Inflammation and Recruitment of Inflammatory Cells Flashcards
What are the 5 cardinal signs of inflammation and how are these caused?
Redness - causes by vasodilation and increased blood flow
Heat - caused by vasodilation and increased blood flow
Swelling - Accumulation of fluid
Pain - irritation of nerve endings
Loss of Function - destruction of tissue or to avoid pain
Why does inflammation occur?
As a response to a threat
What cells are involved in the inflammatory response?
Innate and accute cells
What would happen if you got pricked with a bacteria covered pin?
Chemical signals are generated by resident cells and leukocytes from the blood are recruited to these signals (mainly phagocytes/neutrophils). These digest and kill the pathogen and inflammation is resolved.
What are the inflammatory cells?
Leukocytes - Neutrophils, Eosinophils, Mast cells, Basophils, T-cells, NK cells and platelets.
What is the function of inflammation?
Host defence agaisnt micro-organisms - this can be sterile or infectious.
Control of tumour growth and mestasis
Tissue repair and restoration of organ function
The stages of acute inflammatory response?
The pro-inflammatory response
Anti-inflammatory and pro resolution response
What does the pro-inflammatory response involve?
The pro-inflammatory response to kill and remove pathogens. This involves inflammatory cell recruitment and indentification of the insults.
What does the anti-inflammatory and pro-resolution response involve?
Inflammatory cell phenotypic change, removal of recruited inflammatory cells and repair of damaged tissue.
This is all to return the tissue back to homeostasis.
How does the body identify the insult?
All invasions give of signals - either pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs aka alarmins).
What are examples of PAMPs?
Carbohydrates, lipids, proteins, nucleic acids
Anything that you would not see in your body
What are examples of DAMPs?
Mitochondrial components, nuclear protiens, stess-induced proteins, crystals.
What notices these PAMPs/DAMPs?
Pattern recognition receptors (PRRs)
Examples of Pattern recognition receptors?
Toll like receptors,
NOD-like receptors
C-type lectin receptors
FPRs
Can pattern recognition receptors be membrane bound or cytosolic?
Yes
What do Toll-like receptors recognise?
Microbes and molecules released by stressed/dying cells
What do TLRs differ in?
Membrane localisation and ligands recognised
What does ligation of a TLR do?
Induces signal transduction cascade (e.g. cytokines) that ultimately regulates expression of inflammatory genes.
What do NRS do?
They are intracellular receptors which apon ligation induce an inflammatory response by facilitating the activation of caspase-1, resulting in processing or pro-cytokines and releasing mature cytokines.
What type of cell death are NLRs involved in?
Pyroptosis
What do NLR’s create?
Inflammasomes
What are some types of inflammatory mediators to regulate cellular functions?
-Vasoactive amines e.g. histone, seratonin
-Complement components e.g. C3a and C5a
-Lipid mediators e.g. prostaglandins, leukotrienes and platelet activating factor
-Cytokines and chemokine e..g TNF, IL-1, IL-6, IL-8 etc.
What is the leukocyte adhesion cascade?
Leukocytes role along the endothelial wall and are slowed down by E-selectin. They are then stopped by activated integrins. The leukocyte is then polarised and transmigration occurs (the leukocyte goes through the tissue) to follow the chemokine trail to infection.
What causes leukocytes to roll along the endothelial wall?
Selectins control tethering and rolling
How do selectins control bidning and rolling of leukocytes?
By binding to the carbohydrate ligands - glycoproteins and glycolipids (L-selecting, P-selectin and E-selectin)
What does the L-selectin do?
Its expressed by leukocytes, mediates capture and is shed following activation.
What does P-selectin do?
Its expressed by endothelial cells anf platelets to mediate rolling
What do E-selectins do?
Expressed by activated endothelium (cytokine-induced), mediates slow rolling
What signals do integrins need to stop the rolling leukocyte along the endothelial wall?
Selectin and chemokine signals
When and why are chemokines immobilised?
They are immobilies on the endothelium so they can be presented to circulating leukocytes.
Chemokine receptors - what happens after ligation?
Activation of the rolling neutrophil bu immobilised chemokines causes selectin shedding and LFA-1 integrin activation.
What does integrin activation by chemokines enable?
Firm leukocytes adhesion to the vessel wall
What do integrins bridge?
Extracellular ligans and actin cytoskeleton.
Where are integrin ligands displayed?
On the endothelium
What two positions can ligands have and why would they change positions?
Bent (low affinity)
Extended (high affinity - active and can bind ligand)
Regulated by activation based on chemokines.
What integrin binds the ligand?
LFA-1 and this only occurs after a selectin and chemokine activates it.
What is the ligand integrin binds to on the leukocyte?
ICAM-1
When is ICAM-1 upregulated on endothelial cells and leukocytes?
Cytokine stimulation
What are the two modes of transendothelial migration (through the endothelium)?
Paracellular or transcellular
In vivo what is the main pathway of transendothelial migration?
Paracellular
What is leukocyte adhesion deficiency?
Deficiency in Beta2 integrins characterised bu frequent bacterial disease and is often fatal.
How do you remove a threat.
How do you remove a threat - what do chemokines and chemoattractants do?
Direct leukocyte chemotaxis towards site of inflammation once endothelial barrier has been breached.
How are pathogens killed after following chemoattractants?
Internally following engulfing
Is apoptosis a pro-resolution type of cell death?
Yes
Is necrosis a pro-resolution type of cell death?
No - it shows the immune system the antigen to encourage immune response.
What does killing of phagocytosed microbes initiate?
Pro-resolution signals
How does the phagocyte clear apoptotic cells?
Through efferocytosis
How does efferocytosis occur?
The apoptotic neutrophil generates find me signals causing the macrophage to come over. They ingest the neutrophil and this causes the macrophage to become anti-inflammatory.
What signals do anti-inflammatory signals produce?
Pro-resolving lipids,
Anti-inflammatory cytokines
Why wouldn’t you be able to resolve inflammation?
Inadequate production of resolution mediators, prolonged or excessive response, persistant stimulation, subnormal response, infiltration by myeloid-derived supressor cells and failed phenotypic switch in macrophage and T cell populations.
What are some diseases coming from non-resolved inflammation?
Atherscierosis, COPD, cancer, obesity, asthma, IBD, RA, MS
What are inflammatory disease?
Inappropriate host response leading to disease which can affect virtually every organ in the body.
What is gout?
A common type of arthritis causing painful flare-ups, often in the big toe driven by a build up of uric acid crystals active inflammasome.
How do you treat gout?
IL-1b therapy
How would you therapeutically target inflammation?
Small molecule inhibitors
Antibody-mediated
Use of soluble decoy receptors
