Skip to main content
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian
  • Log in
  • My Cart

Main menu

  • Home
  • Articles
    • Current
    • Latest Articles
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • Archive
  • Front Matter
  • News
    • For the Press
    • Highlights from Latest Articles
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Purpose and Scope
    • Editorial and Journal Policies
    • Submission Procedures
    • For Reviewers
    • Author FAQ
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home

Advanced Search

  • Home
  • Articles
    • Current
    • Latest Articles
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • Archive
  • Front Matter
  • News
    • For the Press
    • Highlights from Latest Articles
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Purpose and Scope
    • Editorial and Journal Policies
    • Submission Procedures
    • For Reviewers
    • Author FAQ

New Research In

Physical Sciences

Featured Portals

  • Physics
  • Chemistry
  • Sustainability Science

Articles by Topic

  • Applied Mathematics
  • Applied Physical Sciences
  • Astronomy
  • Computer Sciences
  • Earth, Atmospheric, and Planetary Sciences
  • Engineering
  • Environmental Sciences
  • Mathematics
  • Statistics

Social Sciences

Featured Portals

  • Anthropology
  • Sustainability Science

Articles by Topic

  • Economic Sciences
  • Environmental Sciences
  • Political Sciences
  • Psychological and Cognitive Sciences
  • Social Sciences

Biological Sciences

Featured Portals

  • Sustainability Science

Articles by Topic

  • Agricultural Sciences
  • Anthropology
  • Applied Biological Sciences
  • Biochemistry
  • Biophysics and Computational Biology
  • Cell Biology
  • Developmental Biology
  • Ecology
  • Environmental Sciences
  • Evolution
  • Genetics
  • Immunology and Inflammation
  • Medical Sciences
  • Microbiology
  • Neuroscience
  • Pharmacology
  • Physiology
  • Plant Biology
  • Population Biology
  • Psychological and Cognitive Sciences
  • Sustainability Science
  • Systems Biology
Research Article

Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus

Pragnesh Mistry, Shuichiro Nakabo, Liam O’Neil, Rishi R. Goel, Kan Jiang, Carmelo Carmona-Rivera, Sarthak Gupta, Diana W. Chan, Philip M. Carlucci, Xinghao Wang, Faiza Naz, Zerai Manna, Amit Dey, Nehal N. Mehta, Sarfaraz Hasni, Stefania Dell’Orso, Gustavo Gutierrez-Cruz, Hong-Wei Sun, and View ORCID ProfileMariana J. Kaplan
PNAS first published November 21, 2019 https://doi.org/10.1073/pnas.1908576116
Pragnesh Mistry
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shuichiro Nakabo
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Liam O’Neil
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rishi R. Goel
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kan Jiang
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carmelo Carmona-Rivera
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sarthak Gupta
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Diana W. Chan
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip M. Carlucci
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xinghao Wang
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Faiza Naz
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zerai Manna
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amit Dey
bNational Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nehal N. Mehta
bNational Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sarfaraz Hasni
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefania Dell’Orso
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gustavo Gutierrez-Cruz
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hong-Wei Sun
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mariana J. Kaplan
aNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mariana J. Kaplan
  • For correspondence: mariana.kaplan@nih.gov
  1. Edited by Marc Feldmann, University of Oxford, Oxford, United Kingdom, and approved October 30, 2019 (received for review May 17, 2019)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

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.

  • autoimmunity
  • neutrophils
  • systemic lupus erythematosus

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.

View Full Text

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.

Subscribers, for more details, please visit our Subscriptions FAQ.

Please click here to log into the PNAS submission website.

PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
Citation Tools
Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus
Pragnesh Mistry, Shuichiro Nakabo, Liam O’Neil, Rishi R. Goel, Kan Jiang, Carmelo Carmona-Rivera, Sarthak Gupta, Diana W. Chan, Philip M. Carlucci, Xinghao Wang, Faiza Naz, Zerai Manna, Amit Dey, Nehal N. Mehta, Sarfaraz Hasni, Stefania Dell’Orso, Gustavo Gutierrez-Cruz, Hong-Wei Sun, Mariana J. Kaplan
Proceedings of the National Academy of Sciences Nov 2019, 201908576; DOI: 10.1073/pnas.1908576116

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus
Pragnesh Mistry, Shuichiro Nakabo, Liam O’Neil, Rishi R. Goel, Kan Jiang, Carmelo Carmona-Rivera, Sarthak Gupta, Diana W. Chan, Philip M. Carlucci, Xinghao Wang, Faiza Naz, Zerai Manna, Amit Dey, Nehal N. Mehta, Sarfaraz Hasni, Stefania Dell’Orso, Gustavo Gutierrez-Cruz, Hong-Wei Sun, Mariana J. Kaplan
Proceedings of the National Academy of Sciences Nov 2019, 201908576; DOI: 10.1073/pnas.1908576116
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley
Proceedings of the National Academy of Sciences: 116 (49)
Current Issue

Submit

Sign up for Article Alerts

Article Classifications

  • Biological Sciences
  • Immunology and Inflammation

Jump to section

  • Article
    • Abstract
    • Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Modulating the body's networks could become mainstream therapy for many health issues. Image credit: The Feinstein Institutes for Medicine Research.
Core Concept: The rise of bioelectric medicine sparks interest among researchers, patients, and industry
Modulating the body's networks could become mainstream therapy for many health issues.
Image credit: The Feinstein Institutes for Medicine Research.
Adaptations in heart structure and function likely enabled endurance and survival in preindustrial humans. Image courtesy of Pixabay/Skeeze.
Human heart evolved for endurance
Adaptations in heart structure and function likely enabled endurance and survival in preindustrial humans.
Image courtesy of Pixabay/Skeeze.
Viscoelastic carrier fluids enhance retention of fire retardants on wildfire-prone vegetation. Image courtesy of Jesse D. Acosta.
Viscoelastic fluids and wildfire prevention
Viscoelastic carrier fluids enhance retention of fire retardants on wildfire-prone vegetation.
Image courtesy of Jesse D. Acosta.
Water requirements may make desert bird declines more likely in a warming climate. Image courtesy of Sean Peterson (photographer).
Climate change and desert bird collapse
Water requirements may make desert bird declines more likely in a warming climate.
Image courtesy of Sean Peterson (photographer).
QnAs with NAS member and plant biologist Sheng Yang He. Image courtesy of Sheng Yang He.
Featured QnAs
QnAs with NAS member and plant biologist Sheng Yang He
Image courtesy of Sheng Yang He.

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Latest Articles
  • Archive

PNAS Portals

  • Classics
  • Front Matter
  • Teaching Resources
  • Anthropology
  • Chemistry
  • Physics
  • Sustainability Science

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Press
  • Site Map
  • PNAS Updates

Feedback    Privacy/Legal

Copyright © 2019 National Academy of Sciences. Online ISSN 1091-6490