The Extracellular Matrix Proteoglycan Decorin is Upregulated by Endothelial Cells During Inflammation and Contributes to Blood‐Brain Barrier Dysfunction

Abstract

The blood‐brain barrier (BBB) selectively regulates solute flux and protects the brain from bloodborne neurotoxic substances. Endothelial cells (ECs) forming the BBB establish highly restrictive cell‐cell contacts known as tight junctions (TJs), which aid in sealing paracellular clefts. The TJ protein claudin‐5 (CLDN5) is the primary constitutive protein responsible for the restriction of paracellular permeability to small molecules and the level of CLDN5 expression has been positively correlated with endothelial barrier tightness. Situated below the ECs is the extracellular matrix (ECM) which not only helps anchor the ECs, but also participates in ECM‐EC regulatory signaling. Under normal conditions, certain ECM proteins, such as collagens, have been shown to enhance the barrier properties of the BBB, whereas during inflammation other ECM proteins can contribute to BBB dysfunction, although the particulars of these mechanisms are still yet to be fully understood. In certain neuroinflammatory diseases, such as multiple sclerosis (MS), the upregulation of the ECM small leucine‐rich repeat proteoglycan (SLRP) decorin has been identified within the perivascular space of vessels in the inflammatory lesions of MS patients. The cellular origin of this decorin release and its potential impact on the BBB, however, has yet to be determined. In this study, we used murine models of inflammation in vivo and in vitro to determine a spatial‐temporal relationship between BBB dysfunction, CLDN5 loss, and increased decorin accumulation in the ECM. Consistent with the MS lesions, we identified increased decorin expression in mouse cerebellar microvessels post‐experimental autoimmune encephalomyelitis (EAE) induction as well as in primary brain microvascular endothelial cells (BMVECs) treated in vitro with inflammatory cytokines. Additionally, we evaluated the effect of different ECM‐EC interactions on CLDN5 expression and BMVEC monolayer integrity in vitro. Primary BMVECs cultivated on collagen‐coated surfaces showed a decrease in baseline solute permeability and increased CLDN5 expression compared to those on non‐coated surfaces, with those on collagen type IV‐coated surfaces showing a greater decrease in baseline permeability and CLDN5 expression compared to those on type I‐coated surfaces. However, surfaces containing decorin resulted in increased monolayer permeability and decreased CLDN5 expression, while matrices containing both decorin and type IV collagen resulted in abrogation of the observed enhancement of monolayer permeability and CLDN5 expression by type IV collagen. Taken together, our data suggest that ECs themselves may be the source of decorin accumulation in perivascular inflammatory lesions and that inflammatory‐induced decorin upregulation may perpetuate BBB dysfunction.Support or Funding InformationSupported by NIH P20 GM109095, 2P20GM103408.