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MEDSCI 314 > Lecture 9; Innate Immunity, Inflammation > Flashcards

Lecture 9; Innate Immunity, Inflammation Flashcards

1
Q

What are the five signs of inflammation?

A
  • Heat (inc. blood flow)
  • Redness (Inc. blood flow)
  • Swelling (accumulation of fluid)
  • Pain (Release of molecules that stimulate nerve endings)
  • Loss of function (Multiple causes)
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2
Q

What is inflammation a reaction of?

A

Inflammation is a reaction of the circulation - serum proteins and leukocytes move from blood to EC space

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3
Q

What is inflammation regulated by?

A

Vasoactive and chemotactic mediators (i.e chemical gradient exists in the site of inflammation to attract cells)

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4
Q

What assists movement of cells from the vasculature in inflammation?

A

Increases microvasculature permability - loss of plasma proteins into the tissue

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5
Q

How does inflammation assist cells moving through the endothelium?

A

Increased expression of adhesion molecules on endothelial cells and release of chemotactic factors from inflamed region- facilitate binding of leukocytes to vessel walls, extravasation and migration to inflamed region

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6
Q

What is the last component of an inflammatory response?

A

Inflammation resolution

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7
Q

Describe the onset, duration and outcomes of acute inflammation;

A

Onset - minutes, hours
Duration- few days

Outcomes; Resolution, abscess formation, , chronic inflammation

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8
Q

Describe the causes and primary mediators of acute inflammation;

A

Causes; Pathogens, injured tissue

Primary mediators; Vasoactive amines, eicosanoids,

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9
Q

What are the cells involved in acute inflammation?

A

Neutrophils, basophils (inflammatory response)

Eosinophils (response to helminth worms, parasites

Mononuclear cells (monocytes, macrophages)

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10
Q

What is the cause of chronic inflammation?

A

Persistant inflammation due to;

  • Non-degradable pathogens,
  • Viral infections,
  • Persistent foreign bodies,
  • Autoimmune reactions
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11
Q

What are the cells involved in chronic inflammation?

A

Mononuclear cells;

  • Monocytes
  • Macrophages
  • Lymphocytes
  • Plasma cells
  • Fibroblasts
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12
Q

What are the primary mediators of inflammation?

A

Inflam cyotkines
Growth factors
ROS
Hydrolytic enzymes

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13
Q

What is the onset, duration and outcomes of chronic inflammation?

A

Onset; Delayed
Duration; Months, years

Outcomes; TIssue destruction, necrosis, fibrosis

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14
Q

What cells respond first to inflammation?

A

Neutrophils

Numbers must be tightly regulated

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15
Q

How can neutrophils contribute to the inflammation response?

A

Contain secretory granules with pro-inflammatory proteins-e.g. MPO, defensins, lactoferrin, lysozyme, MMP9

(respiratory burst (ROS)

Can eliminate microbes by multiple mechanisms (both intracellular and extracellular)

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16
Q

What are the killing mechanisms of neutrophils?

A

Phagocytosis
Degranulation
NETs

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17
Q

What are NETs?

A

Neutrophil extra cellular traps

These can promote inflammation resolution by degrading pro inflammatory cytokines

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18
Q

What is the function of macrophages?

A

Mature tissue macrophages perform immune surveillance activities (phagocytosis, antigen presentation, immune suppression, clearance of scenscent RBC)

(tissue dependant)

19
Q

Describe the temporal profile of leukocyte infiltration;

A

Neutrophils arrive first (hrs), then undergo apoptosis before mononuclear cells (macrophages) arrive (24+hrs)

20
Q

What controls leukocyte recruitment?

A

(Rapid) - H2O2 plays a role

Slow) - Leukocyte extravasartion from the vasculature (cytokines

21
Q

Describe how hydrogen peroxide regulates the immediate recruitment of neutrophils;

A

Duox protein is expressed on epithelial cells, it is an NAPDH oxidase and in response to wounds there is an influx of Ca into epithelial cells, this activates the Duox protein and it creates H2O2, this creates an H2O2 gradient attracting neutrophils

22
Q

How do Neutrophils sense H2O2?

A

Neutrophils express tyrosine kinase Lyn, H2O2 oxidises a residue, this results in a phosphorylation cascade, leading to migration, exactly how is unknown

23
Q

How is the neutrophil response limited?

A

Neutrophils dampen the H2O2 response as neutrophil MPO consumes wound derived H2O2 (this in turn dampens the number of neutrophils responding)

24
Q

Describe leukocyte extravasation from the vasculature;

A
  • Tethering, rolling, adhesion, crawling, transendothelial migration
  • Histamine, leukotrienes, cytokines alter endothelial expression of surface adhesion molecules
  • Tethering (P-selectin and E- selectin)
  • Chemokines activate neutrophil cell surface integrins that bind endothelial ICAMs
  • Leukocytes exit blood vessel

(should know this from previous lecture)

25
Q

What controls the resolution phase?

A
  • Neutrophil apoptosis and M1/M2 macrophage phenotypes

- Leukocyte reverse migration

26
Q

How can tissue resident macrophages recruit neutrophils?

A

Tissue resident macrophages recruit neutrophils via pro-inflammaotry cytokines, Neutrophils extravasate and release pro-inflammatory cytokines, recruited monocytes can differentiate into macrophages

27
Q

What happens eventually to recruited neutrophils?

A

They undergo apoptosis and macrophages phagocytose these in response to signals (important in resolution)

28
Q

Why do neutrophils have a limited life span?

A

To limit their negative effects on host tissues

29
Q

When do neutrophils undergo apoptosis in the inflammatory process?

A
  • After contributing to pathogen clearance they undergo programmed cell death-apoptosis
  • This coincides with arrival monocytes/macrophages
  • Phagocytosis of neutrophil debris drives a phenotype switch in macrophages
30
Q

What determines neutrophil life span/ causes the programmed cell death?

A
  • Bbalance between both pro- and anti- apoptotic stimuli.
  • TNF, GM-CSF and hypoxia act to extend life-span
  • 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
31
Q

How do macrophages phagocytose neutrophils?

A
  • Following apoptosis ‘find me’ signals are released (nucleotides, sphingosine 1-phosphate, lysophosphatidyl-choline)
  • Macrophages navigate these gradients through receptors (e.g. purinergic GPCR)
  • Macrophages recognise apoptotic neutrophils through ‘eat me’ signals (phosphatidylserine is recognised by a variety of receptors on the surface of macrophages either directly or via soluble bridging molecules)
32
Q

What happens to macrophages over time?

A

Following phagocytosis of apoptotic neutrophils, macrophages switch from pro-inflammatory (M1) to pro- resolving (M2) macrophages

33
Q

What is the M2 phenotype?

A

M2 macrophages turn on anti- inflammatory transcriptional program

M2 cells express molecules for antigen presentation and help attract T- and B-lymphocytes

34
Q

Why does the M1 - M2 switch need to occur?

A

Switch critical for the restoration of tissue homeostasis

35
Q

What is the inflammasome?

A

Multiprotein complex that mediates activation of caspase 1
(catalyzes processing of IL-1b and IL-18)

Molecular composition is stimulus-specific

36
Q

Where does the inflammasome occur?

A

Occurs in macrophages, dendritic cells, epithelial cells

37
Q

What activates the inflammasome?

A

intracellular DAMPs and PAMPs

38
Q

What is the inflammasome linked to?

A

Linked to IBD, gout, type 1 and 2 diabetes

39
Q

What does the inflammasome induce?

A
  • Induces maturation and secretion of (‘leaderless’) pro-inflammatory cytokines IL-1b and IL-18
    • IL-1b- and IL-18-independent functions include inducing pyroptotic death, inhibition of bacterial replication and activation of lipid metabolism
40
Q

What is the basic composition of the inflammasome?

A

Basic composition-
- NOD-like receptor family (NLR) ;
- (NLRP1B), (NLRC4) & (NLRP3) .
Possess leucine-rich repeats (LRRs) and caspase recruitment domains or pyrin domain

These can activate;

ASC, =apoptosis-associated speck-like protein + CARD

Which in turn

Induces proximity-induced autoactivation of proteolytic enzyme caspase 1

41
Q

What can inflammasome activation also induce?

A

Inflammasome activation can induce pyroptosis (poorly understood form of cell death that requires caspase 1 activity)

42
Q

What cells do pyroptosis?

A

occurs in leukocytes infected with intracellular pathogenic bacteria

43
Q

Whats the function of pryoptosis?

A

Serves to eliminate infected immune cells-removal of intracellular replication niches

44
Q

Does pyroptosis cause inflammation?

A

Pyroptosis augments inflammation through caspase 1-dependent release of IL-1b and IL-18.

MEDSCI 314 (17 decks)

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