Neutrophil extracellular traps are a source of extracellular HMGB1 in lupus nephritis: associations with clinical and histopathological features

Abstract

Objective This study aimed to analyze the expression of the high mobility group box-1 (HMGB1) protein in neutrophil extracellular traps (NETs) of patients with lupus nephritis (LN) and its association with clinical and histopathological features of the disease. Methods Twenty-three patients with biopsy-confirmed LN and 14 systemic lupus erythematosus (SLE) patients with active disease (SLE Disease Activity Index (SLEDAI) score ≥ 6) and no evidence of LN were included. Clinical and laboratory features were recorded. NETs and the expression of HMGB1 were assessed by confocal microscopy, and serum HMGB1 levels were measured by ELISA. Results In comparison to patients without kidney disease, patients with LN had a higher expression of HMGB1 in spontaneous (57 vs. 30.4; p = 0.027) and lipopolysaccharide (LPS)-induced (55.8 vs. 24.9; p = 0.005) NETs. We found a positive correlation between serum HMGB1 and the expression of HMGB1 in LPS-induced NETs ( r = 0.447, p = 0.017). The expression of HMGB1 in spontaneous NETs correlated with SLEDAI score ( r = 0.514, p = 0.001), anti-dsDNA antibodies ( r = 0.467, p = 0.004), the rate of glomerular filtration descent ( r = 0.543, p = 0.001), and diverse histopathological components of active nephritis in the kidney biopsy, such as the activity index ( r = 0.581, p = 0.004), fibrinoid necrosis ( r = 0.603, p = 0.002), and cellular crescents ( r = 0.486, p = 0.019). Conclusions In patients with SLE, NETs are a source of extracellular HMGB1. The expression of HMGB1 in NETs is higher among patients with LN, which correlates with clinical and histopathological features of active nephritis and suggest a possible role of this alarmin in the pathophysiology of kidney damage in SLE.

Cf‐02, a novel benzamide‐linked small molecule, blunts NF‐κB activation and NLRP3 inflammasome assembly and improves acute onset of accelerated and severe lupus nephritis in mice

“…3 Growing evidence from multiple investigations suggests that increased systemic exposure to bacterial infection is implicated in SLE. [4][5][6] Increased serum levels of antimicrobial response factors and of soluble CD14, a lipopolysaccharide (LPS) receptor, are observed in SLE patients. [6][7][8][9][10] Moreover, neutrophil extracellular traps, a primary defense mechanism against microorganisms, contribute to the evolution of LN.…”

Neutrophil Extracellular Traps (NETs) Take the Central Stage in Driving Autoimmune Responses

“…Other DAMPs secreted with NETs are the high-mobility group box 1 (HMGB1) and LL37. NET-derived HMGB1 is associated with SLE [36,37], but not with AAV [36]. Contrarily, HMGB1 contributed to ANCA-induced NET formation [57].…”

The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

“…In addition, extracellular HMGB1 was shown to be a source of NET as evidence that HMGB1 levels was high to greater certain among lupus nephritis [ 191 ]. HMGB1 provoked self-DNA-induced macrophage activation by facilitating DNA accumulation in endosomes, which was involved in the development of lupus nephritis [ 192 ].…”