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
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.
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