bone and fat immunity Flashcards
M-CSF
released by Osteoblasts and promotes Osteaoclasts survival and proliferation
where is RANK expressed
Pre-osteoclasts and osteoclast
OPG (Osteoprotegerin)
mainly produced by OB (but also stromal and immune cells), it acts as a decoy receptor binding RANKL and preventing its effects on RANK
RANKL
key cytokine that directs terminal differentiation of preosteoclasts to osteoclast thereby driving bone resorption
determining bone loss vs increase
mainly the balance between RANKL-RANK-OPG. Any condition that alters this ratio will be associated with bone PATHOLOGY
Osteoblast secretes
M-CSF, OPG, RANKL
RANKL is induced by
proinflammatory cytokines: IL 1, 6, 8, and INF-a and especially IL 17
RANKL is inhibited by
anti-inflammatory cytokines like IL 4, 10 (inhibit OC)
Th1 response
INF-g and activated macrophages result in pro-clastogenic and bone resorption
Th17
potent OC activators. IL 17 both directly promotes OC differentiation and proliferation and stimulates OBs to make more RANKL
normal Th1/Th2 balance
suppresses Th17 via either IL-4 or INF-g suppressing IL-17 production- good
osteoblast come from
osteochondral precursors
osteoclast come from
monocyte precursors (retain some macrophage proteries)
Rheumatoid Arthritis
IL-23-stimulus unknown- appears in high levels in synovium of a joint
Th17 cells infiltrate the synovium
IL-17 activates neighboring OC and they proliferate
The RANK/RANKL/OPG balance is pro-bone loss and causes bony erosions and loss of joint function
Osteoporosis and menopause
Premenopausal state: estrogen promotes normal OB & OC function
Post menopausal state: OPG/RANKL balance is altered
High levels of RANKL cause net increase in OC activity
Blocking RANKL with a monoclonal antibody can lead to decreased bone loss
White adipose tissue (WAT)
Super endocrine organ and critical for homeostasis
Produces hormones, chemokines and cytokines
Regulates energy storage and expenditure, body mass and immune responses.
Composed of pre-adipocytes, adipocytes, stromal/vascular cells and macrophages
2 types of macrophages in WAT
M1- pro-inflammatory
M2- anti-inflammatory
Osteopontin
Produces by activated macrophages. pro-inflammatory and potent chemotactic signal for monocytes and macrophages. recruits macrophages and converts them to M1.
Resistin
antagonist of adiponectin and promotes TNF-α and IL-6
Macrophage cytokines in WAT
Osteopontin, Resistin, IL-1,6,8 & TNF-α
adipocytes produce
adipocytokines- Leptin, Adiponectin, macrophage inhibitory cytokine, visfatin
adipocytokines
act like cytokines & hormones and have broad spectrum effects
Leptin
pro-inflammatory, incresases production of IL-1,6 and TNF-g
Adiponectin
anti-inflammatory, suppresses TNF-a and opposes leptin
Macrophage inhibitory cytokine
promotes adiponectin release and decreases inflammation
Visfatin
pro-inflammatory and pro-angiogenic
Normal (non-obese) WAT
Yin/yang relationship between inflammatory and anti-inflammatory adipocytokines with a net effect of slightly anti-inflammatory milieu in health
macrophage population in M2 phenotype
Obese WAT
loss of balance
pro-inflammatory by recruiting large # of monocytes and macrophages into it
The portal vein carries the problem into the liver and (probably) also into atheromatous plaques.
Increasing evidence that gut microbiota may have strong influence on development of obesity
How is fatty artery is “local obesity”
Cholesterol in the plaque attract M1 macrophages
Macrophages secrete CCL2 to attract monocytes and then prohibit them from exiting.
Big plaque to ruptured plaque is clinical problem of huge dimensions
CCL2
chemokine found in coronary plaques, macrophages use it to attract more monocytes to the plaque
Innate responses in the CNS
Innate immune responses in the brain are held in active suppression by microglia and Il-10 and TGF- β
2 subsets of microglia in CNS
- migrate early in development and have DC and macrophage characteristics and act like M2 Macrophages (anti-inflammatory)
They are highly branched and display little MHC - Other subset is perivascular and derived from circulating monocytes- can cause problems
Activation of the glial system by DAMPS/PAMPS causes
conversion the M2 to M1 and then they secrete pro-inflammatory cytokines
They upregulate MHC and change morphology
IL-6 in the brain
causes delirium
