proteoglycans
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What is the glycocalyx?
A carbohydrate rich pericellular matrix surrounding cell membranes
Where is the glycocalyx found?
On virtually all cells including endothelial, immune, epithelial, and bacterial cells
Why is the glycocalyx considered evolutionarily ancient?
It appeared early in evolution including in marine single celled organisms
What is the thickness range of the endothelial glycocalyx?
Approximately 200 nm to 3 microns depending on context
What is the primary role of the endothelial glycocalyx in immune cell recruitment?
To act as a barrier inhibiting interaction between leukocytes and endothelium
Why does the glycocalyx pose a problem for leukocyte recruitment?
It protrudes further than endothelial adhesion molecules
Where are most immune cells produced?
In the bone marrow
Which immune cells are considered long lived?
Macrophages
Why is immune cell recruitment beneficial?
It allows immune cells to reach sites of infection
Why is immune cell recruitment harmful when uncontrolled?
It drives chronic inflammation such as rheumatoid arthritis
What are the main steps of leukocyte recruitment?
Rolling, chemokine signalling, integrin activation, firm adhesion, and extravasation
What happens during extravasation?
Leukocytes cross the endothelium usually between endothelial cells
What imaging techniques demonstrate the presence of the glycocalyx?
Electron microscopy, intravital imaging, and lectin staining
What happens to the glycocalyx after enzymatic digestion of glycans?
It becomes thinner and more disrupted
What do lectins bind to in glycocalyx imaging?
Specific glycan structures
How does glycocalyx structure differ between arteries and veins in the brain?
Arteries show distinct lectin peaks while veins often do not
What does heterogeneity of the glycocalyx mean?
Its structure varies by vessel type tissue and physiological state
What is a major component of the endothelial glycocalyx?
Proteoglycans
Which glycosaminoglycan is especially important in the endothelial glycocalyx?
Heparan sulfate
What role does hyaluronan play in the glycocalyx?
It contributes to structure and hydration
How is the glycocalyx remodeled during inflammation?
By enzymatic shedding and structural reorganisation
Which enzyme cleaves heparan sulfate?
Heparanase
What enzymes degrade proteoglycan core proteins?
Metalloproteinases
Which inflammatory cytokine is key in glycocalyx remodeling?
TNF
What is meant by patchy glycocalyx remodeling?
Localised thinning that allows immune cell interaction
Why must glycocalyx remodeling be local rather than systemic?
To restrict immune recruitment to specific sites
What experimental tool is used to mimic inflammation in vivo?
fMLP
What happens to lectin coated beads after fMLP injection?
Their interaction with vasculature decreases
What does decreased lectin bead binding indicate?
Shedding of glycocalyx glycans
What happens to leukocyte adhesion when the glycocalyx is degraded?
Leukocyte adhesion increases
How does pertussis toxin affect fMLP induced effects?
It reverses them by blocking GPCR signalling
What happens when heparan sulfate is enzymatically removed?
Adhesion molecule accessibility increases
Why is the glycocalyx not purely anti migratory?
Some glycans are required for immune cell recruitment
What other functions does the endothelial glycocalyx have?
Regulating vascular permeability and protecting from shear stress
How does the glycocalyx relate to the Starling principle?
It contributes to vascular filtration control
What role does the glycocalyx play in mechanosignalling?
It senses shear stress and triggers endothelial responses
What happens to the glycocalyx during sepsis?
It becomes degraded and thinned
What experimental molecule is used to model sepsis?
LPS
What effect does LPS have on glycocalyx thickness?
It causes a reduction in thickness
What happens in mice lacking TNF signalling after LPS exposure?
Glycocalyx thickness is preserved
What does this demonstrate?
TNF signalling is required for glycocalyx degradation
How does glycocalyx degradation affect neutrophil adhesion?
It increases adhesion to endothelium
What drug can reduce glycocalyx degradation effects?
Heparin
Why does heparin reduce leukocyte adhesion?
It inhibits enzymes involved in glycocalyx shedding
What happens in heparanase deficient mice during inflammation?
Leukocyte adhesion is reduced
Which diseases are associated with glycocalyx damage?
Sepsis, ARDS, viral infections, and COVID
Why are serum glycocalyx components measured in disease?
To indicate glycocalyx shedding
What cell types also possess a glycocalyx?
Immune cells themselves
Which immune cells show high heparan sulfate expression?
Neutrophils and monocytes
What happens to immune cell glycocalyx during inflammation?
It is shed or remodeled
How was immune cell glycocalyx studied experimentally?
Using flow cytometry
What did psoriasis models reveal about glycocalyx shedding?
Heparan sulfate was shed from immune cells not endothelium
Why might immune cells remodel their own glycocalyx?
To facilitate adhesion and migration
What happens when immune cell heparan sulfate is enzymatically removed?
Their adhesion to endothelium increases
Why must leukocyte recruitment consider two glycocalyces?
Both endothelial and immune cell glycocalyces regulate interaction
Where else is the glycocalyx critically important?
Epithelial surfaces kidney glomerulus and tumours
What role does the glycocalyx play in cancer?
It protects tumour cells and limits immune infiltration
How might glycocalyx structure affect metastasis?
By regulating tumour cell extravasation
What is the overall conclusion of the lecture?
The glycocalyx is a dynamic regulator of immune cell recruitment and disease
What role do glycans play in immune cell trafficking?
They are involved in every step of leukocyte recruitment
Which stages of immune cell recruitment involve glycans?
Rolling firm adhesion and transendothelial migration
What type of proteins are activated integrins?
Glycoproteins
What family of molecules mediate leukocyte rolling?
Selectins
What type of lectins are selectins?
Mucin like C type lectins
Which selectin is expressed on endothelial cells and platelets?
P selectin
Which selectin is expressed on activated endothelium?
E selectin
Which selectin is expressed on leukocytes?
L selectin
Why do leukocytes adhere to veins but not arteries?
Veins express selectins required for rolling
What happens to leukocyte rolling in the absence of selectins?
It is abolished
What is PSGL1?
P selectin glycoprotein ligand 1
What type of protein is PSGL1?
An O linked glycoprotein
What is the structure of PSGL1?
A disulfide linked dimer
Where is PSGL1 expressed?
On the leukocyte cell surface
What type of glycans does PSGL1 present?
O linked glycans
What glycan motif is central to selectin binding?
Sialyl Lewis X
What modification can increase selectin ligand diversity?
Sulfation
Why does isolated sialyl Lewis X bind weakly to P selectin?
It lacks cooperative protein interactions
How much weaker is isolated glycan binding than intact PSGL1?
Approximately 10 to 100 fold
Which amino acids contribute to selectin binding besides glycans?
Sulfated tyrosines
Why is high affinity binding required during leukocyte rolling?
Because interactions occur under blood flow
What unusual bond behaviour do selectins exhibit?
Catch bond behaviour
What is a catch bond?
A bond whose lifetime increases with applied force
What structural change under force strengthens selectin binding?
Transition to an open high affinity conformation
How do platelets contribute to immune cell recruitment?
They act as bridges between immune cells
Which immune cells can be bridged by platelets?
Neutrophils and monocytes
What happens when fucose residues are missing from glycans?
Selectin binding is lost
What is the consequence of fucose deficiency on immunity?
Leukocytes cannot be recruited to infection sites
What emerging molecule has been shown to regulate immune cell migration?
GlycoRNA
What happens when glycoRNA is removed from immune cells?
Migration is impaired
Which glycan is important for dendritic cell migration in lymphatics?
Hyaluronan
What receptor binds hyaluronan on lymphatic endothelial cells?
LYVE1
What is the key conclusion of the lecture?
Glycans are essential regulators of immune cell trafficking
What is the main focus of Part 2 of glycans in immune cell trafficking?
Proteoglycans heparan sulfate GAGs and chemokine regulation
What are proteoglycans composed of?
A protein core with glycosaminoglycan side chains
Which proteoglycans are major membrane associated types in endothelium?
Syndecans and glypicans
What is a key functional feature of HS chains on proteoglycans?
Sulfated islands that create high negative charge and binding specificity
What proteins are a major focus for HS binding in immune recruitment?
Chemokines
What are chemokines?
Chemoattractant cytokines that guide immune cell migration
How are chemokines classified?
By cysteine spacing into CC CXC XCL and CX3CL families
Which rare chemokine family members were mentioned as brain associated?
XCL1 and CX3CL1