Bone marrow Th17 TNFα cells induce osteoclast differentiation, and link bone destruction to IBD
- Thomas Ciucci1,2,
- Lidia Ibáñez1,2,
- Agathe Boucoiran1,2,
- Eléonore Birgy-Barelli1,2,
- Jérôme Pène3,4,
- Grazia Abou-Ezzi1,2,
- Nadia Arab5,
- Matthieu Rouleau1,2,
- Xavier Hébuterne2,5,
- Hans Yssel3,4,
- Claudine Blin-Wakkach1,2,
- Abdelilah Wakkach1,2
- 1CNRS, UMR 7370, LP2M, Faculté de médecine, 28 avenue de Valombrose, Nice, France
- 2Université Nice Sophia Antipolis, parc Valrose, Nice, France
- 3Inserm, U844, Hôpital saint Eloi, Montpellier, France
- 4Université Montpellier 1, 5 bd Henri IV 34967, Montpellier, France
- 5Centre Hospitalier Universitaire de Nice, Hôpital de l'Archet, service de gastro-entérologie et nutrition, Nice, France
- Correspondence to Dr Abdelilah Wakkach, CNRS, UMR 7370, LP2M, Faculté de médecine, 28 avenue de valombrose, Nice 06107, cedex 2, France;
- Received 8 February 2014
- Revised 10 September 2014
- Accepted 12 September 2014
- Published Online First 8 October 2014
Objective Under both physiological and pathological conditions, bone volume is determined by the rate of bone formation by osteoblasts and bone resorption by osteoclasts. Excessive bone loss is a common complication of human IBD whose mechanisms are not yet completely understood. Despite the role of activated CD4+ T cells in inflammatory bone loss, the nature of the T cell subsets involved in this process in vivo remains unknown. The aim of the present study was to identify the CD4+ T cell subsets involved in the process of osteoclastogenesis in vivo, as well as their mechanism of action.
Design CD4+ T cells were studied in IL10−/− mice and Rag1−/− mice adoptively transferred with naive CD4+CD45RBhigh T cells, representing two well-characterised animal models of IBD and in patients with Crohn's disease. They were phenotypically and functionally characterised by flow cytometric and gene expression analysis, as well as in in vitro cocultures with osteoclast precursors.
Results In mice, we identified bone marrow (BM) CD4+ T cells producing interleukin (IL)-17 and tumour necrosis factor (TNF)-α as an osteoclastogenic T cell subset referred to as Th17 TNF-α+ cells. During chronic inflammation, these cells migrate to the BM where they survive in an IL-7-dependent manner and where they promote the recruitment of inflammatory monocytes, the main osteoclast progenitors. A population equivalent to the Th17 TNF-α+ cells was also detected in patients with Crohn's disease.
Conclusions Our results highlight the osteoclastogenic function of the Th17 TNF-α+ cells that contribute to bone loss in vivo in IBD.