Article Text

Download PDFPDF
Monocyte and bone marrow macrophage transcriptional phenotypes in systemic juvenile idiopathic arthritis reveal TRIM8 as a mediator of IFN-γ hyper-responsiveness and risk for macrophage activation syndrome
  1. Grant S Schulert1,2,
  2. Alex V Pickering3,
  3. Thuy Do1,
  4. Sanjeev Dhakal1,
  5. Ndate Fall1,
  6. Daniel Schnell4,
  7. Mario Medvedovic2,
  8. Nathan Salomonis2,4,
  9. Sherry Thornton1,2,
  10. Alexei A Grom1,2
  1. 1Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  2. 2Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  3. 3Harvard Medical School, Boston, Massachusetts, USA
  4. 4Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  1. Correspondence to Dr Grant S Schulert, Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; grant.schulert{at}


Objectives Systemic juvenile idiopathic arthritis (SJIA) confers high risk for macrophage activation syndrome (MAS), a life-threatening cytokine storm driven by interferon (IFN)-γ. SJIA monocytes display IFN-γ hyper-responsiveness, but the molecular basis of this remains unclear. The objective of this study is to identify circulating monocyte and bone marrow macrophage (BMM) polarisation phenotypes in SJIA including molecular features contributing to IFN response.

Methods Bulk RNA-seq was performed on peripheral blood monocytes (n=26 SJIA patients) and single cell (sc) RNA-seq was performed on BMM (n=1). Cultured macrophages were used to define consequences of tripartite motif containing 8 (TRIM8) knockdown on IFN-γ signalling.

Results Bulk RNA-seq of SJIA monocytes revealed marked transcriptional changes in patients with elevated ferritin levels. We identified substantial overlap with multiple polarisation states but little evidence of IFN-induced signature. Interestingly, among the most highly upregulated genes was TRIM8, a positive regulator of IFN-γ signalling. In contrast to PBMC from SJIA patients without MAS, scRNA-seq of BMM from a patient with SJIA and MAS identified distinct subpopulations of BMM with altered transcriptomes, including upregulated IFN-γ response pathways. These BMM also showed significantly increased expression of TRIM8. In vitro knockdown of TRIM8 in macrophages significantly reduced IFN-γ responsiveness.

Conclusions Macrophages with an ‘IFN-γ response’ phenotype and TRIM8 overexpression were expanded in the bone marrow from an MAS patient. TRIM8 is also upregulated in SJIA monocytes, and augments macrophage IFN-γ response in vitro, providing both a candidate molecular mechanism and potential therapeutic target for monocyte hyper-responsiveness to IFNγ in cytokine storms including MAS.

  • arthritis
  • juvenile
  • inflammation
  • cytokines

Statistics from


  • Handling editor Josef S Smolen

  • Twitter @GrantSchulert

  • Contributors GS and AAG designed the study. GS, TD, SD, NF and ST performed the experiments. GS, AP, DS, MM, NS and AAG performed gene expression analysis. GS and AAG wrote the first draft of the manuscript. All authors contributed to the final manuscript and approved its submission.

  • Funding This work was supported by the Systemic Juvenile Idiopathic Arthritis Foundation; National Institutes of Health K08-AR072075 (GS), R01-AR059049 (AAG) and P30-AR070549; Cincinnati Children’s Research Foundation ARC Grant (GS&AAG); and an unrestricted gift from the Jellen Family Foundation.

  • Competing interests GS has served as a consultant for Novartis and Sobi. AAG has served as a consultant for Juno and Novartis, and has received research support from Sobi and AB2Bio. All other authors declare no conflicts of interest.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the institutional review board of CCHMC (IRB# 2012–0160).

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

  • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. Bulk and single-cell RNA-seq datasets have been deposited in gene expression omnibus (GSE147608 and GSE147795, respectively).

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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.