Dendritic cell integrin expression patterns regulate inflammation in the rheumatoid arthritis joint

Schittenhelm, L., Robertson, J., Pratt, A. G., Hilkens, C. and Morrison, V. L. (2021) Dendritic cell integrin expression patterns regulate inflammation in the rheumatoid arthritis joint. Rheumatology, 60(3), pp. 1533-1542. (doi: 10.1093/rheumatology/keaa686) (PMID:33123735) (PMCID:PMC7937020)

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Abstract

Objectives: Immune dysregulation contributes to the development of RA. Altered surface expression patterns of integrin adhesion receptors by immune cells is one mechanism by which this may occur. We investigated the role of β2 integrin subunits CD11a and CD11b in dendritic cell (DC) subsets of RA patients. Methods: Total β2 integrin subunit expression and its conformation (‘active’ vs ‘inactive’ state) were quantified in DC subsets from peripheral blood (PB) and SF of RA patients as well as PB from healthy controls. Ex vivo stimulation of PB DC subsets and in vitro-generated mature and tolerogenic monocyte-derived DCs (moDCs) were utilized to model the clinical findings. Integrin subunit contribution to DC function was tested by analysing clustering and adhesion, and in co-cultures to assess T cell activation. Results: A significant reduction in total and active CD11a expression in DCs in RA SF compared with PB and, conversely, a significant increase in CD11b expression was found. These findings were modelled in vitro using moDCs: tolerogenic moDCs showed higher expression of active CD11a and reduced levels of active CD11b compared with mature moDCs. Finally, blockade of CD11b impaired T cell activation in DC–T cell co-cultures. Conclusion: For the first time in RA, we show opposing expression of CD11a and CD11b in DCs in environments of inflammation (CD11alow/CD11bhigh) and steady state/tolerance (CD11ahigh/CD11blow), as well as a T cell stimulatory role for CD11b. These findings highlight DC integrins as potential novel targets for intervention in RA.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Robertson, Dr Jamie and Hilkens, Dr Catharien and Morrison, Dr Vicky and Pratt, Dr Arthur
Authors: Schittenhelm, L., Robertson, J., Pratt, A. G., Hilkens, C., and Morrison, V. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Rheumatology
Publisher:Oxford University Press
ISSN:1462-0324
ISSN (Online):1462-0332
Published Online:30 October 2020
Copyright Holders:Copyright © The Author(s) 2020
First Published:First published in Rheumatology 60(3):1533–1542
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190682Rheumatoid Arthritis Centre of Excellence (RACE - Towards a Cure)Iain McInnesVersus Arthritis (ARTRESUK)MP20298III - Immunology
171075Integrin-mediated regulation of leukocytes in autoimmunity.Vicky MorrisonVersus Arthritis (ARTRESUK)20848III - Immunology
301789Exploring the therapeutic potential of targeting beta2 integrins in Rheumatoid ArthritisVicky MorrisonTenovus Scotland (TENOVUS)S17-18III - Immunology