“…LL-37); (3) active MMP-9 that mediates endothelial dysfunction [ 80 – 82 ]. Active MMP-9 is externalized on NETs at significantly higher levels by a distinct proinflammatory subset known as low-density neutrophils [ 82 , 83 ]. Another related protein is lipocalin-2, an acute phase reactant protein that is found in close association with MMP-9 in the granules of neutrophils [ 84 ].…”