Lecture 2 Inflammation and resolution Flashcards
M0- produce cytokines: IL-6b, IL-6 & TNF-a:
Where do they act? (5)
Effects they have?
Liver: Acute phase proteins (C-reactive protein, mannose-binding-lectin)
Bone marrow/endothelial: - neutrophil mobilization, -phagocytosis.
Hypothalamus: Increase body temperature, - decreases infection replication, increases antibody processing and increases specific immune response.
Fat/muscle: Increase metabolism to increase temperature. - same effects as above.
Dendritic cells: TNF-a stimulates migration to lymph nodes and maturation. - Initiation of the adaptive response.
Acute Phase response:
What does IL-6 do in the liver?
What is released from the liver?
effects?
IL-6 binds hepatocytes causing upregulation of acute phase proteins.
-SP-A, SP-D: Surfactant proteins (Collectins)
Mannose-binding-lectin (Collectins)
C-reactive protein (pentraxins)
Amyloid protein (pentraxins)
CRP + MBL bind to pathogens acting as opsonin’s for phagocytosis. (Lectin pathway, classical pathway).
What is inflammation?
Beneficial if?
What happens if resolution doesn’t occur?
A protective response to infection/damage.
Beneficial but only if the tissue returns to its pre-inflammation state (Resolution)
The tissue must return back to normal or chronic inflammation occurs.
Consequences of loss of function in chronic inflammation:
Persistent inflammatory cells leads to? (4)
- Chronic inflammation
- Fibrosis
- Scarring
- Loss of function
Basic resolution in inflammation:
N0 migrate to site of infection
- kill bacteria
- age and die by apoptosis
Monocytes follow and mature into M0
M0
Clear remaining bugs
Clear neutrophils
= Resolution of inflammation.
Prostaglandin E2: PGE2 What is it? Induced by cytokines? How is it produced? What therapy can inhibit it? What does it cause?
Is an Eicosanoid:
PGE2 is a pro-inflammatory lipid mediator.
Induce by cytokines: IL1-b, IL-6, TNF-a
Processed by cyclooxygenase 2 (COX2)
substrate is fatty acid from membranes.
Released by phospholipase A2 (PLA2)
Causes vascular changes and functions on the hypothalamus to promote fever and pain.
Therapy: NSAID inhibit COX2 enzyme.
Active resolution:
when PGE2 it activates what?
These new eicosanoids mediators are? (4)
What do these new eicosanoids do?
PGE2 pro-inflammatory mediators turn on enzymes that make new Eicosanoids mediators.
These new eicosanoids are specialist pro-resolving mediators.
- lipoxins derived from arachidonic acid
- resolvins : poly unsaturated fatty acids (PUFA)
- Protectins: derive from PUFA
- Maresins - derive from PUFA
They actively promote resolution.
‘the beginning programs the end’.
What do specilist pro-resolving mediators do?
- name the mediators
- What they do
Lipoxins, resolvins and protectins.
Reduce neutrophil infiltration
Increase monocyte infiltration
Increase uptake of apoptotic cells
Increase exit to lymphatics
Stop recruitment and increase clearance.
Active resolution in depth
5 steps of resolution?
Lipid mediators decrease neutrophil infiltration.
- Current neutrophils die by apoptosis. releasing lactoferrin which further reduces neutrophil infiltration.
- Apoptotic neutrophils express CCR5 this depletes CCL3 and CCL5 decreasing neutrophil infiltration.
- Lactoferrin, LPC, nucleotides, CX3CL1 and ICAM 3 and extracellular vesicles attract more monocytes (EAT ME SIGNALS).
- Uptake of apoptotic neutrophils start macrophage differentiation to M” macrophage which are pro-resolving and release TGF-b and IL-10 + more lipoxins and resolvins.
- M0 - M2
Silent clearance of apoptotic cells
M2 Clearance of apoptotic cells
M1 clearance of necrotic cells /bacteria
M2 macrophages: Binds apoptotic cells by: scavenger receptors, CD14-ICAM3, phosphatidyl serine receptors.
- cause increase in anti-inflammatory cytokines: TGF-b and decreases in pro-inflammatory cytokines: TNF, IL-1b, IL-8
M1 macrophages bind necrotic cells by Fc receptor or complement receptors.
-causes increase in pro-inflammatory cytokines: TNF, IL-1b, IL-8.
Decreases anti-inflammatory cytokines: TGF-b1
