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A10HA > 4 - Macrophages pt. 1 > Flashcards

4 - Macrophages pt. 1 Flashcards

1
Q

Macrophage features

A
  • irregular shaoe
    -many membrane extensions
  • diverse receptors, including toll-like, mannose and scavenger receptors
  • numerous granules: majority peroxidase-negative
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2
Q

Main functions of macrophages

A
  • phagocytosis
  • removal of dead/dying cells
  • sentinel activity
  • antigen presentation to other cells
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3
Q

What can macrophages acquire?

A

Can also acquire anti-microbial peptides (AMPs) through ingestion of apoptotic neutrophils

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4
Q

Steady state macrophages

A
  • tissue macrophages in steady state are intrinsically anti-inflammatory
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5
Q

Macrophages in the body

A
  • BONE: osteoclast, bone marrow macrophage
  • LIVER: Kupffer cell
  • LUNG: alveolar macrophage
  • EYE: intraoccqular macrophage
  • BRAIN: microglia
  • SPLEEN: splenic macrophage
  • SMALL INTESTINE (intestinal macrophage
  • LYMPH NODE: subcapsular sinusoidal macrophages and medullary macrophages
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6
Q

Role of osteoclast

A

Bone resorption

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7
Q

Role of kupffer cell

A

Clearance of pathogens and toxins

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8
Q

Role of alveolar macrophage

A

Elimitation of dust, allergens and microorganisms

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9
Q

Role of splenic macrophage

A
  • clearance on senescent red blood cells by red pulp macrophages
  • clearance of blood-borne particular antigens by magical zone macrophages
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10
Q

Role of intestinal macrophage

A
  • recognition and removal of enteric pathogens
  • tolerance to food antigens and microbiota
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11
Q

Role of lymph node macrophages

A

Antigen capture and presentation to B cells

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12
Q

Antigen presentation

A
  1. the macrophage takes up the antigen by phagocytosis
  2. the macrophage breaks down the antigen into fragments in the lysosome
  3. a class II MHC proteins binds an antigen fragment
  4. the MHC protein presents the antigen to a TH cell
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13
Q

What does MHC stand for?

A

Major Histocombatibility Complex

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14
Q

MHC in humans

A

Humans: MHC aka Human Lymphocyte Antigens (HLA)
- MHC molecules present modified antigens
- two classes exist

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15
Q

Class I MHC

A

Present in all nucleated cells

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16
Q

Class II MHC

A

Present in endocytic vesicles of macrophages , dendritic and B cells

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17
Q

MHC class I steps

A
  1. virus infects cells - viral proteins synthesised in cytosol
  2. peptide fragments of viral proteins bound by MHC class I molecules
  3. bound peptides transported by MHC class I to cell surface
18
Q

Importance of MHC class I

A
  • important in immune responses against intracellular pathogens such as viruses
  • any cell could be vulnerable to viruses, all cells express MHC class I
19
Q

MHC class I steps

A
  1. bacterium/foreign protein is endocytose by macrophage, contained within endocytic vesicle
  2. vesicle fusion
  3. bound peptides transported by MHC class II to cell surface
20
Q

Distribution of MHC class II

A

Fewer cells are specialised to take up and present extracellular antigens, thus distribution of MHC class II expression restricted to macrophages, dendritic and B cells – recently, eosinophils

21
Q

Macrophage classification: distinct subsets or spectrum of activated phenotypes

A

M1 (classically activated macrophages) <—> M2 (alternatively activated macrophages

OR

Spectrum of wound-healing macrophages (M2), classically activated macrophages (M1) and regulatory macrophages

22
Q

M1: classically-activated (pro-inflamm.) macrophage

A
  • Input cells: TH1 cell (adaptive), NK cell (innate), APC/TLR
  • Main cytokine signals: interferon-gamma (IFN), tumour necrosis factor (TNF)
  • tissue macrophage in ‘steady state’, tissue macrophage are intrinsically anti-inflammatory
  • produces pro-inflammatory cytokines: interleukins (IL-) 1, 6, & 23
23
Q

M2: alternatively activated macrophage

A
  • input cells: TH2 cell (adaptive), granulocyte (innate)
  • main cytokine signal: IL-4
  • tissue macrophage in ‘steady state’, tissue macrophage are intrinsically anti-inflammatory
  • expression of macrophage mannose receptor up-regulated
24
Q

Regulatory Macrophage

A
  • inputs: regulatory T cell, immune complexes, prostaglandins, GPCR ligands, glucocorticoids, apoptotic cells, IL-10
  • main cytokine signal: IL-10
  • tissue macrophage in ‘steady state’, tissue macrophage are intrinsically anti-inflammatory
  • express high levels of IL-10
25
Q

Are tissue macrophages under enough stress/infection?

A
  • Monocyte recruitment needed to supply tissues with macrophages
  • Monocytes attracted from cell ‘reservoirs’ by cytokine gradient (CCL2)
  • After extravasation, monocytes differentiate into macrophages
  • Adaptive element from T Helper cells drives activation into M1Φ
26
Q

Are tissue macrophages under enough stress/infection? - Leishmania example

A
  • During infection and tissue stress, monocyte recruitment has a key role in providing the damaged tissues with adequate numbers of macrophages.
  • The figure depicts an exemplar of the monocyte-to-macrophage recruitment and deposition process.
  • Here, Leishmania major parasites that have infiltrated the skin after a sandfly bite elicit a weak local macrophage response that is insufficient to generate a protective response.
  • The body compensates by depositing platelets on the parasite surface that release platelet-derived growth factor (PDGF).
  • The local PDGF then increases the levels of CC-chemokine ligand 2 (CCL2), possibly by the stimulation of fibroblasts and other PDGF-responsive interstitial cells.
  • CCL2 is a key monocyte attractant that causes monocyte efflux from the bone marrow and presumably the splenic monocyte reservoir. Extravasation of the monocytes is followed by differentiation into macrophages that phagocytose the parasites and present their antigens to T cells.
  • Interferon-γ (IFNγ) production from T cells drives an M1 response that contains parasite growth
27
Q

Local, in situ mΦ proliferation also possible

A

a. recognition
b. amplification
c. dual polarisation of M1 macrophage

28
Q

In situ proliferation: recognition

A

Local secretion of interleukin-4 (IL-4) initiates macrophage proliferation in situ, followed by amplification of the IL-4 response, which is mediated by antigen-specific TH2 cells

29
Q

In situ proliferation: amplification

A
  • The increase in macrophage numbers has been proposed to play an important part in both killing the worms and driving a resolving phase of the infection.
  • The underlying mechanism of IL-4-induced proliferation may involve multiple signals from the IL-4 receptor (IL-4R), including activation of signal transducer and activator of transcription 6 (STAT6).
  • Individually or collectively, these signals may repress macrophage-activating factor (MAF) and MAFB, causing entry into the cell cycle
30
Q

In situ proliferation: dual polarisation of M1 macrophage

A

IL-4 can also cause M1-polarized macrophages to enter the cell cycle. In this case, an M1-polarized macrophage receives dual polarizing signals that drive gene expression characteristic of both M1 and M2 macrophages

31
Q

What has recent discoveries shown about proliferation?

A
  • A recent discovery has shown that, contrary to previous thinking, macrophages can enter the cell cycle and proliferate locally.
  • Thus far, in situ proliferation has been shown to be specific for T helper 2 (TH2)-type responses to worms.
  • In the example shown, a nematode is recognized through unknown mechanisms that may involve basophils, nuocytes and other sentinel lymphocytes and granulocyte
32
Q

What is released when tissues are damaged?

A

When tissues are damaged, inflammatory mediators are released, triggering an antifibrinolytic-coagulation cascade that activates clotting and the development of a provisional extracellular matrix (ECM)

33
Q

What is promoted for the recruitment of monocytes?

A

Platelet activation and degranulation also promotes blood vessel dilation and increased permeability, allowing efficient recruitment of inflammatory monocytes to the site of tissue injury, where they differentiate into macrophages and become activated by various cytokines, such as interferon-γ (IFNγ), that are released from neighbouring inflammatory cells, including neutrophils, natural killer (NK) cells, resident tissue macrophages and T cells.

34
Q

What can contribute to the activation of dendritic cells?

A

Pattern recognition receptor engagement can also contribute to the activation of resident dendritic cells (DCs) and recruited monocytes

35
Q

What do macrophages display in the initial leukocyte migration phase?

A

During this initial leukocyte migration phase, inflammatory macrophages often display an M1-like phenotype, producing nitric oxide (NO), reactive oxygen species (ROS), interleukin-1 (IL-1) and tumour necrosis factor (TNF), which are important components of the antimicrobial arsenal

36
Q

What facilitates recruitment of inflammatory cells to the site of tissue injury?

A

Secretion of matrix metalloproteinases (MMPs) such as MMP2 and MMP9 by inflammatory M1 macrophages also helps to degrade the ECM, facilitating the recruitment of inflammatory cells to the site of tissue injury.

36
Q

What facilitates recruitment of inflammatory cells to the site of tissue injury?

A

Secretion of matrix metalloproteinases (MMPs) such as MMP2 and MMP9 by inflammatory M1 macrophages also helps to degrade the ECM, facilitating the recruitment of inflammatory cells to the site of tissue injury.

37
Q

What happens if the tissue damage continues?

A
  • If the tissue-damaging irritant persists, activated M1 cells can further exacerbate the inflammatory response by recruiting large numbers of T helper 17 (TH17) cells and neutrophils, leading to substantial tissue damage

-The damaged epithelial cells also release alarmins, including IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), which induce IL-4 and IL-13 secretion by a variety of innate and adaptive immune cells, including nuocytes, mast cells, basophils and TH2 cells. When the inflammatory stimulus or pathogen is eliminated

38
Q

What happens in the final stage of wounding response

A
  • In the final stages of a wounding response, macrophages take on a regulatory/suppressive phenotype, which is characterized by the expression of arginase 1 (ARG1), resistin-like molecule-α (RELMα), programmed death ligand 2 (PDL2) and IL-10, which have all been shown to facilitate the resolution of wound healing and restore homeostasis while limiting the development of fibrosis, in part by suppressing T cell proliferation and collagen synthesis by activated myofibroblasts.

-M2 macrophages also promote the resolution of wound healing by antagonizing inflammatory M1 responses

39
Q

Characteristics of macrophages

A

Macrophages have high degree of plasticity, numerous phenotypes exist, broadly classified into M1, M2 and regulatory macrophages

A10HA (18 decks)

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