Targeting monocytic Occludin impairs transendothelial migration and HIV neuroinvasion

Transmigration of circulating monocytes from the bloodstream to tissues represents an early hallmark of inflammation.

This process plays a pivotal role during viral neuroinvasion, encephalitis, and HIV-associated neurocognitive disorders.

How monocytes locally unzip endothelial tight junction-associated proteins (TJAPs), without perturbing impermeability, to reach the central nervous system remains poorly understood.

Here, we show that human circulating monocytes express the TJAP Occludin (OCLN) to promote transmigration through endothelial cells.

We found that human monocytic OCLN (hmOCLN) clusters at monocyte-endothelium interface, while modulation of hmOCLN expression significantly impacts monocyte transmigration.

Furthermore, we designed OCLN-derived peptides targeting its extracellular loops (EL) and show that transmigration of treated monocytes is inhibited in vitro and in zebrafish embryos, while preserving vascular integrity.

Monocyte transmigration toward the brain is an important process for HIV neuroinvasion and we found that the OCLN-derived peptides significantly inhibit HIV dissemination to cerebral organoids.

In conclusion, our study identifies an important role for monocytic OCLN during transmigration and provides a proof-of-concept for the development of mitigation strategies to prevent monocyte infiltration and viral neuroinvasion.

This study highlights the contribution of Occludin (OCLN) expressed by monocytes during transmigration.

Targeting monocytic Occludin prevents monocyte transmigration, which is sufficient for potent inhibition of HIV neuroinvasion.

Silencing monocytic OCLN decreases transmigration through endothelial cells, while its re-expression increases transmigration.

Using a short peptide from the extracellular loop 2 of OCLN prevents transmigration of monocytes in vitro and in zebrafish.

HIV-carrying monocyte transmigration is critical for HIV neuroinvasion of cerebral organoids.

HIV neuroinvasion is abrogated by OCLN-derived peptides.

This study highlights the contribution of Occludin (OCLN) expressed by monocytes during transmigration.

Targeting monocytic Occludin prevents monocyte transmigration, which is sufficient for potent inhibition of HIV neuroinvasion.