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MICI3115 > Lecture 6: Inflammation and Leukocyte Migration > Flashcards

Lecture 6: Inflammation and Leukocyte Migration Flashcards

1
Q

Inflammation cause and characteristics

A 
Caused by local injury or tissue trauma
Characterized by:
-Redness (rubor)
-Heat (calor)
-Swelling (Tumor)
-Pain (dolor)
-Loss of tissue function
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2
Q

CAMs

A

Cell adhesion molecules that are crucial for leukocyte-tissue interactions during inflammation. Include: selectins, mucins, integrins, and immunoglobulin-superfamily CAMs

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3
Q

When tissue is injured, endothelial cells will express ____ which causes some leukocytes to _____

A
  • CAMs

- begin rolling along the endothelial cells

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4
Q

Molecules involved in extravasation of neutrophils

A

ROLLING: L-selectin and PSGL-1

Activation by chemokines: IL-8 and MIP-1b/CCL4

ADHESION: LFA-1 and MAC-1

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5
Q

The first type of leukocyte that arrives at the site of inflammation

A

Neutrophils

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6
Q

What do neutrophils respond to within inflamed tissues

A

CSa, bacterial peptides containing N-formyl peptides, and leukotrienes

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7
Q

Molecules involved with extravasation of inflammatory monocytes

A

Rolling: L-selectin

Activation by chemokines: MCP-1/CCL2

Adhesion: VLA-4

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8
Q

Leukocyte type that gets to inflamed tissue second

A

Inflammatory monocytes

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9
Q

What do neutrophils respond to within inflamed tissue?

A

Bacterial peptide fragments and complement fragments

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10
Q

Molecules involved with extravasation of naive lymphocytes

A

Rolling: L-selectin, LFA-1, VLA-4 (in low affininty forms)

Activation by chemokines: CCL21, CCL19, CXCL12 (T cells) and CXCL13 (B cells)

Adhesion: LFA-1 and VLA-4

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11
Q

How do naive lymphocytes enter the lymph nodes?

A

Via high endothelial venules

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12
Q

Selectins

A

Glycoproteins that bind specific carbohydrate groups such as sialyl-Lewisx via a lectin-like domain

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13
Q

Musins

A

Glycosylated proteins that present sialyl-Lewisx and other carbohydrate groups to selectins

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14
Q

Integrins

A

Cell surface heterodimeric proteins that bind extracellular matrix molecules (e.g. fibronectin) and intracellular adhesion molecules (ICAMs)

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15
Q

ICAMs

A

Immunoglobulin-superfamily glycoproteins that bind integrins

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16
Q

How do selectins, musins, integrins, and ICAMs pair up?

A

Musins present to selectins

Integrins bind ICAMs

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17
Q

Chemokines control:

A

Leukocyte adhesion, chemotaxis, and activation

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18
Q

(T/F) Chemokines are only produced in response to inflammation

A

False. They are constitutively expressed and also produced in response to inflammation

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19
Q

Main chemokine subgroups

A

CC and CXC

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20
Q

Chemokine receptors

A

Seven transmembrane proteins that signal through heterotrimeric G proteins (GPCRs). Receptors can bind to more than one chemokine. Receptor expression is limited to certain cell types to confer specificity to the action of given chemokines; cells will only respond to chemokines they have receptors for.

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21
Q

Second messenger pathways activated by chemokine receptor signalling

A

JAK->PKC->Akt->Survival

Gprotein->Ras->MAP kinase cascade->AP-1-> Gene expression

G protein -> Cell movement

G-protein-> PLCBeta -> NK-kB-> gene expression

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22
Q

Chemokine receptors on neutrophils

A

CXCR4, CXCR2, CXCR1

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23
Q

Chemokine receptors on basophils

A

CCR4, CCR2, CCR3

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24
Q

Chemokine receptors eosinophils

A

CCR3 CCR4

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25
Chemokine receptors on monocytes
CXCR4, CCR2, CCR1, CCR4
26
Chemokine receptor on resting T cell
CXCR4
27
Chemokine receptors on activated T cell
CXCR3, CCR4, CCR2, CCR3, CXCR4, CCR1
28
What mediates the migration of leukocytes across the endothelial cell layer of blood vessels?
Chemoattractants and CAM interactions
29
Extravasation
The process by which blood-borne neutrophils and monocytes enter sites of inflammation
30
CAM expression by endothelial cells is increased by
Cytokines and other products of inflammation
31
Chemokines (such as IL-8) activate
Neutrophils
32
Neutrophils bind _____, which assume a high affinity confirmation that allows for:
Integrins Neutrophil arrest and adhesion to immunoglobulin-superfamily CAMs
33
Molecules involved in cell rolling
Selectins and chemokines
34
Molecules involved in activation during extravasation
Integrins and Ig superfamily members, chemokines
35
Molecules involved in arrest/adhesion during extravasation
Integrins and Ig superfamily members, chemokines
36
Molecules involved in transendothelial migration during extravasation
Integrins and Ig superfamily members, chemokines
37
Neutrophil and monocyte extravasation in terms of molecule binding
- Cytokines bind to receptors on endothelial cells, causing an increase in CAMs and selectins - Increased selectins on allows for binding of neutrophils/monocytes via musin-like CAM. - Chemokines (e.g. IL-8) binding to chemokine receptors on neutrophils/monocytes change integrins to their active confirmation, allowing them to bind Ig-superfamily CAMs.
38
Mac1
A cell receptor on monocytes, neutrophils and macrophages that binds to iCAM-1, iC3b, and fibrinogen. Involved in the tight adhesion step of extravasation.
39
PSGL-1
A cell receptor on neutrophils that binds to P-selectin and Sialyl-Lewisx. Involved in the rolling/tethering of extravasation
40
Where do lymphocytes recirculate from/to?
Lymphocytes recirculate from the blood to the bone marrow, spleen, lymph nodes and tertiary extralymphoid tissue at least once every 24 hours
41
Why is it important that lymphocytes recirculate?
Recirculation ensures that the greatest number of antigen-specific lymphocytes have the opportunity to encounter and interact with antigen in lymphoid tissue.
42
Migration of lymphocytes into lymph nodes takes place across
high endothelial venules
43
Rolling is promoted by
Weak interactions between lymphocyte L-selectin and endothelial cell mucin
44
Rolling is promoted by
Weak interactions between lymphocyte L-selectin and endothelial cell musin
45
Integrins mediate
lymphocyte arrest and adhesion to immunoglobulin-superfamily CAMs.
46
Junctional adhesion molecules
Mediate transendothelial migration of lymphocytes
47
Molecules involved in the rolling stage of Naive T Lymphocyte extravasation
L-selectin binds musin (CD34) on endothelial surface
48
Molecules involved in activation stage of naive T lymphocyte extravasation
Interaction with a chemokine receptor transduces an activating signal that changes the confirmation of the integrin (LFA-1)
49
Molecules involved in arrest/adhesion of naive T lymphocyte extravasation
The activated integrin binds to an ICAM-1 and the rolling stops, allowing transendothelial migration into the lymph node to occur.
50
Molecules involved in arrest/adhesion of naive T lymphocyte extravasation
The activated integrin binds to an ICAM-1 and the rolling stops, allowing transendothelial migration into the lymph node to occur.
51
Where does a naive T cell go/what does it do after transendothelial migration?
It enters the lymph node, specifically it goes to the paracortex where it can encounter antigen presented by interdigitating dendritic cells
52
What mediates the differential migration of lymphocyte subsets into different tissues?
Homing receptors on lymphocytes that recognize specific CAMs
53
MIP-1β and RANTES
Chemokines involved in lymphocyte homing/trafficking. MIP-1β: Attracts naive T cells RANTES: Attracts memory T cells
54
Homing of naive lymphocytes
Naive lymphocytes do not show tissue specific homing; rather they traffick to secondary lymphoid tissues
55
Effector lymphocytes home to:
Sites of inflammation
56
Memory lymphocytes home to:
The tissue type where a specific antigen was first encountered
57
Mucosal-homing of effector T cell vs skin-homing effector T cell
-Both bind the same integrin and ICAM (LFA-1/ICAM-1). However, the selectin-musin pairing is different. Mucosal: MAdCAM-1/LPAM-1 Skin: E-selectin/CLA
58
Lipid mediators of inflammation (3)
Thromboxane, prostaglandins, and leukotrienes
59
Where are lipid mediators of inflammation produced?
By tissue mast cells and macrophages
60
Thromboxane function
Causes vasoconstriction (of local blood vessels) and platelet aggregation
61
Prostaglandins function
Increase vascular permeability, vascular dilation, and neutrophil chemotaxis
62
Leukotrienes C4,D4, E4 function
Mediate lung inflammation
63
Leukotriene B4 function
Neutrophil chemotaxis
64
Platelet activating factor function
Platelet aggregation, neutrophil activation, and eosinophil chemotaxis.
65
Biosynthesis of lipid mediators of inflammation
- Pathway begins with membrane phospholipids | - Two first paths: arachidonic or lyso-PAF
66
Arachidonic acid pathway of lipid mediator biosynthesis
Can follow one of two paths: -Cyclooxygenase pathways: Lead to prostaglandins and thromboxane -Lipooxygenase pathway: Leads to leukotrienes C4, D4, E4, and B4
67
Lyso-PAF pathway of lipid mediator biosynthesis
Produces platelet activating factor
68
The expression and conformation of CAMs is regulated by
Chemokines, which attract leukocyte subsets to sites of inflammation
69
Anaphylatoxins (C3a, C5a)
Trigger tissue mast cell release of histamine, leading to smooth muscle contraction and increased vascular permeability during acute inflammation
70
Interferon-γ and TNFα as mediators of inflammation
Important in chronic inflammation, and can cause tissue damage
71
Inflammasomes
Consist of certain nod like receptors (NLRs) that assemble with proteins such as proteases to form a complex that converts precursor forms of IL-1 and IL-18 into active inflammation-promoting cytokines that are then secreted
72
What comes together to form an inflammasome complex?
NLRs and proteins such as proteases
73
NLRP3 inflammasome is expressed by
Monocytes, macrophages, neutrophils, dendritic cells, some lymphocytes, and epithelial cells
74
NLRP3 can be activated by
Microbial components such as flagellin, and by non-microbial substances such as DAMPs
75
How do inflammasomes prime the inflammatory response?
They act in tandem with other PRRs in response to PAMPs or DAMPs to generate mature IL-1 and IL-18 via caspase-1-mediated cleavage.
76
3 models of inflammasome activation:
- Triggering of pore formation by ATP - Lysosomal rupture - ROS production in response to PRRs (the respiratory burst) Methods are NOT mutually exclusive

MICI3115 (3 decks)

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