Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Blood-Brain Barrier

• Endothelium-immune cell interaction

• IQGAP2

Main Findings

Highly functional and selective BBB is critical for the protection of CNS, therefore even slightest alterations in its structure may initiate biochemical cascades favouring immune infiltration and ultimately leading to various neurological diseases. In this preprint, establishment of mature BBB with acquisition of proper barrier functions was associated with a significant increase in the expression of IQGAP2. Importantly, loss or downregulation of Iqgap2 increased BBB permeability and promoted immune cell infiltration into the CNS, sequence of events characteristic to and likely underlying many neurodegenerative diseases. Moreover, pathway analyses performed on DEGs in Iqgap2 knockouts indicated significant alterations in response to viruses, as well as antigen processing and presentation pathways, all processes implicated in the pathogenesis of autoimmune diseases, including multiple sclerosis.

Limitations

• The authors used IQGAP2 knock-out mice in this study. As Iqgap2 can be expressed by immune cells, potential influence on BECs phenotype may come from loss of immune-derived Iqgap2. Although not ideal either, EC-specific KO could be of value for the investigation of the role of Iqap2 more specifically in BECs.

• The present study focuses on the role of Iqgap2 predominantly in the mouse BBB, however it would be particularly important to evaluate changes in the expression of IQGAP2 also in diseased human brains with the impairment of BBB (MS, ALS, Parkinson’s disease, Huntington’s disease). Although an attempt has been made to investigate this issue in the Parkinson’s disease no significance was seen and therefore further studies may be required.

•  It would be interesting to understand the mechanistic role of Iqgap2. Do the downstream mechanisms include B catenin and/or Wnt signaling, or may there be completely novel pathways to be considered?

Significance/Novelty

Novelty of the preprint lies in the discovery of IQGAP2 as a protein likely critical for the regulation of BBB integrity and BBB-immune cell interactions. Considering IQGAP2 is also present in human brain vasculature and expressed by inflammatory cells such as monocytes, T cells, B cells and microglia, it could constitute a new potentially interesting target for prevention/treatment of CNS-related autoimmune diseases. Further comprehensive in-depth research on its role in regulation of BBB and its permissiveness for immune cell extravasation into the brain is warranted.

Credit

Reviewed by Urszula Rykaczewska as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.

The author declares no conflict of interests in relation to their involvement in the review.