The role of pericytes in immune trafficking and its effects on the blood-brain barrier integrity

Identification: Tsai, Hsing-Chuan


Description

The role of pericytes in immune trafficking and its effects on the blood-brain barrier integrity
 
Hsing-Chuan Tsai1, Orsolya Török2, Annika Keller2 and May Han1
1Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA; 2Division of Neurosurgery, Zürich University Hospital, Zürich University, Zürich, Switzerland
 
The central nervous system (CNS) is immune privileged by the virtue of the blood-brain barrier (BBB). Loss of pericytes, a critical component of the BBB, has been shown to increase leukocyte transmigration in the BBB and may be related to the pathogenesis of neuroinflammatory and neurodegenerative disorders. However, it is unclear how pericytes regulates immune trafficking in the BBB and neuroinflammation. To elucidate this, we utilized platelet-derived growth factor (PDGF) retention motif knockout mice (Pdgfbret/ret), in which mice have reduced pericyte coverage in the CNS, to study the interplay between the BBB and immune cells. We examined brain micro-vessel transcriptomes of control Pdgfbret/+ and Pdgfbret/ret mice by RNA sequencing, and their peripheral and CNS immune cell subsets by multicolor flow cytometry in homeostasis and during MOG35-55 immunization. As with prior studies, angiogenesis and leukocyte extravasation signaling pathways were activated in the naïve Pdgfbret/ret brain endothelium, in parallel with increased immune cells in the brain, especially monocytes and T lymphocytes. Unexpectedly, Pdgfbret/ret mice, but not the control mice, showed atypical experimental autoimmune encephalomyelitis (EAE) symptoms upon MOG35-55 immunization. The transcriptomic data also revealed that brain endothelial cell junctions were disturbed and immune chemotaxis was enhanced at the pre-onset of the disease in the absence of pericytes. In addition, we observed particular extracellular matrix changes during inflammation, which may facilitate cell migration in the parenchyma. Longitudinal analysis of brain immune cells of these mice showed that massive monocyte infiltration occurred at the peak of the disease and lymphocytes continued accumulating even when the disease alleviated. Interestingly, microglia significantly increased at the recovery phase of the disease. In conclusion, our data suggest that pericytes are required for the brain endothelial barrier to prevent leukocyte transmigration, especially monocytes and T lymphocytes, and that microglia may play a role in resolving brain inflammation.
 

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