Neuroinflammation 1 Flashcards
TNF-a is a pro-inflammatory cytokine with numerous roles. List 3 of them.
1) apoptosis
2) inducing glucose uptake & release
3) disrupting tight junctions of BBB
Distinguish between the roles of TNF-a and TGF-B.
TNF-A activates immune cells & increases BBB permeability
TGF-B inhibits immune cell activation, regulates neuroinflammation, & induces tissue regeneration
How does TGF-B signal?
It signals through Type I, II, and III receptors, activating intracellular pathways like the Smad pathway to regulate gene expression
After BBB is compromised, which cells are the first to enter?
Neutrophils are the first to infiltrate the injury site bc of their greater tendency to follow chemotaxic signals
followed by release of pro-inflammatory cytokines, ROS, and other cytotoxic molecules which can activate glial cells & increase inflammation
Where is SFO found?
On the anterior wall of the 3rd ventricle
The injection of glutamate at the RVLM causes. . .
an increase in BP and SNA
Stretch receptors are found on the aortic arch and carotid sinus. Explain how they detect increased BP and respond to it.
Via vagus nerve, they cause the release of Glu at NTS
1) excitation of AMB –> via parasympathetic system –> signals to vagus nerve –> slows heart rate and drop in BP
2) excites CVLM –> inhibits RVLM through GABAergic neurons —> reducing SNS input & lowering BP
So it doesn’t constrict blood vessels too much and lowers heart rate
SFO neurons have high expressions of which receptor?
AngII receptors
send projections to PVN
causes drinking response → regulating blood vol is critical in regulating blood pressure
SFO neurons sends projections to both compartments of the paraventricular nucleus of hypothalamus
1) mPVN → posterior pituitary → releases AVP (ADH) → conserves water, increases blood pressure
2) pPVN → RVLM → SNA (and some directly to the intermediolateral cell column of spinal cord - pre-sympathetic neurons)
Blocking TNFR1’s receptor in the AP of hypertensive rats led to….
DROP in BP
indicates TNFR1’s role in maintaining high BP
(When TNF-a was injected into SFO and AP, blood pressure increased significantly)
Injections of IL-1B into SFO also led to increases in BP
Outline the pathways by which gut microbiota can influence brain function?
1) releasing EE cell hormones
2) Releasing cytokines that can pass through BBB
3) stress-hormone (e.g. norepinephrine) induced changes in microbial composition
4) bacterial products (E.g. SCFAs, GABA)
5) afferent neural pathways (e.g. vagus nerve)
Distinguish between GF and SPF mice
GF mice - have more lba-1 cells (newly born cells) & more ramified (branched) microglia, also have higher levels of Ddit4 (gene expressed in stressed cells)
SCFA administration to GF mice restores the number of microglia to levels similar to SPF mice, decreased Ddit4 expression, and normalizes microglia morphology and function
What is the reaction that follows an increase in Ang II levels?
1) Ang II levels increase
2) Activates PVN neurons
3) Increase in CCL2
4) Changes in brain (disruption of BBB, activation of microglia)
5) Release of inflammatory factors (CCL2, TNF-A, IL-6, IL-1B)
6) Exacerbates neuroinflammation & disrupts homeostasis
7) Increase in SNA from areas like PVN
8) Increased SNA drives changes in gut permeability + gut microbiota
9) Oxidative stress, release of cytokines, stimulation of inflammatory cells
10) Increases hypertension
After Ang II levels increase causes a rise in SNA from areas like PVN, what does SNA do to bone marrow?
1) Increase in SNA affects bone marrow
2) Increase in inflammatory cells
3) Some inflammatory progenitors migrate to PVN
4) Differentiate into BM-derived microglia & macrophages
5) Release of cytokines, chemokines
6) Increased SNA activity, increased BP
