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

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: CD177MFI-hi neutrophils and CD177MFI-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.