Blood-Brain Barrier and Immune Cell Transmigration: Pathways Overview

Click on one of the molecules below to see the signaling pathway activated by that molecule and the changes it induces in the integrity of the blood-brain barrier.

Actions on BBB
Actions on BBB

Redistribution of TJ and AJ Proteins

Redistribution of TJ and AJ Proteins

Actions on BBB
Actions on BBB

MMP Expression and TJ Protein Degradation

MMP Expression and TJ Protein Degradation

Stress Fiber Formation

Stress Fiber Formation

Integrin
alpha4 beta1
(VLA-4)
Integrin
alpha4 beta1
(VLA-4)
Chemokine R
Chemokine R
Integrin
alpha L beta 2
(LFA-1)
Integrin
alpha L beta 2
(LFA-1)
VCAM-1/CD106
VCAM-1/CD106
HSPG
HSPG
Chemokine
Chemokine
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ICAM-1/CD54
ICAM-1/CD54
ProductsClose
ProductsClose
CCR2
CCR2
ProductsClose
CCL2/MCP-1
CCL2/MCP-1
VEGF R2/KDR
VEGF R2/KDR
VEGF
VEGF
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Actions on BBB
Actions on BBB

Redistribution of TJ and AJ Proteins

Redistribution of TJ and AJ Proteins

Stress Fiber Formation

Stress Fiber Formation

Actions on BBB
Actions on BBB

Loss of Pericytes

Loss of Pericytes

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MMP-9
MMP-9
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Pericyte
Migration
Pericyte
Migration
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LRP-1
LRP-1
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ProductsClose
MMP-9
MMP-9
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Caspase-3
Cleavage
Caspase-3
Cleavage
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IL-1 R
IL-1 R
IL-1 beta
IL-1 beta
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TNF-alpha
TNF-alpha
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TNF RI
TNF RI
Actions on BBB
Actions on BBB

ECM Degradation

ECM Degradation

Brain ECs
Brain ECs
Cerebral Capillary
Cerebral Capillary

Chemotaxis

Chemotaxis

Leukocyte
Leukocyte
I. Rolling
I. Rolling
II. Activation
II. Activation
III. Adhesion
III. Adhesion
Actin Cytoskeleton
Actin Cytoskeleton
IV. Crawling
IV. Crawling
V. Transmigration
V. Transmigration
PSGL-1
PSGL-1
P-Selectin
P-Selectin
Actions on BBB
Actions on BBB

ECM Degradation

ECM Degradation

CXCL8/IL-8
CCL2/MCP-1
CXCL8/IL-8
CCL2/MCP-1
MMP-9
MMP-9
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Astrocyte
Astrocyte
IL-1 beta
TNF-alpha
VEGF
CCL2/MCP-1
IL-1 beta
TNF-alpha
VEGF
CCL2/MCP-1
Stimulation
Stimulation
Brain Tissue
Brain Tissue
Microglia
Microglia
IL-1 beta
TNF-alpha
CCL2/MCP-1
IL-1 beta
TNF-alpha
CCL2/MCP-1
MMP-2
MMP-9
MMP-2
MMP-9
ProductsClose
Actions on BBB
Actions on BBB

ECM Degradation

ECM Degradation

Pericyte
Pericyte
Astrocyte
Astrocyte
Neuron
Neuron

Chemotaxis

Chemotaxis

CXCL8/IL-8
CCL2/MCP-1
CCL3/MIP-1 alpha
CXCL8/IL-8
CCL2/MCP-1
CCL3/MIP-1 alpha
Gene
Expression
Gene
Expression
TNF RI
TNF RI
TNF-alpha
TNF-alpha
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IL-1 R
IL-1 R
IL-1 beta
IL-1 beta
Microglia
Microglia
Stimulation
Stimulation

Overview of Blood-Brain Barrier and Immune Cell Transmigration: Overview

The blood-brain barrier (BBB) is a highly specialized, multi-cellular structure that functions as a selective diffusion barrier between the peripheral circulation and the central nervous system (CNS). The BBB is composed of specialized endothelial cells (ECs) that are linked by complex tight junctions (TJs) and adherens junctions (AJs). These cells are also surrounded by astrocytes and pericytes. Under normal conditions, the specialized structure of the BBB hinders paracellular transport of most hydrophilic compounds across the cerebral endothelium and restricts migration of blood-borne cells into the CNS. As a result, microglia, the resident immune cells of the CNS, are the initial responders to pathogens or tissue damage. However, prolonged tissue insult triggers inflammatory conditions that cause the BBB to lose its restrictive features, resulting in the subsequent infiltration of peripheral immune cells.

Reactive microglia, astrocytes, and pericytes, as well as ECs, release numerous molecules that promote invasion of peripheral immune cells into the CNS. Secreted inflammatory mediators, including CXCL8/IL-8, CCL2/MCP-1, TNF-alpha, IL-1beta/IL-1F2, recruit immune cells and stimulate the expression of adhesion molecules on ECs that participate in integrin-mediated leukocyte tethering, rolling, and activation. These pro-inflammatory molecules also trigger the dynamic reorganization of junction complexes between ECs, thereby promoting the formation of paracellular gaps. Matrix metalloproteases (MMPs), which are also released, degrade proteins present in the extracellular matrix (ECM) and may contribute to the loss of pericytes. These events lead to an increase in the permeability of the BBB and invasion of peripheral immune cells.

To learn more, please visit our Neuroinflammation Research Area.

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