Article Text

Download PDFPDF
Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome
  1. Pragnesh Mistry1,
  2. Carmelo Carmona-Rivera1,
  3. Amanda K Ombrello2,
  4. Patrycja Hoffmann2,
  5. Nickie L Seto1,
  6. Anne Jones2,
  7. Deborah L Stone2,
  8. Faiza Naz3,
  9. Philip Carlucci1,
  10. Stefania Dell’Orso3,
  11. Gustavo Gutierrez-Cruz3,
  12. Hong-Wei Sun4,
  13. Daniel L Kastner2,
  14. Ivona Aksentijevich2,
  15. Mariana J Kaplan1
  1. 1 Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA
  2. 2 Inflammatory Disease Section, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
  3. 3 Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, NIH, Bethesda, Maryland, USA
  4. 4 Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, Maryland, USA
  1. Correspondence to Dr Mariana J Kaplan, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MA 20892, USA; mariana.kaplan{at}


Objectives Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is characterised by flares of sterile arthritis with neutrophil infiltrate and the overproduction of interleukin (IL)-1β. The purpose of this study was to elucidate the potential role of neutrophil subsets and neutrophil extracellular traps (NET) in the pathogenesis of PAPA.

Methods Neutrophils and low-density granulocytes (LDG) were quantified by flow cytometry. Circulating NETs were measured by ELISA and PAPA serum was tested for the ability to degrade NETs. The capacity of NETs from PAPA neutrophils to activate macrophages was assessed. Skin biopsies were analysed for NETs and neutrophil gene signatures.

Results Circulating LDGs are elevated in PAPA subjects. PAPA neutrophils and LDGs display enhanced NET formation compared with control neutrophils. PAPA sera exhibit impaired NET degradation and this is corrected with exogenous DNase1. Recombinant human IL-1β induces NET formation in PAPA neutrophils but not healthy control neutrophils. NET formation in healthy control neutrophils is induced by PAPA serum and this effect is inhibited by the IL-1 receptor antagonist, anakinra. NETs from PAPA neutrophils and LDGs stimulate IL-6 release in healthy control macrophages. NETs are detected in skin biopsies of patients with PAPA syndrome in association with increased tissue IL-1β, IL-8 and IL-17. Furthermore, LDG gene signatures are detected in PAPA skin.

Conclusions PAPA syndrome is characterised by an imbalance of NET formation and degradation that may enhance the half-life of these structures in vivo, promoting inflammation. Anakinra ameliorates NET formation in PAPA and this finding supports a role for IL-1 signalling in exacerbated neutrophil responses in this disease. The study also highlights other inflammatory pathways potentially pathogenic in PAPA, including IL-17 and IL-6, and these results may help guide new therapeutic approaches in this severe and often treatment-refractory condition.

  • inflammation
  • cytokines
  • fever syndromes

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • Handling editor Josef S Smolen

  • Contributors PM, CCR, NLS and PC performed the experiments. AKO, PH, AJ, DLS, DLK and IA characterised the clinical cohort, patient recruitment and genetic analysis/pedigree. FN, SDO and GGC were involved in RNA sequencing support. HWS was involved in analysis of RNA sequencing. PM and MJK conceived the study and drafted the manuscript.

  • Funding This study was supported by the Intramural Research Program at NIAMS/NIH (ZIAAR041199 and the Office of Science and Technology NIAMS). This study utilised the high-performance computational capabilities of the Helix Systems at the NIH (

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval NIDDK/NIAMS IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The RNA sequencing data have been submitted to GEO and a GEO accession number will be provided at the time of publication (currently pending).