Soluble TREM2 Mediates Blood Brain Barrier Permeability through Astrocyte Reactivity

The Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein predominantly expressed by cells of the myeloid lineage. In the CNS, it is mainly expressed by microglia and macrophages, where it regulates their reactive state. This protein can be shed to release soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of people with neurocognitive disorders. However, it remains unknown how sTREM2 contributes to neuropathogenesis. We examined the effects of sTREM2 on the inflammatory state of astrocytes, and how these impact blood-brain barrier (BBB) integrity using an in vitro BBB model composed of primary human Brain Microvascular Endothelial Cells (BMVEC) and primary human astrocyte cells. We found that sTREM2 induced an inflammatory state in astrocytes, characterized by increased AKT phosphorylation, NF-kB activation, and upregulation of activation markers including GFAP, all consistent with a reactive astrocyte (RA) phenotype. In addition, we found an increase in BBB permeability when astrocytes were exposed to sTREM2 that correlated with decreased levels of the tight junction (TJ) protein Occludin in BMVEC from the BBB. sTREM2 promoted release of astrocyte-derived molecules implicated in BBB disruption, with Matrix Metalloproteinases-2 (MMP2) appearing to be a major contributor to the loss of barrier integrity. Our findings demonstrate a novel role for sTREM2 in BBB dysfunction in the context of neuropathogenesis.