lecture 4 Flashcards
function 1
recruited to inflammation site after neutrophil
- destroy any surviving microbes through oxidative/nonox mechanisms (finishers!)
function 2
phagocytose dead or dying neutrophils
- prevent any tissue damage that is caused by neutrophil enzyme
function 3
secrete cytokines/chemokines which initiates a local and systemic response
function 4
generate nitric oxide - powerful oxidizing agent
function 5
remove foreign particles from bloodstream and respiratory tract
function 6
initate repair of damaged tissues
function 7
essential antigen presenting cells (APCs) for the adaptive immune system
blood cell count
2-8 % of WBC - 0-800
monocyte properties
- round w kidney shaped nucleus
- phagosomes/lysosomes for phagocytosis and killing (not the best at monocyte stage)
- circulate 3 days then enter tissues
monocyte location
bone marrow (myelopoesis) blood (released from bone marrow to circulate)
monocyte function
recruited to the sites of tissue inflammation to become macrophages
macrophage properties
- derived from blood monocytes
2. phagosomes that contain killing chemical and proteins (higher than monocytes) - good!
macrophage location/subsets
brain: microglial connective tissue: histiocytes lung: alveolar macrophages, intravascular macrophages liver: kupffer cell lymph node: macrophage spleen: macrophage blood: monocyte bone marrow: macrophage (osteoclast) serosa: macrophage dendritic cell!
macrophage function
key sentinel
express PRR to act as radar (eyes) to react and recombine pathogens
active phagocyte
trap and clear particulate matter from the blood circulation
can see from injected mouse that the liver and spleen macrophages take up particulate dye
bacterial/particle clearance from the blood
differs among species
kupffer cells (liver) and macrophages in spleen - dogs and rodents
lung pulmonary intravascular macrophages - cats, horses, ruminants, pigs
aerosol route - nose, tracheal cilia, bronchia and bronchioles, alveolar macrophages in lung
dermal route - antigen trapped by macrophages/dendritic cells of skin then migrate to lymph nodes (to training! nearest to site of infection) which will stimulate an adaptive immunity
M1 series
resting macrophage -> TLRs and related receptors (alarmins, cytokines etc) from inflammation -> innate activation (^ lysosomal enzymes, phagocytosis, membrane receptors, protease secretion) -> IFNg (through IL12 which stimulates NK to release IFg) -> classical activation of M1 (^ size, movement, membrane activity, lysosomal enzymes, phagocytosis, bactericidal activity, MHC class 2 expression, NO production!)
M2 series
resting macrophage -> IL4, IL13, IL10 -> alternative activation (^ tissue repair, MHC class 2 expression, reduced microbial killing)
happens after M1s do their job when the inflammation is lower these come in!
M1 o2 dependent killing
oxygen dependent (similar to neutrophil + NOS)
phagosome: NADPH oxidase - superoxide anion & H202
phagolysosome: NOS2 (oxidizes arginine to citrulline and NO! NO combines w superoxide anion to produce NO free radicals (BIG killers of microbial)
NOS2 is unique to M1
M1 nonO2 dependent killing
natural resistrance associated macrophage protein (NRAMP) - M1 only
- transports divalent metals out of phagosome which inhibits the bacterias metabolic mechanism = death! and this is helpful if bacteria is resistant to NOS
lysozyme: proteolytic enzyme degrades cell wall
defensins (cationic peptides): makes holes in pathogen cell wall
acidic pump: add H+ ions and reduce pH
siderophore on bacteria and binds metals to keep to eat but NRAMP better!
M2 function
clean up dying/dead neutrophils (die every 24 hrs)
produce protease inhibitors to neutralize the neutrophil enzymes (elastase)
produce growth factors (TGF, FBF)
neutrophils have increased number at the site of infection
major macrophage surface receptors
cytokine (CD25 - interleukin 2) complement receptors (CR3/CD11b/18, CRI/CD35) antibody receptors (CD16/FcgRIII, CD32/FcgRII, CD64/FcgRI) transport receptors (CD71 - transferrin) other (TLR2 & TLR4 - PAMPs, CD40)
complement receptors are well sutied to efficiently take up the opsonized pathogens
opsonization: antibody to FcgR’’ receptors which initiates the opsonization uptake
antibody and complement receptors injections decrease the bacteria in blood by 5ish minutes compared to no antibody the bacteria is never removed
cytokine production by macrophage
interleukin 23 interleukin 1 interleukin 6 interleukin 12 interleukin 18 tumor necrosis factor a
all are considered cytokine receptors
IL23
cytokine produced by macrophage that stabilizes Th17 cells
IL1
cytokine produced by macrophage that costimulates Th2 cells
stimulates acute phase responses
increases expression of selectins and integrins
IL6
cytokine produced by macrophage that promotes B cell differentiation
stimulates acute phase responses
IL12
cytokine produced by macrophage that costimulates Th1 cells
stimulates NK cells to release IFNgamma which activates macrophage!
IL18
cytokine produced by macrophage that promotes IFNgamma production by Th1 cells - activating macrophages
TNFa
cytokine produced by macrophage that is cytotoxic
stimulates Tcell growth
stimulates acute phase responses
triggers inflammation
enhance killing of virus/bacterial (LPS) infected cells and tumor cells by assembling NADPH oxidase!!
increase expression of selectins and integrins w IL1
IL8
cytokine that is involved in local inflammation (w IL1 & TNFa) that attracts neutrophils through chemotaxis
systemic inflammatory response from TLR4 macrophage as result of LPS
LPS is PAMPs that binds to TLR4 PRR on macrophage:
- IL1, TNFa, IL6 -> brain -> ^ prostaglandins (vasodilation and smooth muscle relaxation - inflammation) -> fever
- IL1, TNFa, IL6 -> liver -> acute phase proteins (leukotrienes can use this value to see if sick in blood)
- IL1, TNFa, IL6 -> effect bone marrow; ^ release & myelopoieses -> neutrophilia or _ erythropoiesis -> anemia
TNFa biological actions at diff levels
low (<10^-9): local inflammation - endothelial cell has adhesion molecules and is producing IL1 and chemokines, leukocyte activation
medium: systemic effects - brain (prostaglandins - fever), liver (acute phase proteins), bone marrow (leukocytes released & decreased RBC)
high (>10^-7): septic shock - heart (low Q), blood vessel (low pressure w thrombosis and low resistance), liver (hypoglycemia - high sugar)
acute phase proteins
positive: concentration in blood increases
- complement proteins (many functions; chemotaxis, vascular changes - takes care of business!)
- fibrinogen (blood coagulaent)
- serum protease inhibitors (dampen enzyme activity of neutrophils - elastase)
- iron binding proteins (lactoferrin! - tie up iron so bacteria cant nibble on it)
negative: concentration in blood decreases
- albumin (stabilizes blood, a decrease will disregulate blood and lower bp)
- transferrin (transports iron into tissues)
endotoxic shock
bacterial endotoxin (LPS PRR) -> TLR4/CD14 on macrophage -> IL1, IL6, TNFa, CCL8, NO -> fever, acidosis, hypotension, complement activation, intravascular coagulation, endothelial damage (ACT ON VASCULAR ENDOTHELIUM) -> multiple organ system failure -> death
toxic shock syndrome
macrophage is bound to Th cell by staphylococcus aureus toxins -> overproduction of IL2 & IFNgamma -> secondary overproduction of IL1 & IFNgamma -> rash, fever, hypotension, organ failure -> death
