Immunomodulatory role of proteinase-activated receptor-2

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.
LanguageEnglish
Pages1559-66
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume71
Issue number9
Early online date6 May 2012
DOIs
Publication statusPublished - Sep 2012

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PAR-2 Receptor
Experimental Arthritis
Collagen
Arthritis
Joints
Lymph Nodes
Chemokine CCL3
Histology
Interleukin-17
Gene Deletion
Pathology
Interleukin-12
Granulocyte-Macrophage Colony-Stimulating Factor
Neutralizing Antibodies
Interleukin-1beta
Interleukin-6
Assays
Suspensions
Peptide Hydrolases

Cite this

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title = "Immunomodulatory role of proteinase-activated receptor-2",
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.",
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Immunomodulatory role of proteinase-activated receptor-2. / Plevin, Robin.

In: Annals of the Rheumatic Diseases, Vol. 71, No. 9, 09.2012, p. 1559-66.

Research output: Contribution to journalArticle

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AB - 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.

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