Protease-activated receptor 2 signalling promotes dendritic cell antigen transport and T-cell activation in vivo.
Deficiency of protease-activated receptor-2 (PAR2) modulates inflammation in several models of inflammatory and autoimmune disease, although the underlying mechanism(s) are not understood. PAR2 is expressed on endothelial and immune cells, and is implicated in dendritic cell (DC) differentiation. We investigated in vivo the impact of PAR2 activation on DCs and T cells in PAR2 wild-type (WT) and knockout (KO) mice using a specific PAR2 agonist peptide (AP2). PAR2 activation significantly increased the frequency of mature CD11c(high) DCs in draining lymph nodes 24 hr after AP2 administration. Furthermore, these DCs exhibited increased expression of major histocompatibility complex (MHC) class II and CD86. A significant increase in activated (CD44(+) CD62(-)) CD4(+) and CD8(+) T-cell frequencies was also observed in draining lymph nodes 48 hr after AP2 injection. No detectable change in DC or T-cell activation profiles was observed in the spleen. The influence of PAR2 signalling on antigen transport to draining lymph nodes was assessed in the context of delayed-type hypersensitivity. PAR2 WT mice that were sensitized by skin-painting with fluorescein isothiocyanate (FITC) to induce delayed-type hypersensitivity possessed elevated proportion of FITC(+) DCs in draining lymph nodes 24 hr after FITC painting when compared with PAR2 KO mice (0.95% versus 0.47% of total lymph node cells). Collectively, these results demonstrate that PAR2 signalling promotes DC trafficking to the lymph nodes and subsequent T-cell activation, and thus provides an explanation for the pro-inflammatory effect of PAR2 in animal models of inflammation.
Service of Rheumatology, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Giancarlo
G
Ramelli
Silvia
S
Fuertes
Sharmal
S
Narayan
Nathalie
N
Busso
Hans
H
Acha-Orbea
Alexander
A
So
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D007114:Immunization; D008198:Lymph Nodes / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000276:immunology; D044464:Receptor, PAR-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D015703:Antigens, CD; D010446:Peptide Fragments; D044464:Receptor, PAR-2; D016650:Fluorescein-5-isothiocyanate