The DDR1 Tyrosine Kinase Promotes Th17 Cell Migration in Three-Dimensional Collagen and into the Joints During...

Th17 cells play an important role in adaptive immunity and inflammation; however, the mechanisms regulating their migration into inflammatory tissues are not fully understood. In this study, we found that ex vivo human effector/memory but not central/memory Th17 cells express and use the discoïdin domain receptor 1 (DDR1) to migrate in collagen gels. The tyrosine kinase activity of DDR1 is essential to this process since its blockade with the DDR1 kinase inhibitor 7rh and the DDR1 kinase-dead construct inhibited the migration of human Th17 cells. Our results indicated that the DDR1 kinase activity enhanced Th17 cell migration by activating the MAPK/ERK pathway. We then examined the role of DDR1 in the inflammatory model of collagen-induced arthritis (CIA). Treatment of CIA mice with the DDR1 kinase inhibitor 7rh led to reduced arthritis severity, synovial inflammation and cartilage destruction. DDR1 expression is higher on T cells isolated from CIA mice than on those from naïve mice, and its blockade inhibited Th17 cell infiltration into the joints, which was associated with the inhibition of IL-17 levels. Along these lines, isolated T cells from 7rh-treated arthritic mice showed a drastic reduction in migration in collagen gels compared to those isolated from control arthritic mice. Further, the 7rh treatment reduced the levels of TNF-α and IL-1β and increased the levels of IL-10, thus promoting an anti-inflammatory environment. Our findings provide an important role for the DDR1 tyrosine kinase in promoting Th17 cell infiltration into inflammatory tissues, especially in collagen-rich tissues like the joints, and in the development of arthritis.