Elevated circulating pro-inflammatory low-density granulocytes in adult-onset Still’s disease

Abstract

Objectives Neutrophilia is a hallmark of adult-onset Still’s disease (AOSD). This study aimed to investigate the role of a distinct subset of granulocytes, the low-density granulocytes (LDGs) in the pathogenesis of AOSD. Methods A total of 56 patients with AOSD were included in the study. LDGs were quantified by flow cytometry. Correlations between LDGs with disease activity and laboratory parameters were determined by Spearman’s nonparametric test. The cellular sources of the pro-inflammatory cytokines in AOSD were determined by intracellular staining. Results Active AOSD patients displayed significantly higher levels of LDGs compared with inactive AOSD patients and healthy controls (HCs) (P<0.001). Circulating LDGs were significantly correlated with CRP, ESR and the modified Pouchot score in patients with AOSD (P<0.01). The levels of LDGs were significantly decreased after the active AOSD patients achieved disease remission (P=0.0391). CD14+ monocytes constituted over 90% IL-1β+ peripheral blood mononuclear cells (PBMCs) and over 80% TNF-α+ PBMCs in both active AOSD patients and HCs, respectively. In active AOSD, CD14+ monocytes accounted for 24.6% to 75.0% of IL-6+ PBMCs, while LDGs comprised 22.8% to 72.2% of IL-6+ PBMCs. In contrast, over 90% IL-6+ PBMCs were CD14+ monocytes in HCs. A significant correlation was identified between the levels of LDGs and serum IL-6 levels in AOSD (P<0.0001). Conclusion Active AOSD is associated with elevated levels of a pro-inflammatory subset of neutrophils, the LDGs that produce IL-6. Our data highlight an unappreciated role of LDGs in the aberrant innate immune responses in AOSD.

An Update on the Pathogenic Role of Neutrophils in Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still’s Disease

“…LDGs with pro-inflammatory features were also found to be increased in active SJIA and AOSD. Increased IL-6 producing LDGs contributes to the pathophysiology of AOSD, and activation of neutrophils due to elevated transcription of genes encoding LDGs with pro-inflammatory features has potential implications for the mechanism of SJIA [ 90 , 91 ]. Additionally, evidence of functional and gene expression of neutrophil alterations has been reported in SJIA patients, and persistent proinflammatory activation in neutrophils has been shown not only in active disease but also in long-standing clinically inactive disease in SJIA [ 90 , 92 ].…”

Neutrophil-mediated mechanisms of damage and in-vitro protective effect of colchicine in non-vascular Behçet's syndrome

“…NETs are structures produced by neutrophil death in response to infectious or inflammatory stimuli; they are mainly composed of extruded cell‐free DNA and histones, microbicidal proteins and proteases, and are used to trap and kill micro‐organisms [ 13 , 14 ]. In particular, NETs are mainly produced by a specific subset of proinflammatory neutrophils, the low‐density granulocytes (LDGs), which are involved in the pathogenesis of cardiovascular manifestations associated with various autoimmune and autoinflammatory disorders [ 15 , 16 , 17 ]. ROS are directly involved in the mechanisms of NET formation, including the induction of morphological changes, increase in membrane permeability, release of neutrophil elastase from granules and induction of histones degradation and chromatin decondensation [ 18 ].…”

Pathogenesis of Behçet's Syndrome: Genetic, Environmental and Immunological Factors

“…Notably, among the major producers of NETs is a specific subtype of neutrophils with proinflammatory activity, namely low-density granulocytes (LDGs) that are widely involved in the pathogenesis of cardiovascular manifestations associated with various autoimmune and autoinflammatory disorders (60,61). Moreover, NETs are now recognized as a key factor in the initiation and progression of thrombosis in pathological conditions such as deep vein thrombosis in mice and humans, but also in arterial diseases such as stroke and myocardial infarction (62,63).…”