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.
Statistics from Altmetric.com
Funding Provided by Arthritis Research UK.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We aim to publish our findings in quality, high impact peer reviewed journals preferably with open access; this may be limited by any potential intellectual property issues (see below). Any supplementary data that cannot be published will be available after a certain period either to bona fide request to the PI/Co-PIs or by downloading from University web profile pages. When permitted, publications will be added to the University of Glasgow repository (Enlighten; https://eprints.gla.ac.uk/). All data are routinely stored electronically as well as in hard copy format, and data are stored for at least 7 years and are available for scrutiny.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.