Inflammation, Macrophages, & Neutrophils

Inflammation

A concerted action between various mediators, inflammatory enzymes and vascular response mechanisms

Defensive cells

Once sentinel cells recognize invaders, signals are generated that activate and attract ____ cells to the site of invasion

Dendritic cells, mast cells, eosinophils, neutrophils, macrophages and lymphocytes

Cell types involved in inflammation

Innate immunity

Type of immunity where there are molecules and cells that distinguish host from infectious agents by recognizing conserved motifs

Adaptive immunity

Type of immunity where there are cells with exquisitely specific receptors for a potentially unlimited number of targets

Macrophages, neutrophils and dendritic cells

Which cells are known as the phagocytes of innate immunity?

Eosinophils, basophils, mast cells and natural killer cells

Which cells are known as the granulocytes of innate immunity?

B and T cells

Adaptive immunity cell types

Damage associated molecular patterns; these are used internally to recognize invaders

What does DAMPS stand for and what do they do?

Pathogen associated molecular patterns; these are used externally to recognize microbial invaders

What does PAMPS stand for and what do they do?

-Immunological reactions

-Nutritional imbalances

-Genetic defects

-Hypoxia

-Microorganisms

-Chemical agents

-Physical agents

What are some things that DAMPS are involved in?

T

T/F - All PAMPS are DAMPS but not all DAMPS are PAMPS

F; they are essential to survival of the microorganism though

T/F - PAMPS are found on normal host animal tissue

Nonspecific (these receptors are called Toll-like receptors)

Are PAMPS receptors specific or nonspecific?

T; this ensures that the correct response is elicited to fight that pathogen

T/F - Stimulation and triggering of different TLRs will lead to different signal transduction pathways depending on the nature of the PAMP causing the response

1) Receptor binding triggers signal transduction pathways

2) This leads to new gene activation

3) This in turn leads to inflammatory cytokine production and release

What are the following steps after something binds to a TLR (toll like receptor)?

Sentinel cells

Cells of inflammation that detect invaders or tissue damage

Cytokines and other substances that cause necessary vascular changes and attract and activate phagocytic cells

What do sentinel cells release?

Vasodilation (THINK: this is why you see redness, warmth and swelling with acute inflammation - due to the increase in blood flow to the area)

Vaso____ is the hallmark of acute inflammation

Neutrophils and then the second ones to arrive are macrophages

Which cells are the first cells to arrive to inflamed areas?

1) Macrophages

2) Dendritic cells

3) Mast cells

What are the three types of sentinel cells that are also known as being part of the mononuclear macrophage system?

Cytokines

What do mast cells produce?

TNFa and IL-1

Which cytokines activate endothelial cells?

IL-6

Which cytokine activates acute phase protein synthesis by the liver?

Chemokines

Which cytokine regulates cell movement?

TNFa, IL-1, IL-6 and chemokines

Which specific cytokines are made from the macrophages?

IL-1, IL-6 and chemokines

Which specific cytokines are made from endothelial cells?

Macrophages, NK cells and T cells

What is the source of TNFa?

TNFa, IL-1 and IL-6

Which cytokines are known as the pro-inflammatory cytokines?

Systemic effects

Inflammatory cytokines have ____ effects

Fever (pyogen)

Inflammatory cytokines stimulate the hypothalamus to produce prostagaldins into what?

acute-phase proteins

Inflammatory cytokines stimulate the liver to produce ____

T; this can include septic shock and cachexia. They can also cause sickness behavior such as loss of appetite, lethargy and protein catabolism (muscle wasting)

T/F - Inflammatory cytokines are responsible for clinical illnesses

-Promotes inflammation

-Activates cells

-Enhances collagen synthesis, bone resorption and fibroblast growth

-Toxic effects such as killing tumor cells, septic shock, sickness behavior and altered lipid metabolism

How does TNF alpha affect the body?

-Affects metabolism

-Affects blood flow

-Affects cell growth

-Affects leukocytes

-Kills cells

-Promotes inflammation

-Affects the brain

How does IL-1 affect the body?

-IL-6

-IL-1

-TNFa

Which factors are responsible for acute-phase response?

IL-1

Interleukin that is a co-stimulator of Th2 cells

IL-6

Interleukin that promotes B cell differentiation

TNFa

Cytokine that stimulates T cell growth

It stimulates hepatocytes to produce acute-phase proteins

How do IL-1, IL-6 and TNFa affect the liver?

When there is a response to severe infections or massive tissue damage where there are very large amounts of cytokines and oxidants escaping into the blood stream causing a lethal form of shock

What is systemic inflammatory response syndrome (SIRS)?

Activated macrophages, endothelial cells and other types of cells

What are the sources of chemokines?

Attract leukocytes to sites of infection, stimulates actin polymerization/depolymerization and increase expression of adhesion molecules (B-integrins) on leukocytes

What are the actions of chemokines?

-Loss of appetite

-Fever

-Depression

-Neutrophilia

-Acute phase protein response

What are the systemic effects of chemokines?

T

T/F - illness is part of the response of the body to inflammatory stimulus

-Mast cells

-Macrophages

-Dendritic cells

Which cells secrete IL-1, IL-6, TNFa and HMGB-1?

Stimulates neutrophil production from bone marrow

How do cytokines affect the bone marrow?

-Activation of immune system (innate and specific immunity)

-Increased liver function

-Active excretion of toxins

-Bacteriostatic and bactericidal effects

What are the positive things associated with a fever?

-Functional overload of organs (lungs, heart, endocrine glands)

-Hypohydration and blood hemolysis may lead to disturbances of blood clotting

-Disturbances of GIT function due to increased level of toxic substances

What are negative things associated with a fever?

Increase in a1, a2 and B serum protein fractions

What is the lab diagnosis of inflammation?

Produced by the liver and it rises when there is inflammation throughout the body (*indicator of inflammation) (Binds to surface of dying cells and activates the complement system, promoting phagocytosis by macrophages which clears necrotic and apoptotic cells and bacteria)

What is C-reactive protein (CPR) and when does it rise?

-TGFb

-IL-10

What are the anti-inflammatory cytokines?

-TNFa

-IL-1

-IL-6

-chemokines

What are the pro-inflammatory cytokines?

1) Arterioles dilate, increasing blood flow to the affected area

2) Capillaries become more permeable, allowing extra fluid plus large serum proteins to escape the blood

3) Leukocytes migrate through venule walls into extravascular tissue (exudate)

What are the 3 vascular changes due to inflammation of the small blood vessels in the area of infection?

1) Pain

2) Redness and Heat

3) Swelling

4) Loss of function

What are some signs associated with inflammation?

Vasodilation and therefore inflammation

What do prostaglandins promote?

Phospholipases (enzymes that breakdown the cell membrane)

What do steroids inhibit in the arachidonic acid cascade?

1. Margination

2. Rolling

3. Integrin activation by chemokines

4. Stable adhesion

5. Migration through endothelium

What are the steps of the leukocyte adhesion cascade?

Cytokines such as TNF and IL-1, macrophages

In the leukocyte adhesion cascade, margination is facilitated by what chemical messenger? What produces these chemical messengers?

Rolling

Glycoproteins of leukocytes interact with selectins

Integrin activation by chemokines

Integrins change to a high affinity state

Stable adhesion

The integrin ligands stop the leukocytes at the site of injury

CD31

What modulates the leukocyte's migration through the endothelium?

Neutrophils

What WBC is the most abundant in most species?

Neutrophils

_____________ are the first cells to arrive and they deal with most if not all of the invading organisms

Macrophages

_____________ follow neutrophils and deal with the remaining invaders and also clean up the mess

Neutrophil NETs

Neutrophils release histones concentrated with proteolytic enzymes that surround an antigen and kill it

NETosis

Slow cell death of neutrophil when producing NETs

Non-lytic NETosis

Rapid release of NETs from live cells

1. NADPH to NADP+

2. Nitrogen oxides used to convert oxygen to superoxide anion

3. Superoxide dismustase converts to hydrogen peroxide

4. Myeloperoxidase converts chlorine to hypochlorite (which kills microbes)

What are the steps of respiratory burst in neutrophils?

T

T or F: Neutrophils contain both primary and secondary granules

T

T or F: Neutrophils can only phagocytose once and then they have to be removed by a macrophage

F

T or F: Macrophages can only phagocytose once

Bone marrow

Where are macrophages produced?

Myeloid stem cell

Macrophages arise from what?

Monocytes

Before macrophages are macrophages, what are they in the blood?

Microglia

Macrophages in brain

Histiocyte

Macrophage in connective tissue

Dendritic cell

Specialized type of monocyte that displays antigens on its cell surface and presents them to components of the immune system

Osteoclast

Macrophage in bone

Kupffer cell

Macrophage in liver

Alveolar macrophage

Macrophage in lung

Acute phase responses (fever and pain)

IL-1 produced by macrophages is involved in stimulating what?

1. Stimulates T cell growth (part of adaptive immunity)

2. Stimulates acute phase response

3. Triggers inflammation

TNFA produced by macrophages has what actions?

Cytokines

All resting macrophages are activated by what?

Killing

M1 macrophages function

Repairing

M2 macrophages function

IFN-y (gamma)

What causes classical activation of a macrophage to an M1 cell?

IL-4, IL-13, and IL-10

What causes alternate activation of a macrophage to an M2 cell?

1. Chemotaxis

2. Adherence

3. Ingestion

4. Digestion

Steps of phagocytosis

Find-me signals

LPC is an example of what?

Monocytes, tissue macrophages, other phagocytes

Find-me signals recruit what cells?

Phagocytosis

___________ is triggered by the binding of a pathogen to receptors on the surface of the phagocyte

T

T or F: More than one receptor must be triggered in order to initiate the phagocytic response

Opsonization

Binding of antibodies or complements to bacteria that make them susceptible to phagocytosis

Opsonins

Antibodies and complement molecules that tag particles to be ingested

FC receptors

Receptors on the phagocyte's surface that specifically bind to antibodies

Phagosome

Intracellular vesicle containing antigen taken up by phagocytosis

Phagolysosome

Intracellular vesicle formed by fusion of a phagosome with a lysosome, in which the phagocytosed material is broken down by degradative lysosomal enzymes

Phagolysosome

If this structure does not form, the microbe will not die even if it has been phagocytosed