Lecture 15 Flashcards
What are the 5 signs of inflammation?
Heat (due to increased blood flow)
Redness (due to increased blood flow)
Swelling (due to an accumulation of fluid)
Pain (release of molecules that stimulate nerve endings)
Loss of function (multiple causes)
What is the general process of inflammation?
Inflammation is a reaction of the circulation where serum proteins and leukocytes mover from the blood to extravascular tissues
It is regulated by vasoactive and chemotactic mediators
Vasodilation increases blood flow to the inflamed region
Increased microvasculature permeability leads to a loss of plasma proteins into the tissue
Increased expression of adhesion molecules on endothelial cells and release of chemotactic factors from the inflamed region lead facilitate the binding of leukocytes to vessel walls, extravasation and migration to the inflamed region
There is eventually a resolution to the inflammation
What is the difference in cause of acute vs chronic inflammation?
Acute causes are often pathogens and injured tissues while chronic causes are more numerous including persistent inflammation due to non-degradable pathogens, viral infection, persistent foreign bodies or autoimmune reactions
What is the difference in the cells involved in acute vs chronic inflammation
The cells involve in acute inflammation are typically neutrophils, basophils, eosinophils and mononuclear cells while those involved in chronic inflammation are mononuclear cells, lymphocytes and plasma cells and fibroblasts
What is the difference in the primary mediators involved in acute vs chronic inflammation
In acute inflammation the mediators are vasoactive amines and eicosanoids while in chronic inflammation the mediators are inflammatory cytokines, growth factors, reactive oxygen species and hydrolytic enzymes
What is the difference in onset of acute vs chronic inflammation
The onset of acute inflammation occurs within minutes or hours while the onset of chronic inflammation is delayed
What is the difference in duration of acute vs chronic inflammation
The duration of acute inflammation is a few days while that of chronic inflammation can be many months or years
What is the difference in outcomes of acute vs chronic inflammation
Acute inflammation typically results in either resolution, abscess or the formation of chronic inflammation while chronic inflammation itself with often result in tissue destruction, fibrosis or necrosis
How are neutrophils involved in inflammation?
These are the first responders to inflamed tissues and contain secretory granules with pro-inflammatory proteins such as MPO, defensisn, lactoferrin, lysozyme and MMP9
These can eliminate microbes through both intracellular and extracellular mechanisms
These cells also require their numbers to be tightly regulated
How are monocytes/macrophages involved in inflammation?
Monocytes are macrophage precursors which are released into the circulation
They often play an important homeostatic role
Monocytes mature into tissue macrophages where they will begin to perform immune surveillance activites such as phagocytosis, antigen presentation and immune suppression
They exhibit functional heterogeneity
What is the temporal profile of white blood cells at a site of inflammation?
The neutrophils arrive first, they then undergo apoptosis with the macrophages arriving after the midpoint of this apoptotic phase
What are the two phases of acute inflammation?
The inflammatory phase and the resolution phase
What is the role of Hydrogen peroxide in white blood cell recruitment?
This is released by damaged cells and a gradient is established through the actions of Duox
This hydrogen peroxide is sensed by neutrophils through oxidation of cysteine residue causing phosphorylation of the tyrosine kinase Lyn causing them to migrate to the inflammatory site this leads to monoperoxidase activity from the neutrophil which consumes the wound derived hydrogen peroxide to produce the bactericidal hypocholorus acid
How is neutrophil apoptosis as a driver of inflammation resolution?
Neutrophils have a short lifespan to limit their negative effect on host tissues
After contributing to pathogen clearance they undergo programmed cell death-apoptosis
This co-incides with arrival monocytes/macrophages of which phagocytosis neutrophil debris causes a phenotype switch in macrophages
How is neutrophil life span controlled?
Life span depends on a balance between both pro and anti apoptotic stimuli
TNF, GM-CSF and hypoxia act to extend life-span while reactive oxygen species, annexin A1 and lactoferrin act to induce apoptosis
These signalling factors can have opposite effects on neutrophil life-span depending on their concentration
How does macrophage clearance of apoptotic neutrophils occur?
Following the neutrophil apoptosis find me signals are released by the neutrophils including nucleotides, sphingosine 1-phosphate, lysophosphatidyl-choline
Macrophages detect gradients of these through receptors with purinergic G and protein coupled receptor, they then recognise the apoptotic neutrophils through ‘eat me’ signals like phosphatidylserine leading to phagocytosis and a phenotypic switch
What occurs to macrophages after phagocytozing an apoptotic neutrophil?
This causes neutrophils to switch from a proinflammatory M1 macrophage to pro-resolving M2 macrophage which expresses molecules for antigen presentation and helps attract T and B lymphocytes, this switch is critical for the restoration of tissue homeostasis
What are the mechanisms of internalization?
Reaching phagocytosis, sinking phagocytosis and triggered phagocytosis
What is endocytosis?
This is an actin independent process of internalisation with multiple mechanisms including internalization via clatherin coated pits
This leads to the formation of endosomes which contain the internalised molecules and will fuse with lysosomes to facilitate digestion
What is phagocytosis?
This is and actin dependent mechanism of internalising molecules used for larger targets (greater than .75 micrometers) than endocytosis and has many different mehcanisms like micropinocytosis
What intracellular signalling occurs through phagocytosis?
Leukocytes acquire information about the target at various stages of phagocytosis with the initial detection occurring by cell-surface receptors to asses if it is a PAMP or DAMP
Degradation of the target exposes new ligands that are detected by intracellular receptors
The information collected by all of these signals is integrated to control the immune cell response through influencing target gene expression
What is autophagy?
Engulfment of cytosolic content, where autophagosomes fuse with lysosomes for degradation of contents leading o recycling of organelles to amino acids, fatty acids etc to fuel catabolic and anabolic process ensuring cellular survival during starvation
What is the inflammasome?
A intracellular multiprotein complex that mediates activation of caspase 1 (catalyzes processing of IL-1beta and IL-18)
It is found in macrophages, dendritic cells and epithelial cells and activated in response to intracellular DAMPs and PAMPs
Molecular composition of this is stimulation specific
It has been linked to IBD, gout, type 1 and 2 diabetes
Induces maturation and secretion of pro-inflammatory cytokines IL-1beta and IL-18 which have independent functions which include inducing pyroptotic death, inhibition of bacterial replication and activation of lipid metabolism
What is the structure of inflammasome?
This is a multiprotein oligomer consisting of caspase 1, PYCARD, NALP and occasionally caspase 5 showing how this structure of composition is stimulus specific
How does the inflammasome induce pyroptosis?
Pyroptosis is a form of poorly understood programmed cell death that requires caspase 1 activity it serves to eliminate infected immune cells allows the removal of intracellular replication niches
This apoptosis is immunologically silent as cytoplasmic contents packaged in apoptotic bodies
