It is shown that pericytes indirectly restrict immune cell transmigration into the CNS under homeostatic conditions and during autoimmune-driven neuroinflammation by inducing immune quiescence of brain endothelial cells.
Abstract:
Brain endothelium possesses several organ-specific features collectively known as the blood-brain barrier (BBB). In addition, trafficking of immune cells in the healthy central nervous system (CNS) is tightly regulated by CNS vasculature. In CNS autoimmune diseases such as multiple sclerosis (MS), these homeostatic mechanisms are overcome by autoreactive lymphocyte entry into the CNS causing inflammatory demyelinating immunopathology. Previous studies have shown that pericytes regulate the development of organ-specific characteristics of brain vasculature such as the BBB and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking remains elusive. Using adult, pericyte-deficient mice ( Pdgfb ret/ret ), we show here that brain vasculature devoid of pericytes shows increased expression of VCAM-1 and ICAM-1, which is accompanied by increased leukocyte infiltration of dendritic cells, monocytes and T cells into the brain, but not spinal cord parenchyma. Regional differences enabling leukocyte trafficking into the brain as opposed to the spinal cord inversely correlate with the pericyte coverage of blood vessels. Upon induction of experimental autoimmune encephalitomyelitis (EAE), pericyte-deficient mice succumb to severe neurological impairment. Treatment with first line MS therapy - fingolimod significantly reverses EAE, indicating that the observed phenotype is due to the massive influx of immune cells into the brain. Furthermore, pericyte-deficiency in mice that express myelin oligodendrocyte glycoprotein peptide (MOG 35-55 ) specific T cell receptor ( Pdgfb ret/ret ; 2D2 Tg ) leads to the development of spontaneous neurological symptoms paralleled by massive influx of leukocytes into the brain, suggesting altered brain vascular immune quiescence as a prime cause of exaggerated neuroinflammation. Thus, we show that pericytes indirectly restrict immune cell transmigration into the CNS under homeostatic conditions and during autoimmune-driven neuroinflammation by inducing immune quiescence of brain endothelial cells.
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Q1. What are the future works in "Pericytes regulate vascular immune homeostasis in the cns" ?
In the future, it would be interesting to investigate early changes in the brain vasculature of MS patients and determine whether vascular alterations regulate the localization of MS lesions.
Q2. What is the effect of FTY-720 on the brain endothelium?
Pericyte deficiency alters endothelial cell phenotype and leads to up-regulation of LAMs on the brain endothelium, which are important for leukocyte transmigration.
Q3. What is the mechanism by which pericytes control leukocyte trafficking?
In addition, increased vascular permeability to plasma proteins (e.g., fibrinogen) due to increased transcytosis in pericyte-deficient mice could contribute to leukocyte trafficking.
Q4. What is the role of vascular dysfunction in MS?
Since vascular dysfunction modulates leukocyte entry and neuroinflammation, vasoprotective therapies combined with preexisting treatments could lead to improved clinical outcomes in MS.
Q5. What is the phenotype of Pdgfbret/ret mice?
After active induction of EAE, which replicates both the induction and effector phase of the disease, Pdgfbret/ret mice presented with a severe, early-onset (4–5 d postimmunization) atypical phenotype as well as reduced survival (Fig. 4 A and B and SI Appendix, Fig. S9A and Table S2).
Q6. What is the effect of a humanized monoclonal antibody against 4-?
H-B iblio thek on Mar ch2 4,2 021natalizumab, a humanized monoclonal antibody against α4-integrin on leukocytes, has been proven to be an effective treatment in MS (25).
Q7. What is the effect of FTY-720 on the death of Pdgfbret?
All IgG isotype control-treated Pdgfbret/retmice reached termination criteria similarly to previous experiments, whereas anti–VCAM-1 and anti–ICAM-1 treatment ameliorated the ataxia symptoms and rescued the mortality of Pdgfbret/ret mice (Fig. 6 B and C).
Q8. What is the reason for the severe atypical phenotype in Pdgf?
Adoptive transfer (passive) EAE resulted in the same aggravated atypical EAE in Pdgfbret/ret mice as seen in active EAE (Fig. 4C), indicating that the severe phenotype is not due to a pathologically enhanced induction phase in pericyte-deficient mice.
Q9. What causes the death of pericyte-deficient mice after induction of EAE?
the authors conclude that the mortality of pericyte-deficient mice after induction of EAE is caused by excessive entry of peripheral immune cells into the brain and neuroinflammation.