Alpha9 integrin and its ligands constitute critical joint microenvironments for development of autoimmune arthritis.
Osteopontin is critically involved in rheumatoid arthritis; however, the molecular cross-talk between osteopontin and joint cell components that leads to the inflammatory joint destruction is largely unknown. We found that not only osteopontin but also tenascin-C and their common receptor, alpha(9) integrin, are expressed at arthritic joints. The local production of osteopontin and tenascin-C is mainly due to synovial fibroblasts and, to a lesser extent, synovial macrophages. Synovial fibroblasts and macrophages express alpha(9) integrin, and autocrine and paracrine interactions of alpha(9) integrin on synovial fibroblasts and macrophages and its ligands contribute differently to the production of proinflammatory cytokines and chemokines. alpha(9) integrin is also involved in the recruitment and accumulation of inflammatory cells. Inhibition of alpha(9) integrin function with an anti-alpha(9) integrin Ab significantly reduces the production of arthrogenic cytokines and chemokines and ameliorates ongoing arthritis. Thus, we identified alpha(9) integrin as a critical intrinsic regulator that controls the development of autoimmune arthritis.
Kanayama
Masashi
M
Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Kurotaki
Daisuke
D
Morimoto
Junko
J
Asano
Tsuyoshi
T
Matsui
Yutaka
Y
Nakayama
Yosuke
Y
Saito
Yoshinari
Y
Ito
Koyu
K
Kimura
Chiemi
C
Iwasaki
Norimasa
N
Suzuki
Koji
K
Harada
Tanenobu
T
Li
Hong Mei
HM
Uehara
Jun
J
Miyazaki
Tadaaki
T
Minami
Akio
A
Kon
Shigeyuki
S
Uede
Toshimitsu
T
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005347:Fibroblasts; D007167:Immunotherapy; D039001:Integrin alpha Chains / Q000276:immunology / Q000378:metabolism*; D007596:Joints / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C
D000906:Antibodies; D016207:Cytokines; D039001:Integrin alpha Chains; D008024:Ligands; C084613:integrin alpha9