Therapeutic strategies against multiple sclerosis (MS) should focus on blocking two distinct ways rogue immune cells attack healthy neurons, according to a new study, “Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation,” in Cell Reports.
In MS, immune cells degrade the insulation that protects neurons and allows them to signal to one another; however, little is known about how immune cells penetrate the blood–brain barrier to get to neurons. Researchers led by Sarah Lutz, Ph.D., University of Illinois at Chicago (UIC) College of Medicine while she was a postdoctoral fellow at Columbia University, and Sunil Gandhi, Ph.D., University of California, Irvine, have uncovered two different ways immune cells gain access to neurons and wreak their havoc.
“Lymphocytes cross vascular boundaries via either disrupted tight junctions (TJs) or caveolae to induce tissue inflammation. In the CNS [central nervous system], Th17 lymphocytes cross the blood-brain barrier (BBB) before Th1 cells; yet this differential crossing is poorly understood. We have used intravital two-photon imaging of the spinal cord in wild-type and caveolae-deficient mice with fluorescently labeled endothelial tight junctions to determine how tight junction remodeling and caveolae regulate CNS entry of lymphocytes during the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis,” write the investigators.
“We find that dynamic tight junction remodeling occurs early in EAE but does not depend upon caveolar transport. Moreover, Th1, but not Th17, lymphocytes are significantly reduced in the inflamed CNS of mice lacking caveolae. Therefore, tight junction remodeling facilitates Th17 migration across the BBB, whereas caveolae promote Th1 entry into the CNS. Moreover, therapies that target both tight junction degradation and caveolar transcytosis may limit lymphocyte infiltration during inflammation.”
“In autoimmune diseases like multiple sclerosis, immune cells that enter the brain and spinal cord cause disease,” said Dr. Lutz, now assistant professor of anatomy and cell biology in the UIC College of Medicine. “A better understanding of how these cells cross the blood–brain barrier will aid our efforts to develop specific therapies to keep them out.”
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