α9 Integrin and Its Ligands Constitute Critical Joint Microenvironments for Development of Autoimmune Arthritis

Abstract

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, α9 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 α9 integrin, and autocrine and paracrine interactions of α9 integrin on synovial fibroblasts and macrophages and its ligands contribute differently to the production of proinflammatory cytokines and chemokines. α9 integrin is also involved in the recruitment and accumulation of inflammatory cells. Inhibition of α9 integrin function with an anti-α9 integrin Ab significantly reduces the production of arthrogenic cytokines and chemokines and ameliorates ongoing arthritis. Thus, we identified α9 integrin as a critical intrinsic regulator that controls the development of autoimmune arthritis.

Transcriptional Regulation of the Endogenous Danger Signal Tenascin-C: A Novel Autocrine Loop in Inflammation

“…Tenascin-C expression correlates with disease activity in RA synovia WithintheRAsynovium, tenascin-C hasbeenreportedtobespecifically but widelydistributed; itlocalizestotheinvadingpannus,superficialand deep cells of the synovial layer, subsynovial tissue, blood vessels, lymphoid aggregates, and areas of fibrosis (15,(18)(19)(20). We confirmed this pattern of localization by immunohistochemical staining of synovial membranes isolated from RA patients undergoing joint replacement.…”

“…Immunohistochemical analyses revealed little tenascin-C expression in joints from healthy individuals or in non inflamed joints from patients with osteoarthritis (OA) (18)(19)(20). However, high levels of tenascin-C are localized to pathogenic foci in the synovium of RA patients (15,(18)(19)(20), where expression correlates with inflammatory cell infiltration (19). High levels of tenascin-C are also expressed in cartilage (20) and synovial fluid (21-23) from RA patients.…”

“…It induces cytokine synthesis in primary human macrophages and synovial fibroblasts via activation of the pattern recognition receptor, TLR4 (3). It can also stimulate cytokine and matrix metalloproteinase synthesis in murine synovial fibroblasts via activation of a 9 integrins (15). Little or no tenascin-C is found in most healthy adult tissues, but expression is specifically and rapidly induced in response to tissue injury.…”

“…Addition of exogenous tenascin-C stimulates cytokine synthesis in synovial membranes isolated from the joints of RA patients, an ex vivo model of human disease (3). In addition, tenascin-C expression is upregulated at both the mRNA and protein levels in synovial tissues in mouse models of joint inflammation (3,15), and tenascin-C is also arthritogenic in vivo when injected intra-articularly into mice (3). Furthermore, its activation of TLR4 is essential for driving persistent joint inflammation in vivo (3).…”

Osteopontin expression by CD103−dendritic cells drives intestinal inflammation

“…Thus, it appears that inflammatory stimuli propagate circles of interactions of Opn and integrin α9. It has to be emphasized that there are other candidate ligands of integrin α9, such as TN-C, vascular cell adhesion molecule-1, and VEGF-A (19,(82)(83)(84), some of which are overexpressed in the colitic microenvironment (85,86). It is unknown whether interactions of these molecules with integrin α9 on CD103 − DCs enhance or restrain the described proinflammatory function of Opn.…”