Do not Rho tight junctions (or they become leaky)

Comment on Persidsky et al, page 4770

Impaired functions of brain vasculature contribute to the neurodegenerative changes associated with HIV infection.

The article by Persidsky and colleagues in this issue of Blood sheds new information on the processes that regulate monocyte trafficking into the brain. It is also the next logical step from this highly productive research group targeting the mechanisms of HIV-1 entry into the brain and the establishment of HIV-1 reservoirs in the central nervous system (CNS).^1,2 

Persidsky and colleagues provide evidence that monocytes migrate across brain microvascular endothelial cell monolayers at the cell-cell borders. This process involves the break-down of tight junctions, as indicated by the disruption of immunoreactivity of occludin and claudin-5, 2 critical tight junction proteins. The authors demonstrate that the alteration of tight junction protein expression and its correlation with monocyte infiltration occur not only in cocultures of brain microvascular endothelial cells (BMECs) with monocytes but also in clinical specimen from HIV-1 patients. These clinical data are in agreement with previously reported changes in tight junction proteins in HIV-1–infected patients.³  The significance of these observations is related to the fact that tight junctions allow for very close contact between adjacent endothelial cells. Therefore, they are directly involved in regulating the integrity of the brain endothelium and proper functions of the blood-brain barrier.

To study the mechanisms of alterations of tight junction protein expression, Persidsky et al focused on the role of the Rho signaling pathway. The Rho (Ras homologous) proteins belong to a class of proteins called small GTPases. The name originates from the small molecular masses of these proteins, which is between 20 and 35 kDa. Inactive Rho proteins are sequestered in the cytoplasm. Activation of Rho involves transfer to cell membranes, where Rho can phosphorylate a variety of effector molecules. The current study provides strong evidence that activation of Rho is induced by interaction between monocytes and BMECs. Even more importantly, inhibition of Rho completely blocks transendothelial passage of monocytes and restores the integrity of BMEC monolayers. These effects are striking, and the inhibition of Rho is equally effective in protecting against migration of normal and HIV-1–infected monocytes.

From the study by Persidsky et al, it is apparent that occludin and claudin-5 are critical targets for Rho-mediated phosphorylation and disruption of endothelial integrity. The authors demonstrate that interaction of normal monocytes with BMECs leads to increased phosphorylation of occludin and claudin-5 on both serine and tyrosine residues. These effects are even more enhanced by HIV-1–infected monocytes. Most importantly, inhibition of the Rho pathway markedly attenuates the phosphorylation of both occludin and claudin-5.

In conclusion, transendothelial monocyte migration is the pathologic event not only of HIV-1 infection but also of several other acute and chronic CNS disorders. Thus, Persidsky et al provide the foundation for future studies on effective treatment of CNS disorders that involve the disruption of the blood-brain barrier. The effectiveness of Rho inhibitors in protecting against disruption of tight junctions may help to develop treatment regimens to prevent transendothelial monocyte trafficking into the CNS. ▪