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Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus
Edited by Marc Feldmann, University of Oxford, Oxford, United Kingdom, and approved October 30, 2019 (received for review May 17, 2019)

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Significance
The field of neutrophil biology has lagged behind in terms of the understanding of heterogeneity and versatility of cellular functions, limiting the development of therapeutic approaches that target aberrant neutrophil phenotypes. Using bulk and single-cell transcriptomic, epigenetic, and functional analyses, this study highlights aspects of neutrophil heterogeneity and their putative role in the pathogenesis of systemic lupus erythematosus and its associated vascular damage.
Abstract
Neutrophil dysregulation is implicated in the pathogenesis of systemic lupus erythematosus (SLE). SLE is characterized by elevated levels of a pathogenic neutrophil subset known as low-density granulocytes (LDGs). The origin and phenotypic, functional, and pathogenic heterogeneity of LDGs remain to be systematically determined. Transcriptomics and epigenetic assessment of lupus LDGs, autologous normal-density neutrophils, and healthy control neutrophils was performed by bulk and single-cell RNA sequencing and assay for transposase-accessible chromatin sequencing. Functional readouts were compared among neutrophil subsets. SLE LDGs display significant transcriptional and epigenetic heterogeneity and comprise 2 subpopulations of intermediate-mature and immature neutrophils, with different degrees of chromatin accessibility and differences in transcription factor motif analysis. Differences in neutrophil extracellular trap (NET) formation, oxidized mitochondrial DNA release, chemotaxis, phagocytosis, degranulation, ability to harm the endothelium, and responses to type I interferon (IFN) stimulation are evident among LDG subsets. Compared with other immune cell subsets, LDGs display the highest expression of IFN-inducible genes. Distinct LDG subsets correlate with specific clinical features of lupus and with the presence and severity of coronary artery disease. Phenotypic, functional, and pathogenic neutrophil heterogeneity are prevalent in SLE and may promote immune dysregulation and prominent vascular damage characteristic of this disease.
Footnotes
- ↵1To whom correspondence should be addressed. Email: mariana.kaplan{at}nih.gov.
Author contributions: P.M. and M.J.K. designed research; P.M., S.N., L.O., C.C.-R., D.W.C., and P.M.C. performed research; G.G.-C. contributed new reagents/analytic tools; P.M., S.N., L.O., R.R.G., K.J., C.C.-R., S.G., P.M.C., X.W., F.N., Z.M., A.D., N.N.M., S.H., S.D., H.-W.S., and M.J.K. analyzed data; and P.M., L.O., H.-W.S., and M.J.K. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE139360).
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1908576116/-/DCSupplemental.
Published under the PNAS license.
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- Immunology and Inflammation