Pericytes regulate vascular immune homeostasis in the CNS
Summary (2 min read)
Introduction
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- Pericyte | blood–brain barrier | leukocyte trafficking | autoimmune neuroinflammation | MOG35–55–specific T cell receptor Central nervous system (CNS) vasculature possesses specificfeatures collectively referred to as the blood–brain barrier (BBB), which localizes to endothelial cells.
- The authors show that pericytes play a crucial role Significance The CNS vasculature tightly regulates the passage of circulating molecules and leukocytes into the CNS.
Increased Expression of Leukocyte Adhesion Molecules in the Brain
- Having established that the brain parenchyma of Pdgfbret/ret mice contains CD45hi cells, the authors used flow cytometry to identify immune cell populations.
- Subsequent analysis of leukocyte populations did not show a skewing between Pdgfbret/ret and control mice in blood, lymph nodes, and spleen .
- The observed reduction (∼26%) of pericyte coverage in the spinal cord vasculature of Pdgfbret/ret mice is notably less than the previously reported reduction of pericyte coverage in the cortex or deep brain regions (∼75%) (1, 17) or in the brainstem and cerebellum .
- Finally, the authors investigated whether higher capillary pericyte coverage in the spinal cord of Pdgfbret/ret mice parallels normalized expression of VCAM-1 and ICAM-1.
Pericyte-Deficient Mice Present an Aggravated, Atypical Experimental
- The authors next investigated whether leukocyte-permissive vasculature modifies the course of autoimmune neuroinflammation.
- Previous studies have reported that ∼5% of 2D2 mice develop spontaneous EAE with classical symptoms (24).
- Of note, the ataxia scores of individual Pdgfbret/ret;2D2tg mice fluctuated over the monitored time period.
- Immune cell infiltrates in the brains of Pdgfbret/ret and Pdgfbret/ret;2D2tg mice consisted of Ly6Chi monocytes, MdCs, and CD4+ and CD8+ T cells (Fig. 7C).
Discussion
- Pericytes have been shown to regulate BBB integrity at the level of endothelial transcytosis (1, 2).
- In addition, increased vascular permeability to plasma proteins (e.g., fibrinogen) due to increased transcytosis in pericyte-deficient mice could contribute to leukocyte trafficking.
- Thus, the mechanism by which pericytes control leukocyte extravasation is likely multifaceted, and the increased leukocyte trafficking and aggravated neuroinflammation in pericyte-deficient mice is caused by a combination of changes in acellular (basement membrane, increased presence of plasma proteins in the brain parenchyma) and cellular components (endothelium, astrocytes) of the NVU .
- This relatively spared vasculature of spinal cord vessels with a higher pericyte coverage and relatively small upregulation of ICAM-1 and VCAM1 (∼3–4%) compared with brain vessels could explain the preferential location of neuroinflammation in the brain in Pdgfbret/ret and Pdgfbret/ret;2D2tg mice.
- BBB breakdown, one of the pathological hallmarks of MS (53, 54), is an early event in the formation of the inflammatory lesions and has been suggested to precede parenchymal inflammation (55).
Materials and Methods
- Transgenic mouse lines, reagents, immunohistochemistry and histochemistry, flow cytometry and data analysis, induction of EAE and scoring, FTY-720, anti–VCAM-1 and anti–ICAM-1 treatment, quantification of immunohistochemical and histochemical stainings, transmission electron microscopy, leukocyte isolation from tissues, Materials and Methods.
- Imaging was performed with equipment maintained by the Center for Microscopy and Image Analysis of the University of Zürich.
- The biology of the blood-brain barrier in health and disease.
- S. A. Lévesque et al., Myeloid cell transmigration across the CNS vasculature triggers IL-1β-driven neuroinflammation during autoimmune encephalomyelitis in mice.
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Frequently Asked Questions (9)
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.