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 DeBari; Iain B. Mcinnes; Gordon D. Brown

doi:10.1136/annrheumdis-2014-206644

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 DeBari, Iain B. Mcinnes, Gordon D. Brown

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	1386-1391
Number of pages	6
Journal	Annals of the Rheumatic Diseases
Volume	75
Issue number	7
Early online date	14 Aug 2015
DOIs	https://doi.org/10.1136/annrheumdis-2014-206644
Publication status	Published - 1 Jul 2016
Externally published	Yes

Bibliographical note

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

ASJC Scopus subject areas

Rheumatology
Immunology and Allergy
Immunology
Biochemistry, Genetics and Molecular Biology(all)

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Redelinghuys, P., Whitehead, L., Augello, A., Drummond, R. A., Levesque, J. M., Vautier, S., Reid, D. M., Kerscher, B., Taylor, J. A., Nigrovic, P. A., Wright, J., Murray, G. I., Willment, J. A., Hocking, L. J., Fernandes, M. J. G., DeBari, C., Mcinnes, I. B., & Brown, G. D. (2016). MICL controls inflammation in rheumatoid arthritis. Annals of the Rheumatic Diseases, 75(7), 1386-1391. https://doi.org/10.1136/annrheumdis-2014-206644

MICL controls inflammation in rheumatoid arthritis. / Redelinghuys, Pierre; Whitehead, Lauren; Augello, Andrea; Drummond, Rebecca A.; Levesque, Jean Michel; Vautier, Simon; Reid, Delyth M.; Kerscher, Bernhard; Taylor, Julie A.; Nigrovic, Peter A.; Wright, John; Murray, Graeme I.; Willment, Janet A.; Hocking, Lynne J.; Fernandes, Maria J.G.; DeBari, Cosimo; Mcinnes, Iain B.; Brown, Gordon D.

In: Annals of the Rheumatic Diseases, Vol. 75, No. 7, 01.07.2016, p. 1386-1391.

Research output: Contribution to journal › Article › peer-review

Redelinghuys, P, Whitehead, L, Augello, A, Drummond, RA, Levesque, JM, Vautier, S, Reid, DM, Kerscher, B, Taylor, JA, Nigrovic, PA, Wright, J, Murray, GI, Willment, JA, Hocking, LJ, Fernandes, MJG, DeBari, C, Mcinnes, IB & Brown, GD 2016, 'MICL controls inflammation in rheumatoid arthritis', Annals of the Rheumatic Diseases, vol. 75, no. 7, pp. 1386-1391. https://doi.org/10.1136/annrheumdis-2014-206644

Redelinghuys, Pierre ; Whitehead, Lauren ; Augello, Andrea ; Drummond, Rebecca A. ; Levesque, Jean Michel ; Vautier, Simon ; Reid, Delyth M. ; Kerscher, Bernhard ; Taylor, Julie A. ; Nigrovic, Peter A. ; Wright, John ; Murray, Graeme I. ; Willment, Janet A. ; Hocking, Lynne J. ; Fernandes, Maria J.G. ; DeBari, Cosimo ; Mcinnes, Iain B. ; Brown, Gordon D. / MICL controls inflammation in rheumatoid arthritis. In: Annals of the Rheumatic Diseases. 2016 ; Vol. 75, No. 7. pp. 1386-1391.

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title = "MICL controls inflammation in rheumatoid arthritis",

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.",

author = "Pierre Redelinghuys and Lauren Whitehead and Andrea Augello and Drummond, {Rebecca A.} and Levesque, {Jean Michel} and Simon Vautier and Reid, {Delyth M.} and Bernhard Kerscher and Taylor, {Julie A.} and Nigrovic, {Peter A.} and John Wright and Murray, {Graeme I.} and Willment, {Janet A.} and Hocking, {Lynne J.} and Fernandes, {Maria J.G.} and Cosimo DeBari and Mcinnes, {Iain B.} and Brown, {Gordon D.}",

note = "This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ Copyright {\textcopyright} and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.",

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T1 - MICL controls inflammation in rheumatoid arthritis

AU - Redelinghuys, Pierre

AU - Whitehead, Lauren

AU - Augello, Andrea

AU - Drummond, Rebecca A.

AU - Levesque, Jean Michel

AU - Vautier, Simon

AU - Reid, Delyth M.

AU - Kerscher, Bernhard

AU - Taylor, Julie A.

AU - Nigrovic, Peter A.

AU - Wright, John

AU - Murray, Graeme I.

AU - Willment, Janet A.

AU - Hocking, Lynne J.

AU - Fernandes, Maria J.G.

AU - DeBari, Cosimo

AU - Mcinnes, Iain B.

AU - Brown, Gordon D.

N1 - This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

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MICL controls inflammation in rheumatoid arthritis

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