Flashcards in Chemotaxis and Phagocyte Infiltration into tissue Deck (45):
The movement of cells in response to a chemical stimulus
why is chemotaxis required?
Enables cells to accumulate where most needed
how does chemotaxis work?
Cell motility achieved by temporary attachment of
“front” of cell to a surface, and by the formation of
actin filaments which pull the back of the cell towards the front
in nature where does chemotaxis and killing occur?
How do the leukocytes “know where to go”?
Signals release by damaged or infected tissues change the local blood vessels
what is a localized acute inflammatory response?
vasodilation, vascular permeability, leukocyte migration
what is the role of neutrophils
central role (get there 1st)
attracted by IL-8 (CXCL8), C3a, C5a, Prostaglandins
whats the role of macrophages?
arrive 5-6 hr later,
attracted by CC chemokines, C3a, C5a
secrete IL-1, IL-6, IL-8 (CXCL8),TNF localized and systemic effects
name the 5 Groups of Chemical Mediators of Inflammation and Chemotaxis
B) Plasma enzyme systems
C ) Vasoactive amines
D) Arachidonic acid metabolites
E ) Chemokines
which cells secrete cytokines?
name 5 cytokines
describe the action of IL-1b
Activates vascular endothelium and lymphocytes
local tissue destruction
increases access of effector cells
describe the action of TNF-a
- Activates vascular endothelium
- increases vascular permeability increasing entry of IgG, cells to tissues and fluid drainage to lymph nodes.
what are the systemic affects of IL-6, IL-1b and TNF-a?
IL-1b- fever and IL-6 production
TNF-a- Fever, mobilisation of metabolites and shock
IL-6- Fever and induces acute phase protein production.
what is the action of IL-6?
- Lymphocyte activation
- increased Ab production
describe the action of CXCL8?
recruits neutrophils, basophils and T cells
describe the action of IL-12
- activates NK cells,
- differentiate CD4 T cells into T helper cells.
what do Plasma Enzyme Systems do?
activates innate immune system even before microbes have entered or been detected
give an example of a Vasoactive amine
what does Histamine do?
- In granules of mast cells, basophils, platelets
- Released by degranulation (triggered by C3a, C5a, etc.)
- Promotes arteriolar dilation, smooth muscle contraction, and venular endothelial contraction,
- Results in widening of interendothelial cell junctions with increased vascular permeability
- Vascular actions similar to Bradykinin
describe the action of Arachidonic Acid Metabolites
- AA released from cell membrane by Phospholipases which have been activated by various stimuli and/or inflammatory mediators
- AA metabolism occurs via two major enzyme pathways:
lipoxygenase and cyclooxygenase
name 3 Arachidonic Acid Metabolites in chemotaxis
prostaglandins, platelet activating factor and leukotriene b4
whats the effect of prostaglandins?
increase vascular permeability
whats the effect of leukotriene B4?
whats the effect of PAF?
name 2 Important anti-inflammatory drugs that interact with the Phospholipid pathway
steroids and aspirin
what does aspirin inhibit?
what do steroids inhibit?
what are Chemokines?
Small polypeptides, approx 100 amino acids in general, 7-16 kDa
what are the Four families of chemokines?
CX3C (fractalkine) 38 kDa
what do Chemoattractant cytokines do?
Orchestrate leukocyte chemotaxis, adhesion, activation
whats the structure of CC chemokines?
Two adjacent cysteine amino acids near start of protein
Bind to CC Receptors (CCRs)
structure of CXC?
Have one amino acid (X) which separates the first 2 cysteines
Bind to CXC Receptors (CXCRs)
name a CXC Chemokine
whats the action of CC Chemokines?
Attract Monocytes not Neutrophils
whats the action of TNF cytokines?
TNF causes Weibel-Palade bodies in endothelial cells to be secreted
Weibel -Palade bodies contain pre-synthesised P-selectin
This enables very rapid (minutes) activation of endothelium (ie binding of leukocytes)
what are Adhesion molecules Required for?
Leukocyte binding to blood vessels
Leukocyte extravasation from blood vessels
Leukocyte migration (chemotaxis) towards inflamed sites
what are The 4 stages of Leukocyte Extravasation and Chemotaxis?
1. Rolling- Leukocyte expresses- Mucin type glycoproteins on neutrophils and sialyl-Lewis-X containing glycoproteins bind to P and E Selectin
2. Firm adhesion- express Integrins bind to ICAMs
3. Extravasation (diapedesis) Integrins and PECAM (CD31) binds ICAMs and PECAM (CD31) on endothelial cell
4. Chemotaxis through tissue- express Chemokine receptors bind to Chemokines
summarise local inflammation / chemotaxis
1. Initial responses
- Tissue macrophages detect microbes, release inflammatory mediators, chemokines, cytokines
- Complement activation releases chemoattractants C3a and C5a
2. Vascular effects
- Macrophages and complement products trigger:
Increase in vascular diameter / permeability
increased blood flow
reduced velocity of blood flow
accumulation of Igs, complement and other blood proteins in the tissue.
- Up-regulation of adhesion molecules on endothelial cells
3. PMN and Monocytes adhere and extravasate
- Selectins on endothelial cells recognize leukocyte glycoproteins (Lewis X) causing them to roll.
- ICAM-1 on endothelium interacts with LFA-1 (CD11a/CD18) and CR3 (Mac-1 or CD11b/CD18) so that leukocytes attach firmly to the endothelium, cross the vascular endothelial wall and enter site of infection
4. Leukocytes migrate up chemotactic gradient
- CXC chemokines promote migration of neutrophils
- CC chemokines promote migration of monocytes
e.g. MCP-1, MIP-1b, RANTES
- Complement components C3a C5a attract both
- Also molecules given off by microbe, e.g. fMet
what do fMet peptides do?
- As well as being an important chemotactic stimulus for phagocytes, fMet peptides have anti-leukocyte properties
- fMLP inhibits killing of Staphylococcus epidermidis in vitro
name a Bacterial chemotactic compound
- Mycobacterium tuberculosis Lipoarabinomannan (LAM) is chemotactic for macrophages but not neutrophils- maybe used by MTB to encourage granulomas to enhance bacterial survival / dormancy?
- LAM also inhibits macrophage phagocytosis
how have bacteria evolved mechanisms to block chemotaxis of phagocytes?
S. aureus inhibits leukocyte chemotaxis using the CHIPS protein
what is CHIPS?
- Chemotaxis-inhibitory protein of S. aureus
- CHIPS is produced by 80% of S. aureus strains
- CHIPS has potential as a novel anti-inflammatory drug
how does CHIPS work?
- CHIPS blocks chemotaxis receptors on leukocytes (fMet R, also affects C5a receptor, a related 7 transmembrane G-protein linked receptor)
- inhibits leukocyte recruitment