Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice

Markus Kindermann,Andreas Ramming,Nico Andreas,Michael Frech,Darja Andreev,Sébastien Lucas,Thomas Kamradt,Aline Bozec,Nataliya Yeremenko,Yasunori Omata,Carina Scholtysek,Stefan Wirtz,Tatjana Primbs,Mario M Zaiss,Kerstin Sarter,Gerhard Krönke,Georg Schett,Dominique L Baeten

doi:10.1016/j.celrep.2018.06.005

Abstract

Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number. To elucidate the role of ILC2 in arthritis, loss- and gain-of-function mouse models for ILC2 were subjected to arthritis. Reduction of ILC2 numbers in RORαcre/GATA3fl/fl and Tie2cre/RORαfl/fl mice significantly exacerbated arthritis. Increasing ILC2 numbers in mice by IL-25/IL-33mini-circles or IL-2/IL-2 antibody complex and the adoptive transfer of wild-type (WT) ILC2s significantly attenuated arthritis by affecting the initiation phase. In addition, adoptive transfer of IL-4/13-competent WT but not IL-4/13-/- ILC2s and decreased cytokine secretion by macrophages. These data show that ILC2s have immune-regulatory functions in arthritis.

Highlights

Innate lymphoid cells (ILCs) are rare immune cells defined by their lack of T cell receptors and absence of lineage markers
Recent work suggested that a specific form of ILCs, ILC3s, which are a source of IL-17 and IL-22, reside in entheses and are enriched in the joints of patients with spondyloarthritis (Ciccia et al, 2012, 2015; Cuthbert et al, 2017; Leijten et al, 2015)
Some analyses have been carried out in rheumatoid arthritis (RA) patients showing that ILC1 and ILC3 reside in the synovial fluid of RA patients (Dalbeth and Callan, 2002; Koo et al, 2013; Ren et al, 2011) and are positively correlated with clinical disease activity (Koo et al, 2013)

Summary

Introduction

Innate lymphoid cells (ILCs) are rare immune cells defined by their lack of T cell receptors and absence of lineage markers. In one study of subjects with pre-clinical RA, in which the authors did not distinguish between ILC1 and ILC2, the combined ILC1/2 population presented a larger proportion of ILCs in lymph nodes compared with healthy controls, suggesting that ILCs may be involved in RA from the very beginning (Rodrıguez-Carrio et al, 2017) Apart from these descriptive studies on ILC1 and ILC3, data on the function of ILCs in RA are rare. We showed that ILC2s induce the resolution of arthritis via the production of IL-9, which in turn restores the suppressive capacity of Tregs, enabling them to suppress chronic inflammation (Rauber et al, 2017) In this context, studies of ILC2s are highly interesting, as they are linked to Th2 cell activation, which has recently been described as a regulatory pathway in RA (Chen et al, 2016)

Results

Discussion

Conclusion