Journal of Translational Neurosciences

RhoA-ROCK Pathway is Important for T-Cell Migration in a Mouse Stroke Model

The small Rho GTPases tightly regulate the cell’s contractility, motility and morphology. Among these, the small GTPase RhoA is the main regulator of T-cell migration. Using T-cell-specific RhoA knock-out mice (RhoA^fl/flLckCre⁺) we hereby show the importance of RhoA expression in the T- cell’s transendothelial migration capacity and in the T-cells’ brain infiltration in an infarct mouse model. We observed that T-cells lacking RhoA expression (RhoA^-/- T-cells) present a ~20% reduction in their capacity of transmigrating across an endothelium compared to wild type RhoA^+/+ T-cells. We also investigated how the inhibition of RhoA signaling affected the post-stroke T-cell response in mice, 21 days after pMCAO and found that lack of RhoA expression markedly reduces T-cells migration into the infarcted brain, evidenced by the presence of significantly less CD3⁺ cells within the infarct area of RhoA^fl/flLckCre⁺ mice compared to control mice. T-cell infiltration into the infarcted brain was not affected when mice were treated with atorvastatin, an inhibitor upstream of RhoA, and fasudil, an inhibitor of the RhoA downstream kinase ROCK. This highlights for the first time RhoA as a key regulator in T-cell transmigration into infarcted brain tissue. Taken together, these results suggest that the activity of the small GTPase RhoA is crucial for T-cells ability to migrate across an endothelial cell layer and into the infarcted brain. It also underlines the therapeutic potential of the RhoA-ROCK pathway in diseases in which cell migration is important for their pathophysiology, such as immunological diseases or cancer.

Author(s):

Alba Manresa-Arraut, Morten Müller Aagaard, Cord Brakebusch, Henrik Hasseldam and Flemming Fryd Johansen

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