Lecture 27: Neuroinflammation and Cardiovascular Function Flashcards
What are the circumventricular organs?
highly vascularised structures located around the 3rd and 4th ventricles characterised by the lack of a blood-brain barrier (BBB)
What makes circumventricular organs significant?
these areas are points of communication between the blood, brain parenchyma and CSF
What do neurons and glia in the circumventricular organs express and what do they receive?
a wide array of receptors and ion channels and receive a wide array of signals from the circulating blood
What do the circumventricular organs have a critical role in?
sodium and water balance, cardiovascular regulation, energy metabolism and immunomodulation
What does the subfornical organ play a role in?
blood pressure regulation
What is involved in the CNS innervation of sympathetic outflow?
paraventricular hypothalamic nucleus, A5 cell group, rostral ventrolateral medulla, ventromedial medulla, caudal raphe nuclei and sympathetic preganglionic nuclei
What does stimulation of the rostral ventrolateral medulla result in?
increased blood pressure and sympathetic nervous activity
The circumventricular organs (CVOs) are areas of the brain with an intact blood-brain barrier. (TRUE / FALSE)
FALSE
Where do primary afferents from the baroreceptors from the carotid sinus terminate?
nucleus of the solitary tract (NTS)
What has proven to be increased in hypertensive vs normotensive rats?
mRNA levels of pro-inflammatory cytokines in BM-derived mononuclear cells
also elevated levels of the chemokine CCL2 in the BM, serum and CSF
What happens if we substitute the bone marrow from hypertensive animals into normotensive animals?
mean arterial pressure increases in the normotensive animal
What happens if we substitute the bone marrow from normotensive animals into hypertensive animals?
mean arterial pressure decreases significantly
What changes do they see in microglia in these chimeric rats (where BM was replaced)?
activated microglia in the hypothalamic paraventricular nucleus are decreased in the hypertensive animals after reconstitution with normotensive bone marrow
What are activated microglia a sign of?
neuroinflammation
What is minocycline?
a tetracycline antibiotic used to treat bacterial infections such as pneumonia
also used in treatment of acne and rheumatoid arthritis
What is minocycline commonly used to inhibit?
microglia activation
specifically polarization to M1 phenotype
What is the result of administering minocycline to hypertensive animals but not normotensive animals?
significantly decreases blood pressure
What do pro-hypertensive signals such as angiotensin II (Ang II) activate?
PVN pre-autonomic neurons to increase sympathetic nerve activity (SNA) and cause release of C-C chemokine ligand 2 (CCL2)
How does SNA affect the bone marrow?
results in an increase in inflammatory cells (IC) and a decrease in angiogenic progenitor cells (APCs)
this imbalance is associated with vascular pathology and increase in BP
Why do inflammatory progenitors migrate to the PVN?
as a result of an increased neuronal release of CCL2 where they differentiate into BM-derived microglia/ macrophages
What happens when resting microglia and BM derived microglia / macrophages are activated?
release an array of cytokines / chemokines
Which cytokine was increased in the bone marrow, serum and cerebrospinal fluid of hypertensive rats compared to normotensive rats?
CCL2
What happened when the bone marrow from WKYs were transplanted into SHRs?
blood pressure decreased
What happened to the number of microglia in the brain when SHRs were transplanted with bone marrow from WKYs (SHR-WKY)?
there were fewer microglia compared to SHR-SHR
What is the subfornical organ and where is it located?
a CVO and lacks a BBB
located on the anterior wall of the 3V
What does the subfornical organ send projections to and why?
both compartments of the paraventricular nucleus to modulate SNA and AVP release
What does the subfornical organ show high expression of? What does stimulation of these receptors lead to?
high expression of AngII receptors and stimulation of these receptors elicits a drinking response
What are the effects of TNF-alpha in the subfornical organ?
elicits a rise in blood pressure and heart rate
What are the effects of TNF-alpha in the subfornical organ influenced by?
captopril = ACE inhibitor losartan = AT1 receptor antagonist NS-398 = selective COX2 inhibitor
What are the effects of TNF-alpha in the area postrema?
elicits an increase in blood pressure
What are the effects of TNF-alpha dependent on? What is this response abolished by?
dose
higher doses cause a larger increase in blood pressure
pre-treatment with a TNFR1 receptor specific antibody
What did microinjection of TNFR1 receptor blocking antibody into the area postrema of hypertensive animals result in?
a significant fall in blood pressure
this was not observed in non-hypertensive animals
What does primary (neurogenic) and secondary (renal stenosis, diet) cause?
an increase in circulating AngII levels which results in an increase in circulating CCL2 (MCP-1)
What does an increase in CCL2 cause in the brain?
leads to disruption of the BBB, infiltration of immune cells and activation of microglia (which release a number of inflammatory factors)
What does an increase in inflammatory factors within the brain lead to?
exacerbation of neuroinflammation which disrupts homeostasis and activates premotor neurons
this eventually leads to an increase in SNA and hypertension
What are some examples of inflammatory factors?
IL-6, TNF-a, IL-1b and CCL2
Which hormone system appears to be critical for the actions of TNF-a and IL-1b in the subfornical organ (SFO)?
the renin-angiotensin system
What are neural pathways by which gut microbiota influences the brain?
enteroendocrine cell release of gut hormones
afferent neural pathways, including the vagus nerve
stress hormones might influence bacterial gene expression, signalling between bacteria which might change microbial composition
What is an immunological pathway by which gut microbiota influence the brain?
cytokine release from mucosal immune cells
What is a metabolic pathway by which gut microbiota influence the brain?
bacterial products such as SCFA, GABA or 5-HT precursors
What does Ang II, salt or aldosterone induced hypertension lead to?
activation of microglia which drives in increase in SNA from areas such as the paraventricular nucleus of the hypothalamus (PVN)
What does an increase in SNA from areas such as the paraventricular nucleus lead to?
a change in gut microbiota and increased gut permeability which results in oxidative stress, change in microbial products, stimulation of inflammatory cells and release of cytokines -> potentially exacerbates neuroinflammation and hypertension
