Receptor tyrosine kinases of the TAM family recognize the phosphatidylserine-binding proteins Gas6 and protein S and contribute to tissue homeostasis. In Nature Medicine, Miner et al. show that two TAM receptors, Axl and Mertk, also contribute to blood-brain barrier function after encephalitic viral infection. Loss of either Axl or Mertk, but not loss of the TAM receptor Tyro3, leads to diminished barrier integrity at baseline and fails to sufficiently tighten junctions between brain microvascular endothelial cells after subcutaneous infection with West Nile virus or La Crosse virus, which are enveloped viruses that can bind Gas6. Mutant mice have higher viral loads in brain and spinal cord tissues than those of similarly infected wild-type mice. TAM signaling acts in synergy with interferon-b to reduce blood-brain barrier permeability via a mechanism that involves activation of the Rho-family GTPase Rac1 and increased colocalization of the junction proteins claudin-5 and ZO-1. Whether direct interaction occurs between the TAM receptors and the signaling receptor IFNAR1 remains unknown.

Nat. Med. (2 November 2015) doi:10.1038/nm.3974