Scavenging of Isolevuglandins Attenuates Neutrophil Migration and Neutrophil Extracellular Trap Formation in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects numerous organs. Neutrophil extracellular traps (NETs) contribute to sterile inflammation and autoantibody generation in SLE. Isolevuglandins (isoLGs) are reactive oxygen species that are formed during NETosis and contribute to chromatin expansion. Scavenging of isoLGs attenuates SLE disease activity and hypertension in murine models of SLE. We hypothesized that isoLGs drive NETosis in SLE.

Neutrophils were isolated from patients with SLE (n = 6), treated with the isoLG scavenger ethyl-2-hydroxybenzylamine (Et-2-HOBA), and evaluated for NETosis by immunofluorescence. Single-cell sequencing was performed on lymphoid tissue from SLE-prone B6.SLE123 mice treated with the isoLG scavenger 2-hydroxybenzylamine (2-HOBA). Flow cytometry was performed to quantify neutrophils and NETs in B6.SLE123 mice (n = 11-15).

In neutrophils isolated from patients with SLE, Et-2-HOBA prevented NETosis (P < 0.05). In SLE-prone mice, 2-HOBA reduced neutrophil counts, inflammatory gene expression, circulating neutrophil counts (P < 0.0001), and aortic NETosis (P < 0.05).

These findings suggest that isoLGs contribute to systemic autoimmunity and vascular inflammation by driving neutrophil migration and NETosis in SLE.