title: CD73 plays a protective role in collagen-induced arthritis.
abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease with significant morbidity and mortality. Recent studies suggest that modulation of adenosine signaling, a potent immunosuppressive pathway, is a promising approach for treatment of RA. Extracellular adenosine can come from two sources: transport of intracellular adenosine and hydrolysis of extracellular adenine nucleotides by CD73. In this study, we investigated the susceptibility of CD73-deficient C57BL/6 mice to collagen-induced arthritis (CIA), a well-established mouse model of RA. Our data demonstrated that CD73-deficient mice are significantly more susceptible to CIA than wild-type mice. CD73 deficiency resulted in an increased production of proinflammatory cytokines in the joints, increased Th1 T cell responses, and increased joint destruction. Surprisingly, this was accompanied by delayed anticollagen IgG responses, suggesting defective isotype class switching in CD73-deficient mice. Using bone marrow chimera mice, we demonstrated that CD73 expression on nonhematopoietic cells, but not on hematopoietic cells, was important for protection from CIA. We further demonstrated that administration of a selective A2A adenosine receptor agonist to CD73-deficient mice resulted in arthritis incidence similar to wild-type mice in support of a protective role for A2A signaling. Taken together, our study identifies CD73 as an important regulator of CIA in mice. It also strengthens the notion that CD73-generated adenosine by nonhematopoietic cells plays a protective role in RA and suggests that strategies able to enhance CD73 activity or expression levels may be a valid therapeutic option.
authors: Centre de Recherche du Centre Hospitalier l'Université de Montréal, Faculté de Pharmacie de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Quebec H2X 0A9, Canada; and.
authors: Pavel
authors: P
authors: Chrobak
authors: Centre de Recherche du Centre Hospitalier l'Université de Montréal, Faculté de Pharmacie de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Quebec H2X 0A9, Canada; and.
authors: Roxanne
authors: R
authors: Charlebois
authors: Department of Radiology, Charles University Hospital, 500 05 Hradec Králové, Czech Republic.
authors: Pavel
authors: P
authors: Rejtar
authors: Centre de Recherche du Centre Hospitalier l'Université de Montréal, Faculté de Pharmacie de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Quebec H2X 0A9, Canada; and.
authors: Rana
authors: R
authors: El Bikai
authors: Centre de Recherche du Centre Hospitalier l'Université de Montréal, Faculté de Pharmacie de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Quebec H2X 0A9, Canada; and.
authors: Bertrand
authors: B
authors: Allard
authors: Centre de Recherche du Centre Hospitalier l'Université de Montréal, Faculté de Pharmacie de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Quebec H2X 0A9, Canada; and john.stagg@umontreal.ca.
authors: John
authors: J
authors: Stagg
mesh_terms: D015720:5'-Nucleotidase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D030161:Avian Proteins / Q000276:immunology; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002645:Chickens; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology*; D004198:Disease Susceptibility / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D007074:Immunoglobulin G / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007596:Joints / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010627:Phenethylamines / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; D030161:Avian Proteins; D024043:Collagen Type II; D016207:Cytokines; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D010627:Phenethylamines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D007371:Interferon-gamma; D015720:5'-Nucleotidase; D000241:Adenosine