The brain is protected by two basement membranes (BMs), protective layers of extracellular martix proteins that prevent cells from leaking out of the circulation and into tissues. According to Agrawal and colleagues (page 1007), the second of these barriers prevents blood cells that trigger the multiple sclerosis (MS)-like mouse disease experimental autoimmune encephalomyelitis (EAE), from invading the brain.

For EAE-causing T cells to escape the circulation and trigger disease, they must traverse both endothelial and parenchymal BMs. One requirement for getting across the first barrier is the expression of integrin α4β1, which allows T cells to bind the vessel endothelium. Once over this hurdle, the cells accumulate in the perivascular space between the two BMs. How the cells eventually cross the parenchymal BM—the disease-causing step—was unknown.

To get across the second barrier, Agrawal and colleagues now show, macrophages in the perivascular space must produce two gelatinases: MMP-2 and MMP-9. These enzymes selectively cleaved β-dystroglycan—a protein that helps anchor brain cells to proteins in the parenchymal BM. β-dystroglycan cleavage created breaks in the BM, allowing blood cells to pass through. In mice lacking both MMP-2 and MMP-9, cells were kept out of the brain, and the mice were protected.

Whether MMP-2 and MMP-9 initiate brain inflammation in humans with MS remains to be determined. If so, combined inhibition of these proteases might provide a way to protect against disease.