Lupus serum induces inflammatory interaction with neutrophils in human glomerular endothelial cells

Abstract

ObjectivesSLE is associated with endothelial cell dysfunction (ECD). Understanding how ECD leads to neutrophil infiltration into glomeruli is essential to finding therapeutic targets for SLE. The aim of this study is to determine the effect of SLE serum from patients with active disease to induce neutrophil adhesion to and chemotaxis towards glomerular endothelial cells and factors induced by serum that associate with neutrophil chemotaxis.MethodsPatients with SLE had serum collected during paired longitudinal visits with lower and higher activity. 13 patients with SLE (5 SLE, 5 SLE with hypertension (HTN) and 3 SLE lupus nephritis (LN) and HTN), and 10 healthy controls (5 with and 5 without HTN) were examined. The adhesion of neutrophils to serum-treated human renal glomerular endothelial cells (HRGECs) or chemotaxis of neutrophils towards conditioned media from serum-treated HRGECs was determined, and levels of cytokines in this conditioned medium were quantified. Pathway analysis of cytokines induced by SLE and LN serum that associated with neutrophil migration was performed.ResultsHRGECs treated with SLE serum induced significantly greater neutrophil chemotaxis and adhesion compared with control serum. When examining specific cohorts, SLE HTN and LN HTN promoted greater neutrophil chemotaxis than control serum, while SLE HTN and LN HTN promoted greater chemotaxis than SLE serum. Serum from active disease visits promoted neutrophil chemotaxis and adhesion over paired inactive visits. Levels of platelet-derived growth factor-BB, interleukin (IL)-15 and IL-8 secreted by SLE serum-treated HRGECs positively correlated with neutrophil chemotaxis. Pathway analysis suggested that LN serum induced pathways important in endoplasmic reticulum and oxidative stress.ConclusionsSLE serum induces expression of mediators by HRGECs that promote neutrophil chemotaxis and adhesion, which increases during disease activity, and associates with factors common to pathways of endoplasmic reticulum and oxidative stress. These findings highlight the potential importance of serum factor-induced ECD in SLE and LN.

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

“…Neutrophils from SLE patients in active flare often produce lower levels of ROS in vitro than those with inactive disease, possibly due to exhaustion of the neutrophils in vivo ( 76 ), or lower expression of Fcγ and complement receptors ( 82 ). As yet unidentified factors within SLE serum induce production of cytokines by human renal glomerular endothelial cells which promote neutrophil chemotaxis and adhesion ( 83 ). In patients with lupus nephritis, immune complexes become deposited within tissues in the kidney ( 6 ).…”

Endoplasmic Reticulum Stress in Systemic Lupus Erythematosus and Lupus Nephritis: Potential Therapeutic Target

“…Few studies have examined the relationship between ERS and endothelial dysfunction in the LN [ 119 ]. Russell et al [ 120 ] and Oates et al [ 121 ] found that human glomerular endothelial cells in SLE-induced neutrophil chemotaxis and adhesion and further aggravated glomerular lesions through ERS and oxidative stress pathways.…”

Endothelial cell activation and glycocalyx shedding - potential as biomarkers in patients with lupus nephritis

“…Increased circulating apoptotic endothelial cells and decreased bone marrow-derived endothelial progenitor cells and myeloid angiogenic cells suggests an imbalance between endothelial cell injury and repair in SLE and LN patients ( 73 ). Stimulation of glomerular endothelial cells with serum from SLE and LN patients increases IL-1β and IL-6 transcripts and IL-8, IL-15 and PDGF-BB secretion and is associated with increased neutrophil recruitment ( 75 , 76 ). These pro-inflammatory mediators also induce glycocalyx shedding.…”