α2β1 integrin regulates Th17 cell activity and its neutralization decreases the severity of collagen-induced arthritis.
Th17 cells play a critical role in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms by which these cells regulate the development of RA are not fully understood. We have recently shown that α2β1 integrin, the receptor of type I collagen, is the major collagen-binding integrin expressed by human Th17 cells. In this study, we examined the role of α2β1 integrin in Th17-mediated destructive arthritis in the murine model of collagen-induced arthritis (CIA). We found that α2β1 integrin is expressed on synovial Th17 cells from CIA mice and its neutralization with a specific mAb significantly reduced inflammation and cartilage degradation, and protected the mice from bone erosion. Blockade of α2β1 integrin led to a decrease in the number of Th17 cells in the joints and to a reduction of IL-17 levels in CIA mice. This was associated with an inhibition of receptor activator of NF-κB ligand levels and osteoclast numbers, and reduction of bone loss. We further show that α2β1 integrin is expressed on synovial Th17 cells from RA patients, and that its ligation with collagen costimulated the production of IL-17 by polarized human Th17 cells by enhancing the expression of retinoic acid receptor-related orphan receptor C through ERK and PI3K/AKT. Our findings provide the first evidence, to our knowledge, that α2β1 integrin is an important pathway in Th17 cell activation in the pathogenesis of CIA, suggesting that its blockade can be beneficial for the treatment of RA and other Th17-associated autoimmune diseases.
*Axe de Recherche sur les Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Ville de Québec, Québec G1V 4G2, Canada;
Mohammed-Amine
MA
El Azreq
Marc
M
Boisvert
Annabelle
A
Cesaro
Nathalie
N
Pagé
Lionel
L
Loubaki
Isabelle
I
Allaeys
Jamila
J
Chakir
Patrice E
PE
Poubelle
Philippe A
PA
Tessier
Fawzi
F
Aoudjit
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D000918:Antibody Specificity; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D002358:Cartilage, Articular / Q000473:pathology; D003094:Collagen / Q000494:pharmacology; D006224:Cricetinae; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007249:Inflammation; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020381:Interleukin-17 / Q000097:blood; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000502:physiology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000096:biosynthesis / Q000235:genetics; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000209:etiology / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D053245:RANK Ligand / Q000097:blood; D038981:Receptors, Collagen / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000502:physiology
D000911:Antibodies, Monoclonal; D038982:Integrin alpha2beta1; D020381:Interleukin-17; D016328:NF-kappa B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D053245:RANK Ligand; C539900:RORC protein, human; D038981:Receptors, Collagen; C505689:Tnfsf11 protein, mouse; C468113:type I collagen receptor; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt