Background/Purpose: Neutrophils are essential for inflammation and host defense against infections. Our group has previously highlighted their key roles in the pathogenesis of diseases that are more common in women, such as systemic lupus erythematosus (SLE) and other systemic rheumatic conditions. We have also reported sex-based differences in neutrophil biology that affect key biologic processes and may influence this differential predisposition to systemic autoimmune disease and response to infections. These differences include variations in sensitivity to type I interferons (IFN-I), immunometabolic activity, and maturation status of neutrophils, all with significant functional and pathogenic implications. Our previous work suggests that sex hormones may contribute to these differences, although the exact mechanisms remain unclear. We hypothesize that estrogen influences neutrophil gene expression and chromatin structure during granulopoiesis, ultimately shaping neutrophil function.

Methods: We used single cell transcriptomics (sc-RNAseq), as well as flow cytometry, to analyze neutrophils. In mouse models, we performed oophorectomy (Oop) and sham surgeries, with or without administration of exogenous estradiol, to manipulate levels of gonadal hormones. Neutrophil extracellular trap (NET) formation was assessed by immunofluorescence microscopy. Human biospecimens were collected at the NIH Clinical Center for similar sc-RNAseq and NET assessments.

Results: Single-cell RNAseq, revealed that Oop significantly reduced a neutrophil subset characterized by high expression of by IFN-I stimulated genes (the “IFN-I cluster”). Neutrophils from Oop mice also showed reduced NET formation in response to danger signals. In contrast, treatment with exogenous estradiol restored IFN-I cluster prevalence and enhanced granulopoiesis in bone marrow and spleen. To translate these findings into humans, we studied individuals with androgen insensitivity syndrome (AIS; XY karyotype) who have higher levels of circulating estrogen compared to healthy volunteer (HV) males. Neutrophils from AIS individuals were more mature, had an expanded IFN-I cluster, and expressed higher IFN-I signatures than neutrophils from healthy men. Functionally, AIS neutrophils resembled those from women, showing enhanced NET formation and different bioenergetics. In SLE, sex differences in neutrophil biology are also observed. Female SLE patients had more IFN-I cluster- neutrophils and a stronger IFN-I-gene signature compared to male patients, though this difference diminished after menopause, further supporting the role for estrogen.

Conclusion: Our findings demonstrate that estrogen modulates neutrophil development and function in both mice and humans. Estrogen promotes granulopoiesis, drives the formation of an IFN-I-responsive neutrophil subset, and enhances neutrophil effector functions such as NET formation. These sex hormone-mediated differences in neutrophil biology may help explain the increased prevalence of autoimmune diseases in women.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/estrogen-modulates-neutrophil-biology-implications-for-autoimmunity/