VMED 5172 - Macrophages

- Detecting pathogens (main sentinel cells**)

- Mounting initial immune response

- Mopping up debris after immune response

What are the general roles of macrophages in the whole of the immune response?

resident

Tissues (esp. those more exposed to pathogens - skin, gut, lungs) have ________________ macrophages that act to sense the presence of antigens and created the right environment for dendritic cells to bring antigens to the lymph nodes for the adaptive response

simple answer - blood monocytes

more accurate - depends on the disease state (more recruited from blood, but could be resident macrophages already in the tissues)

Where do macrophages come from?

- Resident macrophages arrive in tissues during embryogenesis (homeostatically maintained within tissues)

- Blood monocytes remain in circulation - until told to migrate to a tissue with insult

What are the general locations of resident macrophages and monocytes in health (how did they get there)?

•Blood monocytes enter the tissue and become macrophages

•Resident macrophages can also proliferate in response

What to the blood monocytes and resident macrophages of tissues do in response to inflammation?

blood

Monocytes are referred to in the _____________, not in the tissue where they have differentiated into macrophages

1. Early recognition of pathogens and tissue damage (sentinel cell) - Via pattern recognition receptors (PRRs)

2. Promoting inflammation - Via production of cytokines and chemokines

3. Phagocytosis - Via phagocytic receptors and production of bactericidal agents (most efficient)

4. Tissue repair and wound healing - Via promotion of angiogenesis and fibrosis

What are the 4 main functions of macrophages?

- TLRs

- RIG-1 like receptors

- NOD-like receptors

- Lectins

- Dectins

- Mannose receptors

What examples of some PRRs that macrophages possess that help them in the early recognition of pathogens and tissue damage (sentinel cell functions)?

- IL-1

- IL-6

- TNF-alpha

What are the classic proinflammatory cytokines that can be released by macrophages if triggered to promote inflammation?

IL-12

What is a cytokine produced by macrophages that can help trigger the adaptive (cell-mediated) immune response (adaptive and innate working together)?

- CXCL1/CXCL2 = neutrophils and HSC

- CCL5 (RANTES) = T cells and dendritic cells

- CXCL8 (IL8) = neutrophils**

- CXCL9 – 11 = T cells

What are some of the chemokines released by macrophages to recruit other immune cells to a tissue?

IL-8 produced by macrophages recruits neutrophils, neutrophils release chemokines that recruit more macrophages

How do the release of chemokines from macrophages and other immune cells create the exponential effect of inflammation in a tissue (give an example)?

phagocytic

Macrophages are the major _________________ cell in the tissues (others incl. granulocytes and dendritic cells)?

1. Activation

2. Chemotaxis

3. Adherence

4. Ingestion

5. Destruction

What are the 5 main steps in phagocytosis?

PRRs

Activation of macrophages can be by PAMPs and DAMPs binding ____________ on the cells, resulting in another positive feedback as these also activate other immune cells

- Neutrophils at the site of inflammation produce macrophage chemoattractants: zurocidin, defensins, cathelicidins

- Monocyte chemoattractant protein-1 (MCP-1; CCL2) - endothelial cells and neutrophils

- Dying neutrophils release additional chemoattractants (changes phenotype of macrophages to be more wound healing than proinflammatory)

What are examples of chemo attractants produced by other immune cells recruiting macrophages?

- Complement receptors

- Fc receptors (antibodies)

What are the main receptors on the macrophages that allow them to bind (adhere) to the pathogens marked by opsonins (complement proteins, antibodies)?

- Organism becomes enclosed in a vacuole termed a phagosome.

- Phagosome fuses to a lysosome to form a phagolysosome.

How do macrophages ingest/digest pathogens after binding?

•Oxidative mechanisms (via nitric oxide (NO))

•Non-oxidative mechanisms

What are the two types of ways macrophages can digest pathogens within the phagolysosome?

Nitric oxide pathway

- Nitric oxide synthase (iNOS) expression is induced by macrophage activation

i- NOS (aka NOS2) induces ↑ nitric oxide (NO) production from arginine

How can more reactive oxygen species be created within the phagolysosome?

Arginine pathway (more arginase = a macrophage more designed for wound healing, more iNOS = more of a killer macrophage)

What pathway can be followed to make less reactive oxygen species within the phagolysosome?

- Elastase and cathepsins

- Lysozyme

- Proteases

- Acid hydrolases

- Myeloperoxidase

- Lactoferrin

What are non-oxidative mechanisms (enzymes) that help digest pathogens in the phagolysosome?