Monocytes/Macrophages

what are the three main properties of monocytes?

- round w/ kidney shaped nucleus
- phagosomes/lysosomes for phagocytosis and killing
- circulate 3 days and then enter tissues

what are the locations of monocytes?

bone marrow (immature) and blood (mature)

what is the function of monocytes?

recruited to sites of tissue inflammation to differentiate into macrophages

what proportion of leukocytes do monocytes make up?

2-8%

what are the three main properties of macrophages?

- derived from blood monocytes
- phagosomes contain killing chemicals and proteins
- dense mitochondria and Golgi to produce extra energy and vesicles w/killing chemicals

what are some examples of macrophages in different tissues?

serosal macrophages, bone marrow macrophages, blood monocytes, liver Kupffer cells, connective tissue histiocytes, brain microglial cells

what drives both formation of monocytes and differentiation into tissue macrophages?

cytokines

what are the three main functions of macrophages?

- express pattern recognition receptors
- active phagocyte
- trap and clear particulate matterfrom circulation

what kind of macrophages do most of the work in rodents and dogs?

Kupffer cells and spleen macrophages

what kind of macrophages do most of the work in cats, horses, ruminants, and pigs?

lung pulmonary intravascular macrophages

what are the two main ways that particles are captured besides macrophages?

aerosol routes and dermal routes

what are some examples of the aerosol route of particle capture?

nose, tracheal cilia, bronchia/bronchioles, alveolar macrophages

what is the main example of the dermal route of particle capture?

antigen trapped by macrophages/dendritic cells of skin and migrate to lymph nodes to stimulate adaptive immunity

what are the two main subsets of macrophages?

classical (M1) and alternative (M2)

what causes innate activation of resting macrophages?

TLR's and related receptors

what causes classical activation of macrophages after innate activation is complete?

interferon-gamma

what are characteristics of macrophages that arose as a result of classical activation (M1)?

increased size, movement, membrane activity, lysosomal enzymes, phagocytosis, bactericidal activity, MHC class II expression, NO production

what causes alternative activation of resting macrophages?

IL-4, 13, and 10

what are characteristics of macrophages that are alternatively activated (M2)?

increased tissue repair, increased MHC class II expression, reduced microbial killing

what are the oxygen dependent mechanisms of microbial killing in macrophages?

phagosome and phagolysosome

how do macrophages kill using phagosomes?

NADPH oxidase produces superoxide anions and hydrogen peroxide

how do macrophages kill using phagolysosomes?

nitric oxide synthase 2 converts arginine to citrulline and NO which combines with superoxide anions to produce NO free radicals

what are the 4 oxygen independent microbial killing mechanisms of macrophages?

natural resistance-associated macrophage protein, lysozymes, defensins, acidic pumps

what are natural resistance-associated macrophage proteins?

transport divalent metals out of phagosome - these metals are required for bacterial survival

how do the following accomplish microbial killing?
- lysozymes
- defensins
- acidic pump

- enzyme degrades cell wall
- makes holes in cell wall
- add H ions to decrease pH

what is the role of M2 macrophages?

clean up dying/dead neutrophils, produce protease inhibitors that neutralize neutrophil enzymes, produce growth factors

what two growth factors do M2 macrophages produce?

transforming growth factors and fibroblast growth factors

what are the 5 major surface receptor types of macrophages?

transport receptors, cytokine receptors, complement receptors, antibody receptors, pathogen recognition receptors

what is the function of transport receptors in macrophages?

allow ion transport

what is the function of cytokine receptors in macrophages?

stimulate differentiation

what is the function of complement receptors in macrophages?

adhesion functionality

what is the function of antibody receptors in macrophages?

FC receptors bind the the FC region of antibodies to recognize targets for phagocytosis

what cytokines do macrophages produce?

IL 1, 6, 12, 18, and 23 and TNF-a

what is the function of the following cytokines in local inflammation?
- IL-8
- IL-1 and TNFa
- TNFa

- chemotaxis of neutrophils
- increase expression of selectins/integrins
- enhance killing of virus/bacterial/tumor cells by assembling NADPH oxidase

what effect do cytokines have on the following organs?
- brain
- liver
- bone marrow

- cause fever
- acute phase protein release
- increased myelopoeisis -> neutrophilia; decreased erythropoeisis -> anemia

what effect do the following levels of TNFa cause?
- low
- medium
- high

- local inflammation
- systemic effects
- septic shock

what is the difference between a negative and a positive acute phase protein?

positive ones increase in the blood during inflammation, whereas negative ones decrease

what are the positive APP's?

complement proteins, fibrinogen, serum protease inhibitors, iron binding proteins

what are the negative APP's?

albumin, transferrin

what happens during endotoxic shock/toxic shock syndrome?

TNFa acts on vascular endothelium normally, but in endotoxic shock, a toxin prevents macrophages from detaching from the cell that it is signaling to produce TNFa; thus, TNFa levels rise to unhealthy levels and act on the vascular endothelium to cause fever, hypotension, organ failure, and death

what is the "shock" organ of dogs and rodents? what are the clinical signs of shock in these animals?

- liver
- vomiting and diarrhea

what is the "shock" organ of cats, ruminants, pigs, and horses?

- lungs
- dyspnea (and gut in horses)

what is the main treatment option for endotoxemia?

polymyxin B binds LPS of gram- bacteria

what is the result of chronic local inflammation?

constant recruitment of more macrophages leads to more fibroblast growth factor being produced and more fibrous tissue being laid down, to eventually produce a granuloma as macrophages form a wall around stubborn organisms