| Objective:In clinical work,we found that systemic lupus erythematosus(SLE)patients are often accompanied by neutropenia,but the reasons have not been clearly concluded.Furthermore,it is also unclear whether the neutropenia is a concomitant phenotype in the pathogenesis of SLE or an etiological factor leading to the onset or progression of SLE exacerbation.Therefore,this study aimed to explore these questions with the four aspects of lupus:the clinical phenomena,cellular activities,molecular mechanisms,and animal phenotypes.Hoping to explore new diagnostic markers,therapeutic targets and develop new animal models of lupus.And eventually guide the subsequent clinical practice.Methods:More than one hundred patients with SLE were included in the analysis,established the correlation between clinical phenomena and laboratory results.Primary neutrophils from patients were collected for sequencing,validation,culture and identification.In addition,a conditional knockout mouse model was constructed using CRISPR-Cas9 to validate the scientific hypothesis in vivo.Results:We demonstrate that neutrophils from patients with systemic lupus erythematosus(SLE)undergo ferroptosis,a unique form of iron-dependent programmed cell death,which primarily accounts for the neutropenia observed in patients with SLE.In SLE,autoantibodies and interferon-αpresent in the sera increase the production of lipid-reactive oxygen species and induce neutrophil ferroptosis.Mechanistically,the increased binding of the transcriptional repressor CREMα to the glutathione peroxidase 4(GPX4)promoter leads to inhibition of the transcription of GPX4,a key regulator of ferroptosis.Different lupus-prone mice display enhanced neutrophil ferroptosis and treatment with a specific inhibitor for cell ferroptosis significantly ameliorates disease severity by modulating lipid-reactive oxygen species generation.Importantly,mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate many key clinical features of human SLE,including neutropenia,skin lesions,the production of autoantibodies and the development of proteinuria.Therefore,our results,reported herein,identify a central cellular defect and provide the missing link between neutropenia and lupus pathogenesis.Conclusion:1.Neutrophils from patients with active systemic lupus erythematosus undergo spontaneous ferroptosis and this returns to normal levels following effective systemic treatment of patients.2.Autoreactive IgG and type 1 interferon induced neutrophil ferroptosis.3.Inhibition of ferroptosis significantly alleviates disease in lupusprone MRL/lpr mice.4.Myeloid cell specific haploinsufficiency of GPX4,a regulator of ferroptosis,results in the development of a lupus-like disease in otherwise normal mice.5.Serum autoreactive IgG and type 1 interferon inhibit GPX4 expression in neutrophils from SLE patients through the CaMKIV/CREM pathway,resulting in the accumulation of intracellular lipid-reactive oxygen species and neutrophil ferroptosis.Highlights:Whereas the adaptive immune system has been assigned important roles in the induction of systemic autoimmune diseases,we unveil a new paradigm whereby abnormalities in cells of the innate immune system alone can lead to the development of systemic autoimmunity.Specifically,ferroptosis of neutrophils resulting from GPX4-deficiency induces systemic autoimmune disease.Ferroptosis has not previously been studied in autoimmune disease,and the current findings indicate a prominent role not only the leukopenia of this disease,but also in the induction of a cascade of events resulting in the development of SLE. |
