Immunomodulatory role of proteinase-activated receptor-2

Crilly, A., Palmer, H.S., Nickdel, M.B., Dunning, L., Lockhart, J.C., Plevin, R., McInnes, I.B. and Ferrell, W.R. (2013) Immunomodulatory role of proteinase-activated receptor-2. Annals of the Rheumatic Diseases, 71(9), pp. 1559-1566. (doi:10.1136/annrheumdis-2011-200869) (PMID:22563031)

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Abstract

Objective Proteinase-activated receptor-2 (PAR2) has been implicated in inflammatory articular pathology. Using the collagen-induced arthritis model (CIA) the authors have explored the capacity of PAR2 to regulate adaptive immune pathways that could promote autoimmune mediated articular damage.

Methods Using PAR2 gene deletion and other approaches to inhibit or prevent PAR2 activation, the development and progression of CIA were assessed via clinical and histological scores together with ex vivo immune analyses.

Results The progression of CIA, assessed by arthritic score and histological assessment of joint damage, was significantly (p<0.0001) abrogated in PAR2 deficient mice or in wild-type mice administered either a PAR2 antagonist (ENMD-1068) or a PAR2 neutralising antibody (SAM11). Lymph node derived cell suspensions from PAR2 deficient mice were found to produce significantly less interleukin (IL)-17 and IFNγ in ex vivo recall collagen stimulation assays compared with wild-type littermates. In addition, substantial inhibition of TNFα, IL-6, IL-1β and IL-12 along with GM-CSF and MIP-1α was observed. However, spleen and lymph node histology did not differ between groups nor was any difference detected in draining lymph node cell subsets. Anticollagen antibody titres were significantly lower in PAR2 deficient mice.

Conclusion These data support an important role for PAR2 in the pathogenesis of CIA and suggest an immunomodulatory role for this receptor in an adaptive model of inflammatory arthritis. PAR2 antagonism may offer future potential for the management of inflammatory arthritides in which a proteinase rich environment prevails.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Ferrell, Professor William and Plevin, Prof Robin and Crilly, Dr Anne and Dunning, Mrs Lynette and Nickdel, Dr Mohammad and Lockhart, Professor John
Authors: Crilly, A., Palmer, H.S., Nickdel, M.B., Dunning, L., Lockhart, J.C., Plevin, R., McInnes, I.B., and Ferrell, W.R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Annals of the Rheumatic Diseases
Publisher:B M J Group
ISSN:0003-4967
ISSN (Online):1468-2060
Published Online:06 May 2012

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