Article Text

TGFβ promotes low IL10-producing ILC2 with profibrotic ability involved in skin fibrosis in systemic sclerosis
  1. Paôline Laurent1,
  2. Benoit Allard1,
  3. Pauline Manicki2,
  4. Valérie Jolivel1,
  5. Emeline Levionnois1,
  6. Mohamed Jeljeli3,
  7. Pauline Henrot2,
  8. Julien Izotte4,
  9. Damien Leleu1,
  10. Alexis Groppi5,6,
  11. Julien Seneschal7,8,
  12. Joel Constans9,
  13. Carlo Chizzolini10,
  14. Christophe Richez1,2,
  15. Pierre Duffau1,11,
  16. Estibaliz Lazaro1,11,
  17. Edouard Forcade1,12,
  18. Thierry Schaeverbeke1,2,
  19. Thomas Pradeu1,
  20. Frédéric Batteux3,
  21. Patrick Blanco1,13,
  22. Cécile Contin-Bordes1,13,
  23. Marie-Elise Truchetet1,2
  1. 1ImmunoConcEpt, CNRS, UMR 5164, University of Bordeaux, Talence, France
  2. 2Rheumatology Department, CHU de Bordeaux, Bordeaux, France
  3. 3Immunology Department, CHU Cochin Hospital, University of Paris Descartes Faculty of Medicine Paris Center, Paris, France
  4. 4Animal Facility A2, University of Bordeaux, Talence, France
  5. 5Centre de Bioinformatique de Bordeaux (CBiB), University of Bordeaux, Talence, France
  6. 6IBGC, CNRS, UMR 5095, University of Bordeaux, Talence, France
  7. 7Dermatology Department, CHU de Bordeaux, Bordeaux, France
  8. 8INSERM U1035, University of Bordeaux, Talence, France
  9. 9Vascular Medicine Department, CHU de Bordeaux, Bordeaux, France
  10. 10Immunology and Allergy, University of Geneva, Geneva, Switzerland
  11. 11Internal Medicine, CHU de Bordeaux, Bordeaux, France
  12. 12Hematology, CHU de Bordeaux, Bordeaux, France
  13. 13Immunology department, CHU de Bordeaux, Bordeaux, France
  1. Correspondence to Pr Marie-Elise Truchetet, Rheumatology, CHU de Bordeaux, Bordeaux, Aquitaine, France; marie-elise.truchetet{at}


Objective Innate lymphoid cells-2 (ILC2) were shown to be involved in the development of lung or hepatic fibrosis. We sought to explore the functional and phenotypic heterogeneity of ILC2 in skin fibrosis within systemic sclerosis (SSc).

Methods Blood samples and skin biopsies from healthy donor or patients with SSc were analysed by immunostaining techniques. The fibrotic role of sorted ILC2 was studied in vitro on dermal fibroblast and further explored by transcriptomic approach. Finally, the efficacy of a new treatment against fibrosis was assessed with a mouse model of SSc.

Results We found that ILC2 numbers were increased in the skin of patients with SSc and correlated with the extent of skin fibrosis. In SSc skin, KLRG1 ILC2 (natural ILC2) were dominating over KLRG1+ ILC2 (inflammatory ILC2). The cytokine transforming growth factor-β (TGFβ), whose activity is increased in SSc, favoured the expansion of KLRG1- ILC2 simultaneously decreasing their production of interleukin 10 (IL10), which regulates negatively collagen production by dermal fibroblasts. TGFβ-stimulated ILC2 also increased myofibroblast differentiation. Thus, human KLRG1- ILC2 had an enhanced profibrotic activity. In a mouse model of SSc, therapeutic intervention-combining pirfenidone with the administration of IL10 was required to reduce the numbers of skin infiltrating ILC2, enhancing their expression of KLRG1 and strongly alleviating skin fibrosis.

Conclusion Our results demonstrate a novel role for natural ILC2 and highlight their inter-relationships with TGFβ and IL10 in the development of skin fibrosis, thereby opening up new therapeutic approaches in SSc.

  • systemic sclerosis
  • fibroblasts
  • inflammation

Data availability statement

Data are available on reasonable request.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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Data availability statement

Data are available on reasonable request.

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  • PL and BA are joint first authors.

  • Handling editor Josef S Smolen

  • CC-B and M-ET contributed equally.

  • Correction notice This article has been corrected since it published Online First. The funding statement has been updated.

  • Collaborators Victor Racine, Nathalie Dugot-Senant, Sébastien Marais, Atika Zouine, Vincent Pitard, Xavier Gauthereau, Benoit Rousseau, Eric Vivier, Frédéric Vély, Andreas Ramming, Jörg Distler.

  • Contributors PL and BA jointly designed the research, performed the experiments, collected, analysed and interpreted the data, wrote and revised the manuscript. MJ, PM, EL, DL, AG and VJ performed and analysed some experiments. EL, PL, JI, MJ and FB performed mice experiments. TS, CC, TP and PB provided intellectual input and edited the manuscript. PM, DL, PH, JS, JC, CR, PD, TS, EL and EF recruited the study participants and provided patients’ samples and clinical data. CC-B and M-ET jointly designed and supervised the study and wrote the manuscript.

  • Funding This research was supported by grants from the Société Française de Rhumatologie (SFR), Rhumato-Network. It was also supported by the Association des Sclérodermiques de France (ASF). Paôline Laurent was funded by a PhD grant from the University of Bordeaux and Valerie Jolivel by an interdisciplinary project of the IDEX (Initiative d’excellence) of the University of Bordeaux (PI: T. Pradeu)

  • Competing interests None declared.

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

  • 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.