Aberrant expansion of CD177+ neutrophils promotes endothelial dysfunction in systemic lupus erythematosus via neutrophil extracellular traps

Abstract

Objective

Aberrant neutrophil activation is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and its related comorbidities. We found that CD177 was one of the most highly up-regulated genes at the transcriptional level in purified neutrophils from SLE patients. In this study, we aimed to explore the role of CD177⁺ neutrophils in the pathogenesis of SLE.

Methods

Expression of CD177 was analyzed by neutrophil transcriptome and flow cytometry. CD177⁺ neutrophils and CD177⁻neutrophils were isolated to determine the role of neutrophils-derived NETs in endothelium dysfunction. Wild type and CD177^−/− murine model of lupus were analyzed for organ involvement, endothelium-dependent vasorelaxation, serum autoantibodies, and innate and adaptive immune responses in an imiquimod (IMQ)-induced lupus model.

Results

CD177^MFI-hi neutrophils and CD177^MFI-hi low-density granulocytes (LDGs) were expanded in active SLE, which were weakly but significantly associated with disease activity. CD177⁺neutrophils displayed enhanced production of reactive oxygen species (ROS) and NETs, which impaired the murine aortic endothelium-dependent vasorelaxation and induced endothelial cell apoptosis. Moreover, CD177^−/− mice exposed to IMQ showed alleviated splenomegaly, endothelium-dependent vasorelaxation, and renal immune complex deposition.

Conclusions

Our findings indicated that CD177 ^MFI-hi may serve as a novel biomarker for monitoring disease activity in SLE. Further, CD177⁺ neutrophils may play a vasculopathic role in cardiovascular disease (CVD) via NETs formation, suggesting that specific targeting CD177⁺ neutrophil subset may have therapeutic effect in SLE but reducing the levels of NETs-prone neutrophils.