Bone & Fat Immunology Flashcards
define bone homeostasis
bone formation and remodeling - a dynamic, ever changing process orchestrated by osteoblasts, osteoclasts, hormones, and immune cells
What do osteoblasts and osteoclasts differentiate from?
hematopoietic precursor –> preosteoclast –> osteoclast
mesenchymal stem cell –> preosteoblast –> osteoblast
mesenchymal stem cell –> chondrocyte
How do preosteoblasts modulate bone homeostasis?
produce RANKL which increases hematopoietic precursor and preosteoclast differentiation
How do mature osteoblasts modulate bone homeostasis?
produce osteoprotogerin which inhibits RANKLs stimulation of preosteoclast differentiation
What does RANK stand for?
Receptor Activator of Nuclear factor kB
What family are RANK and RANKL part of?
TNF-alpha superfamily
What does RANK and RANKL signaling regulate?
formation of multi-nucleated osteoclasts from their precursors
multinucleated osteoclast formation and survival in normal bone remodeling and in a variety of pathological situations
What does osteoprotogerin (OPG) do?
protects the skeleton from too much bone resorption by binding RANKL and preventing it from binding to its receptor, RANK (a soluble decoy)
What is an important determinant of bone mass and skeletal integrity?
RANKL/OPG ratio
What mediates communication between OB, OC, and immune cells?
RANK-RANKL
What promotes OC survival and proliferation, and what releases it?
OB release M-CSF which promotes OC survival and proliferation
What expresses RANK?
expressed on Pre-OC and OC
What kind of signal is RANKL?
a cytokine
What determines bone formation?
ratio between OPG and RANKL
What can lead to a bone pathology?
any condition that alters or promotes OC dominance
How does Wnt modulate bone homeostasis, and what regulates it?
Wnt promotes MSC and preosteoblast differentiation, and inhibits formation of chondrocytes
Wnt also suppress osteoclast-mediated bone resorption by down regulate expression of RANKL, and upregulation of OPG
DKK-1 is negative regulator of WNT/beta catenin pathway, preventing formation of mature osteoblasts
What produces OPG?
OB/Osteocytes
What external sources can express RANKL?
many innate and adaptive immune cells, including monocytes, neutrophils, DCs, T and B cells
What external sources can induce RANKL, and what does it promote?
proinflammatory cytokines IL1, IL6, IL8, TNF-alpha and especially IL17 induce RANKL and promote OC differentiation
What external sources inhibit OC differentiation?
anti-inflammatory cytokines such as IL4, IL10
What do sex hormones do?
maintain bone homeostasis
What does a Th1 response do in bone?
associated with INF-gamma and activation of macrophages. The result is pro-clastogenic and bone resorption
What does a Th17 response do in bone?
potent OC activators
What inhibits Th17 response in bone?
a normal Th1/Th2 balance
What is greatly increased in the synovium of joints in rheumatoid arthritis?
IL23
discuss the etiology and result of rheumatoid arthritis
Th17 cells infiltrate the synovium, release IL17 which activates neighboring OC which proliferate.
The RANK/RANKL/OPG balance is pro-bone loss and causes bone erosions and loss of joint function
How does PTH modulate bone homeostasis?
Chief cells synthesize PTH in response to low Ca which promotes the expression of RANKL and M-CSF by osteoblasts.
RANKL promotes osteoclast differentiation and maturation.
M-CSF promote osteoclast differentiation and function
What is a drug that treats rheumatoid arthritis, and how does it work?
Denosumab: soaks up RANKL preventing osteoclast proliferation
What sex hormone promotes normal OB and OC function, and when is this altered?
estrogen
post-menopause can result in an altered OPG/RANKL state
What is pannus?
inflammatory synovial tissue that is a source of cytokines that mediate bone loss
Adipose tissue is the largest what?
endocrine organ
What does adipose tissue produce?
wide array of hormones that act like cytokines and vice versa
What is white adipose tissue (WAT)?
super endocrine organ that is critical for homeostasis
What does WAT produce?
hormones, chemokines, cytokines
What does WAT regulate?
energy storage and expenditure, body mass, and immune responses
What is WAT composed of?
pre-adipocytes, adipocytes, stromal/vascular cells, and macrophages
What are the WAT communicators?
macrophages
What are the 2 major types of macrophages and what do they do?
M1 is pro-inflammatory
M2 is anti-inflammatory
What are the macrophage-derived cytokines in WAT and what do they do?
Osteopontin: pro-inflammatory and a potent chemotactic signal for monocytes and macrophages
Resistin: antagonist of adiponectin
IL1, IL6, IL8, TNF-alpha
What kind of cytokines do adipocytes release, and what do they do?
Adipocytes produce adipocytokines that act like cytokines & hormones and have broad spectrum effects
What are some adipocytokines and what do they do?
leptin: pro-inflammatory
adiponectin: anti-inflammatory
macrophage inhibitory cytokine is TNF-like, but promotes adiponectin release
visfatin: pro-inflammatory and pro-angiogenic
What occurs in normal (non-obese) WAT?
yin/yang relationship between inflammatory and anti-inflammatory adipocytokines with a net effect of slightly anti-inflammatory milieu in health
What occurs in obese WAT?
WAT becomes proinflammatory by recruiting large amounts of macrophages and monocytes into it
portal vein carries the problem to the liver and into atheromatous plaques
How do macrophages regulate adipogenesis?
through WNT5a and TNF-like cytokines
What is SFRP5, and what does it do?
Secreted Frizzled-Related Protein 5
membrane receptor for WNT proteins
SFPR5 is increased in obesity and metabolic syndromes
What, in theory, should lead to weight loss?
suppression of inflammation
What can a fatty artery be described as?
local obesity
What does cholesterol in an atherosclerotic plaque do?
attract M1 (pro-inflammatory) macrophages
What do macrophages attracted to an atherosclerotic plaque do?
secrete the chemokine CCL2 which attracts monocytes and prevents them from leaving
What cytokines do M1s produce?
Th1 response: IL1,6,8,TNF-alpha
What cytokines do M2s produce?
Th2 response: IL4,10,13
What is adiponectin?
anti-inflammatory - insulin sensitizer
What else does leptin do?
appetite control at the level of the CNS
What are the most abundant adipocytokines?
leptin and adiponectin
What actively suppresses immune responses in the brain?
microglia, IL10, and TGF-beta
discuss the two subsets of microglia in the brain
one migrates early in development, had DC and macrophage characteristics, and act like M2 macrophages. They are highly branched and display little MHC
the other subset is perivascular and are derived from circulating monocytes
What are the innate immune cells of the CNS?
microglia
astrocytes: participates with endothelial cells to maintain BBB
oligodendrocytes: participates in myelinating axons in CNS (dif from schwann cells in PNS)
What happens when the glial system is activated?
neuroinflammation: PAMPS and DAMPS activation leads to M2 to M1 conversion, the secretion of pro-inflammatory cytokines, the upregulation of MHC, and changes in morphology
What do CD8 and Th17 activated glia produce and what does that result in?
IFN-gamma, TFN-alpha, and IL17 act on endothelial cells and astrocytes. This result in the activation of NF-kB which drives IL6 production. IL6 acts on astrocytes and endothelial cells in an autocrine fashion to amplify the NK-kB response and IL6 production
How do neurons stabilize the inflammatory response?
by secreting neurotransmitters
What are some clinical implications of neuroinflammation?
Pro- inflammatory cytokines, especially IL-6, have potent effects on neural function and survival
May be important cause of delirium, long term traumatic brain damage
