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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
Q

Chemokine receptors on monocytes

A

CXCR4, CCR2, CCR1, CCR4

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26
Q

Chemokine receptor on resting T cell

A

CXCR4

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27
Q

Chemokine receptors on activated T cell

A

CXCR3, CCR4, CCR2, CCR3, CXCR4, CCR1

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28
Q

What mediates the migration of leukocytes across the endothelial cell layer of blood vessels?

A

Chemoattractants and CAM interactions

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29
Q

Extravasation

A

The process by which blood-borne neutrophils and monocytes enter sites of inflammation

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30
Q

CAM expression by endothelial cells is increased by

A

Cytokines and other products of inflammation

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31
Q

Chemokines (such as IL-8) activate

A

Neutrophils

32
Q

Neutrophils bind _____, which assume a high affinity confirmation that allows for:

A

Integrins

Neutrophil arrest and adhesion to immunoglobulin-superfamily CAMs

33
Q

Molecules involved in cell rolling

A

Selectins and chemokines

34
Q

Molecules involved in activation during extravasation

A

Integrins and Ig superfamily members, chemokines

35
Q

Molecules involved in arrest/adhesion during extravasation

A

Integrins and Ig superfamily members, chemokines

36
Q

Molecules involved in transendothelial migration during extravasation

A

Integrins and Ig superfamily members, chemokines

37
Q

Neutrophil and monocyte extravasation in terms of molecule binding

A
  • 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
Q

Mac1

A

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
Q

PSGL-1

A

A cell receptor on neutrophils that binds to P-selectin and Sialyl-Lewisx. Involved in the rolling/tethering of extravasation

40
Q

Where do lymphocytes recirculate from/to?

A

Lymphocytes recirculate from the blood to the bone marrow, spleen, lymph nodes and tertiary extralymphoid tissue at least once every 24 hours

41
Q

Why is it important that lymphocytes recirculate?

A

Recirculation ensures that the greatest number of antigen-specific lymphocytes have the opportunity to encounter and interact with antigen in lymphoid tissue.

42
Q

Migration of lymphocytes into lymph nodes takes place across

A

high endothelial venules

43
Q

Rolling is promoted by

A

Weak interactions between lymphocyte L-selectin and endothelial cell mucin

44
Q

Rolling is promoted by

A

Weak interactions between lymphocyte L-selectin and endothelial cell musin

45
Q

Integrins mediate

A

lymphocyte arrest and adhesion to immunoglobulin-superfamily CAMs.

46
Q

Junctional adhesion molecules

A

Mediate transendothelial migration of lymphocytes

47
Q

Molecules involved in the rolling stage of Naive T Lymphocyte extravasation

A

L-selectin binds musin (CD34) on endothelial surface

48
Q

Molecules involved in activation stage of naive T lymphocyte extravasation

A

Interaction with a chemokine receptor transduces an activating signal that changes the confirmation of the integrin (LFA-1)

49
Q

Molecules involved in arrest/adhesion of naive T lymphocyte extravasation

A

The activated integrin binds to an ICAM-1 and the rolling stops, allowing transendothelial migration into the lymph node to occur.

50
Q

Molecules involved in arrest/adhesion of naive T lymphocyte extravasation

A

The activated integrin binds to an ICAM-1 and the rolling stops, allowing transendothelial migration into the lymph node to occur.

51
Q

Where does a naive T cell go/what does it do after transendothelial migration?

A

It enters the lymph node, specifically it goes to the paracortex where it can encounter antigen presented by interdigitating dendritic cells

52
Q

What mediates the differential migration of lymphocyte subsets into different tissues?

A

Homing receptors on lymphocytes that recognize specific CAMs

53
Q

MIP-1β and RANTES

A

Chemokines involved in lymphocyte homing/trafficking.
MIP-1β: Attracts naive T cells
RANTES: Attracts memory T cells

54
Q

Homing of naive lymphocytes

A

Naive lymphocytes do not show tissue specific homing; rather they traffick to secondary lymphoid tissues

55
Q

Effector lymphocytes home to:

A

Sites of inflammation

56
Q

Memory lymphocytes home to:

A

The tissue type where a specific antigen was first encountered

57
Q

Mucosal-homing of effector T cell vs skin-homing effector T cell

A

-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
Q

Lipid mediators of inflammation (3)

A

Thromboxane, prostaglandins, and leukotrienes

59
Q

Where are lipid mediators of inflammation produced?

A

By tissue mast cells and macrophages

60
Q

Thromboxane function

A

Causes vasoconstriction (of local blood vessels) and platelet aggregation

61
Q

Prostaglandins function

A

Increase vascular permeability, vascular dilation, and neutrophil chemotaxis

62
Q

Leukotrienes C4,D4, E4 function

A

Mediate lung inflammation

63
Q

Leukotriene B4 function

A

Neutrophil chemotaxis

64
Q

Platelet activating factor function

A

Platelet aggregation, neutrophil activation, and eosinophil chemotaxis.

65
Q

Biosynthesis of lipid mediators of inflammation

A
  • Pathway begins with membrane phospholipids

- Two first paths: arachidonic or lyso-PAF

66
Q

Arachidonic acid pathway of lipid mediator biosynthesis

A

Can follow one of two paths:
-Cyclooxygenase pathways: Lead to prostaglandins and thromboxane

-Lipooxygenase pathway: Leads to leukotrienes C4, D4, E4, and B4

67
Q

Lyso-PAF pathway of lipid mediator biosynthesis

A

Produces platelet activating factor

68
Q

The expression and conformation of CAMs is regulated by

A

Chemokines, which attract leukocyte subsets to sites of inflammation

69
Q

Anaphylatoxins (C3a, C5a)

A

Trigger tissue mast cell release of histamine, leading to smooth muscle contraction and increased vascular permeability during acute inflammation

70
Q

Interferon-γ and TNFα as mediators of inflammation

A

Important in chronic inflammation, and can cause tissue damage

71
Q

Inflammasomes

A

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
Q

What comes together to form an inflammasome complex?

A

NLRs and proteins such as proteases

73
Q

NLRP3 inflammasome is expressed by

A

Monocytes, macrophages, neutrophils, dendritic cells, some lymphocytes, and epithelial cells

74
Q

NLRP3 can be activated by

A

Microbial components such as flagellin, and by non-microbial substances such as DAMPs

75
Q

How do inflammasomes prime the inflammatory response?

A

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
Q

3 models of inflammasome activation:

A
  • 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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