Background/Purpose:

Current evidence suggests that neutrophils play an important role in the pathophysiology of lupus nephritis (LN) mainly through the secretion of type I IFN and the production of Neutrophil Extracellular Traps (NETs). This type of cell death releases proinflammatory molecules, including High Mobility Group Box-1 (HMGB1). HMGB1 acts as an alarmin once released into the extracellular space and induces the synthesis of proinflammatory cytokines through its interaction with diverse receptors. Elevated levels of this protein have been associated with global disease activity as well as LN. However, the precise source of extracellular HMGB1 has not been addressed. The aim of this study was to analyze the expression of HMGB1 in NETs of patients with LN and its association with clinical and histopathological characteristics of the disease.

Methods:

Twenty-three patients with LN confirmed by biopsy as well as 14 SLE patients with active disease (SLEDAI ≥ 6) and no evidence of LN were included. Clinical and laboratory features where obtained. NETs and the expression of HMGB1 were assessed by immunofluorescence and confocal microscopy. Besides, serum HMGB1 levels were measured by ELISA.

Results:

81% of the patients were women and the mean age was 30.6 years. Patients with LN were characterized by a higher expression of HMGB1 in NETs compared to patients without LN (Spontaneous: 57 vs 30.4, p=0.027; LPS: 55.8 vs 24.9, p=0.005), even though, we did not find differences in serum HMGB1 levels (p=0.920) nor the amount of NETs (Spontaneous:p=0.230, LPS p=0.263). Nonetheless, we found a positive correlation between serum HMGB1 and HMGB1 expression in LPS-induced NETs (r=0.447, p=0.017). The expression of HMGB1 in spontaneous NETs correlated with serum creatinine (r=0.481, p=0.003), proteinuria/creatinuria index (r=0.34, p=0 .039), % of glomerular filtration rate descent (r=0.543, p=0.001), SLEDAI score (r=0.508, p=0.001), anti-DNAds (r=0.514, p=0.001) and diverse histopathological findings of active LN in the renal biopsy as shown in Table 1.

Conclusion:

Our findings support the hypothesis that NETs are a relevant source of extracellular HMGB1 in patients with LN. The positive correlation between HMGB1 from spontaneous NETs and histopathologic findings of active proliferative LN suggest the role of this alarmin in the pathophysiology of renal damage in SLE.

Table 1: Correlations between the mean fluorescence intensity of HMGB1 in spontaneous NETs and histopathological findings in renal biopsies.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutrophil-extracellular-traps-are-a-source-of-extracellular-high-mobility-group-box-1-association-with-clinical-and-histopathological-features-in-patients-with-lupus-nephritis/