MICL controls inflammation in rheumatoid arthritis

Pierre Redelinghuys, Lauren Whitehead, Andrea Augello, Rebecca A. Drummond, Jean-Michel Levesque, Simon Vautier, Delyth M. Reid, Bernhard Kerscher, Julie A. Taylor, Peter A. Nigrovic, John Wright, Graeme I. Murray, Janet A. Willment, Lynne J. Hocking, Maria J. G. Fernandes, Cosimo De Bari, Iain B. McInnes, Gordon D. Brown

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Abstract

Background Myeloid inhibitory C-type lectin-like receptor (MICL, Clec12A) is a C-type lectin receptor (CLR) expressed predominantly by myeloid cells. Previous studies have suggested that MICL is involved in controlling inflammation.

Objective To determine the role of this CLR in inflammatory pathology using Clec12A−/− mice.

Methods Clec12A−/− mice were generated commercially and primarily characterised using the collagen antibody-induced arthritis (CAIA) model. Mechanisms and progress of disease were characterised by clinical scoring, histology, flow cytometry, irradiation bone-marrow chimera generation, administration of blocking antibodies and in vivo imaging. Characterisation of MICL in patients with rheumatoid arthritis (RA) was determined by immunohistochemistry and single nucleotide polymorphism analysis. Anti-MICL antibodies were detected in patient serum by ELISA and dot-blot analysis.

Results MICL-deficient animals did not present with pan-immune dysfunction, but exhibited markedly exacerbated inflammation during CAIA, owing to the inappropriate activation of myeloid cells. Polymorphisms of MICL were not associated with disease in patients with RA, but this CLR was the target of autoantibodies in a subset of patients with RA. In wild-type mice the administration of such antibodies recapitulated the Clec12A−/− phenotype.

Conclusions MICL plays an essential role in regulating inflammation during arthritis and is an autoantigen in a subset of patients with RA. These data suggest an entirely new mechanism underlying RA pathogenesis, whereby the threshold of myeloid cell activation can be modulated by autoantibodies that bind to cell membrane-expressed inhibitory receptors.

Original languageEnglish
Pages (from-to)1386-1391
Number of pages6
JournalAnnals of the Rheumatic Diseases
Volume75
Issue number7
Early online date14 Aug 2015
DOIs
Publication statusPublished - Jul 2016

Bibliographical note

Acknowledgments
We thank G Milne, D MacCallum, S Hardison, G Wilson, C Wallace, S Hadebe and A Richmond for assistance; H. El-Gabalawy for tissues and the animal facility staff for the care of our animals. Flow cytometry was undertaken in the Iain Fraser Cytometry Centre, University of Aberdeen.

Funding:
GDB was funded by the Wellcome Trust and MRC (UK). AA and CDB are supported by the Arthritis Research UK Tissue Engineering Centre (grant 19429). This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk, and was funded by the Wellcome Trust (076113). MJGF was funded by The Arthritis Society and the Canadian Arthritis Network and J-ML by a scholarship from the Canadian Arthritis Network.

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