Low-Density Granulocytes and Neutrophil Extracellular Traps as Biomarkers of Disease Activity in Adult Inflammatory Myopathies

Abstract

Background/Objective: Biomarkers for disease activity and damage accrual in idiopathic inflammatory myopathies (IIMs) are currently lacking. The purpose of this cross-sectional study is to analyze the relationship among low-density granulocytes (LDGs), neutrophil extracellular traps (NETs), and clinical and immunological features of patients with IIM. Methods:We assessed disease activity, damage accrual, amount of LDGs, NETs, expression of LL-37, and serum cytokines in 65 adult patients with IIM. Differences between groups and correlations were assessed by Kruskal-Wallis, Mann-Whitney U, and Spearman ρ tests. The association between LDGs, NETs, disease activity, calcinosis, and cutaneous ulcers was assessed by logistic regression. To address the capacity of LDGs and NETs to diagnose disease activity, we used receiving operating characteristic curves.Results: Low-density granulocytes were higher in patients with active disease, ulcers, calcinosis, and anti-MDA5 antibodies, which correlated with serum levels of IL-17A and IL-18. Neutrophil extracellular traps were higher in patients with calcinosis, elevated titers of antinuclear antibodies, and positive anti-PM/Scl75 tests. The combination of a high proportion of both total LDGs and NETs was associated with the presence of calcinosis and cutaneous ulcers. LL-37 was higher in NETs originating from LDGs. Normal-density neutrophils were elevated in patients with active dermatomyositis.Conclusions: Low-density granulocytes and NETs containing LL-37 are increased in patients with IIM and active disease, and correlate with proinflammatory cytokines. Both total and CD10 + LDGs are potential biomarkers for disease activity and, in combination with NETs, have the potential to detect patients who are at risk for cutaneous ulcers and calcinosis.

Overproduced bone marrow neutrophils in collagen‐induced arthritis are primed for NETosis: An ignored pathological cell involving inflammatory arthritis

“…These phenomena mimic the role of the BM neutrophils in vivo in the pathogenesis of CIA. Some literature has reported that serum rich in inflammatory cytokines and autoantibodies from individuals with different diseases can induce NETs formation in vitro, 30‐33 while normal serum may inhibit NETs formation 34 . Different results of NETs induction by different serum may also indicate the role of environmental components in neutrophil activation.…”

“…These phenomena mimic the role of the BM neutrophils in vivo in the pathogenesis of CIA. Some literature has reported that serum rich in inflammatory cytokines and autoantibodies from individuals with different diseases can induce NETs formation in vitro,[30][31][32][33] while normal serum may inhibit NETsF I G U R E 6 Impaired maturity of bone marrow (BM) neutrophils from granulocyte colony-stimulating factor (G-CSF)−/− mice. A, Representative dot plots of the relative proportion of mature neutrophils.…”

Promising Neutrophil-Associated Biomarkers in Lung Diseases of Patients with Antisynthetase Syndrome and Dermatomyositis

“…Circulating NETs were reported to be associated with higher levels of anti-MDA5 antibody and skin disease activity [ 30 ]. Low-density granulocytes and NETs containing LL-37 were also increased in patients with IIM and active disease and correlate with proinflammatory cytokines [ 8 ]. IIM NETs decreased the viability of myotubes in a citrullinated histone-dependent manner.…”

“…In addition, other specific biological forms or associated factors of neutrophils, like neutrophil extracellular traps (NETs), may also play an important role in IIM. NETs containing human cathelicidin were reported to be increased in patients with IIM and active disease and correlate with proinflammatory cytokines [ 8 ]. Peripheral NET levels are associated with calcinosis and interleukin (IL)-8 levels [ 9 ].…”

Low-Density Granulocytes in Immune-Mediated Inflammatory Diseases

“…Low-density neutrophils or LDG gene signatures have also been observed in many other immune-mediated disorders, including IIM, RA, juvenile idiopathic arthritis, and Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome [ 9 , 30 , 65 , 83 – 86 ]. The classical enhancement of spontaneous NET formation has been observed in LDGs from IIM, PAPA syndrome, and equine asthma.…”