Lecture 6: cell interactions - cell trafficking Flashcards
What is cell trafficking?
the targeted movement of a cell to a specific tissue or location
Give 2 examples of abnormal cell trafficking processes in disease
- Trafficking of leukocytes to the heart in myocardial infarction, joints in RA and lungs in asthma
- metastasis of cancer cells
What is one process that involves a large amount of cell trafficking?
Inflammation
When can inflammation have serious adverse outcomes, give at least 3 examples?
When inflammation is uncontrolled and occurs in the wrong place, at the wrong time or with the wrong intensity
E.g.
Myocardial reperfusion injury
Rheumatoid arthritis (RA)
Septic or traumatic shock
Asthma
Atherosclerosis
Ischaemic heart disease
How does the endothelium change during inflammation?
Il-1 and TNF-alpha pro-inflammatory cytokines released during inflammation results in the synthesis of new proteins that are expressed on the endothelial surface and makes them adhesive for leukocytes
Describe the tethering a rolling during leukocyte migration
leukocytes interact with the cytokine activated endothelial cells (mediated by selectins and addressins) - initially the interaction is broken by the speed at which the leukocyte is travelling but multiple simultaneous interactions slows downs the leukocyte
The tethering and rolling process of leukocytes is exactly the same as in which other process?
The tethering and rolling of metastasising cancer cells
What are selectins?
They are type I transmembrane glycoproteins which bind to carbohydrates in a calcium-dependent manner
Describe the structure of selectins
long, thin, rod-like structures attached to the plasma membrane via the carboxy terminus (TM c-terminal tail)
They have a carbohydrate binding N-terminal Lectin domain attached to the EGF-like domain
The lectin domain needs calcium
What are the three different types of selectins and how do they differ in terms of expression and function?
L-selectin
- constitutively expressed in virtually all leukocytes
- involved in normal recirculation of leukocytes, adhesion of circulating leukocytes to non-lymphoid tissue inc. endothelium
E-selectin
- expressed on endothelium in response to cytokines
P-selectin
- located on platelets and endothelial cells
- expression on platelets induced by cytokine stimulation
- expression of endothelium following activation by histamine, protein kinase C activators, complement fragments and thrombin
Soon after rolling starts, L-selectin is shed, what does this mean for the leukocytes?
If no firm attachment of the leukocyte to the endothelial cells has been established (mediated by integrins and chemokines) then the cells are released and returned back to the blood
What do all the ligands of selectins possess?
A carbohydrate to which the lectin end of the selectin molecule can bind to
Name a shared ligand binding partner for all 3 selectin types
PSGL-1
Describe the structure of PSGL-1 ligand
PSGL-1 is a mucin-like selectin ligand:
- has a core protein (repetitive sequence rich in ser, thr, and pro)
- abundant O-linked glycosylation of the core protein (covered in carbohydrates for protease resistance)
- contains a 4 residue carbohydrate called Sialyl Lewis X to which the selectin binds to
Which residue of the Sialyl Lewis X group is particularly important and why?
Fucose because this residue is well known to participate in binding between selectins and their ligands
