Neuronális- endokrin- és immunrendszer...
Transcript of Neuronális- endokrin- és immunrendszer...
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Homeostasis 3
Árpád Dobolyi
Department of Physiology and Neurobiology, Eötvös
Loránd University
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Outline of homeostasis
1. Internal environment of living organisms and the principles of
homeostatic regulations
2. Homeostatic regulations – the endocrine system
3. Examples of physiological parameters regulated by the endocrine system
– Potassium ion level in blood plasma
– Calcium ion level in blood plasma
4. Examples of regulations involving the endocrine as well as the nervous
system
– Water balance
– Body temperature regulation
5. Homeostatic regulations by the immune system
6. The role of the nervous and endocrine systems in immune regulations
7. Principles of the behavioural control of homeostasis
– Feeding behaviour
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Immune system
Function:
– Defense against tissue damage:• Bacterial or viral infection, other pathogens
• Ischemic, traumatic damage
• Bleeding
• Tumor cells
Components:
– Barriers: skin, mucose, lung, blood-brain barrier
– Innate (or natural) immune system
– Adaptive immune system
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Innate immune system:
inflammatory processes
Not antigen-specific Antigen-specific
Has no memory Does have a memory
Works immediately Works with a latency
Linearly amplified Exponentially amplified
Comparison of innate and adaptive
immune systems
Adaptive immune system:
Does not have a threshold Does have a threshold
Which one includes more significant interaction with the endicrine and nervous system?
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5
AFR
Time course and major events of adaptive responses
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Innate immune responses can be divided into
2 steps
Step 1: inflammation Step 2: acute phasereaction (APR)
Immediate Starts with a latency
Local Systemic
Without threshold
Goal: separation and elimination of damagedtissue, regeneration
Goal: maintain inflammationbut also prevent itsspreading
Above threshold
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Initiation of inflammation (0-6 hours)
Bleeding
Thrombo-
cyte
activation
IL-1
Bacteria
Complement
activation
C5a C3a
Necrosis
Phagocyte
+ Mast cell
activation
ROI
TNF-, ILs
Lipids
IL: interleukin; ROI: reactive oxygen intermedier, TNF: tumor necrosis factor
Virus-infected
cell
Histamine, ILs
Heparin,
Lipids
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Mechanisms of the activation of phagocytes by bacteria
Resident macrophages and arriving
granulocytes are both phagocytes.
Receptors on the surface of phagocytes:
1. Pattern recognition receptors
E.g. Lipopolysaccharid (LPS; a bacterial
endotoxin) receptor: CD14(+TLR4)
2. Receptors of the complement system
3. IgG receptors
(Necrosis causes activation by Damage-
associated molecular patterns - DAMPs)
The response of phagocytes to
activation:
1. Phagocyte bacteria or necrotic cell
2. Production of cytokines
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©Fülöp AK 2010
Cytokines produced by macrophages, and their functions
What is the molecular
mechanism how cytokines
exert their effects on cells?
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Cytokine receptors
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Signal transduction of IL-1
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Leukocyte infiltration to the site of inflammation
TransendothelialMigration
Vessel Lumen
FirmAdhesion
ActivatedIntegrin
RollingAdhesion
VCAMSelectin
Expression
Leukocyte
Selectin
RestingState
InactiveIntegrin
SelectinCounter-receptor
Endothelial Cell
Subendothelial Matrix
InflammatoryStimulus
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©Fülöp AK 2010 13
Mast cell activation
results in:
1. degranulation
2. lipid mediator synthesis
3. cytokine production
Consequences:
- Vasodilatation
- Increase of tissue
permeability
- Activation of additional
cells
- Activation of
nociceptive sensory
nerve terminals
! !!
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Vasodilation by mast cells
- Mostly by histamine via G-protein-coupled receptors
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Nociceptive ascending neuronal pathways
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The role of nociceptive sensory
system in inflammation
• Materials (e.g. histamine, prostaglandins) released by
mast cells stimulate nociceptive sensory terminals, which
contributes to
– Local pain sensation (via thalamus)
– Behavioural response aimed at avoiding the use of the
inflammed area (via limbic cortex)
– Activation of stress pathways (via hypothalamus)
– Release of substance P from the sensory terminals upon
inflammation: G-protein coupled receptor of substance P is
present in macrophages, through which substance P
increases local inflammation (local action)
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Progression of the innate immune
response (6-12 hours)
Early mediators
Targets:
phagocytes,
mast cell,
endothel,
fibroblast,
keratinocyte,
TH2
Systemic
cytokines:
TNF,
IL-1,
IL-6
INFg
Liver
Bone
marrow
Adipose
tissue
CNS
Production of
proteins
Leukocytosis
Lipid
mobilisation
Fever, anti-
inflammation
Inflammation Acute phase reaction (APR)
Adaptive response
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The mechanisms of inducing fever
• Pyrogene: any substance that leads to fever
• Endogenous pyrogenes:
- Some cytokines produced by macrophages:
Interleukin 1 (α and β), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNFα)
• Exogenous pyrogenes:
- Any inflammatory reaction that activates macrophages. Bacterial lipopolysaccharide (LPS) is particularly effective in inducing fever.
Mechanism of action: Pyrogenes influence the set point of the thermoregulatory pathway.
Where is their site of action?
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Action of PGE2 on
preoptic neurons
of the
thermoregulatory
pathway
Tr. spinothalamicus
PGE2 is synthesized in
preoptic endothels in response
to cytokine hormones.
Then, PGE2 penetrates
through the blood-brain barrier
as a membrane-soluble
molecule to reach nearby
preoptic target neurons.
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Synthesis of Prosta-
glandin E2 (PGE2)
• From arachidonic acid
• Using the following enzymes:
– cyclooxygenase-2 (COX-2),
– prostaglandin E2 synthase
• Pyrogenes stimulate the
enzymes thereby inducing
PGE2 synthesis
Anti-fever drugs inhibit these
enzymes
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– Proliferation of bacteria and viruses
decreases
– T–cell proliferation increases
– Lymphocyte transformation is enhanced
– Gamma-interferon production is elevated
The effects of fever
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Progression of the innate immune
response (6-12 hours)
Early mediators
Targets:
phagocytes,
mast cell,
endothel,
fibroblast,
keratinocyte,
TH2
Systemic
cytokines:
TNF,
IL-1,
IL-6
INFg
Liver
Bone
marrow
Adipose
tissue
CNS
Production of
proteins
Leukocytosis
Lipid
mobilisation
Fever, anti-
inflammation
Inflammation Acute phase reaction (APR)
Adaptive response
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Relationship of the immune system with the
HPA (Hypothalamic-Pituitary-Adrenal) axis
Cytokine
Hypothalamus
Pituitary gland
Adrenal gland
IL1, IL6, TNF, INFg
CRH (Corticotropin Releasing
Hormone)
ACTH (Adrenocorticotropic
Hormone)
Glucocorticoid
Immune system
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Paraventricular hypothalamic nucleus
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Corticotropin-releasing hormon (CRH)-expressing neurons in the PVN
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Inflammatory cytokine hormones activate PVN
similar to other stressors
Paraventricular nucleus (PVN) – c-Fos immunolabeling
How does the action of cytokine hormones reach PVN?
They cannot penetrate blood-brain barrier and do not act via endothels like for fever.
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Activity of the vagal nerve in response to IL-1
injection
IL-1
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Circumventricular organs – humoral inputs
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The effect of
IL-1 on
neuronal
activation
(c-fos
expression)
in different
brain areas
CONCLUSION:
Cytokine
hormones reach
PVN via
viscerosensory
afferents and also
through
circumventricular
organs
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Anti-inflammatory actions of corticosteroids
Activity Effect
IL-1, TNF, GM-CSF,
IL-3, IL-4. IL-5, IL-8
Inflammation
(mediated
by cytokines)
NOS (nitric oxidesynthase)
NO, causing reducedvasodilation
Foszfolipase A2
Ciklooxygenase2
Prostaglandins,
Leukotriens, reducedfever, reduced pain
Adhesion molecules Reduced migration
Induction of
Endonucleases
Apoptosis
of limfocytes, leukocytes
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4,000-
2,000-
400-
300-
100-
10,000-
Neutrophil granulocytes
Lymphocytes
Eozinophils
Monocytes
Basophils
6 h 12 h 24 h
Cell /
mm
3The effect of glucocorticoids on the
number of leukocytes
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To eliminate unwanted immune response:
- Allergy
- Autoimmune diseases
- Organ transplant
a, Antigen-specific immune suppression – selective tolerance
b, Not-antigen- specific
• Corticosteroids (in supraphysiological, pharmacological doses)
• CY-A, FK 506, Rapamycin (T cell proliferation inhibitor)
• Radiation therapy
• Cytostatics
Immunosuppression therapy
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O
OH
O O
O
O
Cortizon
Prednizon
(4x more effective
than Cortizon)
Cortisol
Prednizolon
Synthetic products:
Natural and artificial glucocorticoids
CH2OH
C=OOH
CH2OH
C=OOH
CH2OH
C=OOH
CH2OH
C=OOH
O
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Anti-inflammatory mechanism of glucocorticoids
HSP: heat shock protein; GRE: glucocorticoid receptor element; TLR: toll-like receptor
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The effect of the sympathetic nervous system on
the immune system
Macrophages and lymphocytes possess beta 2 adrenerg receptors, which inhibit their actions
Preganglionic
neuron
Noradrenaline
Postganglionic
neuron
Nikotinic
receptor
Ach
Beta 2 adrenerg
receptor
Target
cell
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Additional effects of the sympathetic nervous
system on inflammation
- In additon to noradrenaline, dopamine and neuropeptide Y are also released from
sympathetic terminals
- Immune cells have receptors for these modulators as well, through which they
inhibit their migration, activation and proliferation, which all contribute to the
localization of inflammation
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How is the
autonomic nervous
system activated by
the immune system?
1. Local reflexes
- spinal cord for sympathetic
responses
- nucleus of the solitary tract
(NTS) for parasympathetic
responses
2. Via higher brain centers.
-E.g., the
hypothalamo-spinal tract and
other descending pathways
can also affect autonomic
functions
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©Fülöp AK 2010
Neuro-
modulation of
inflammation
1. sensory
terminal
(stimulatory)
2. sympath.
(inhibitory)
3. parasymp.
(inhibitory) via
nicotinic Ach
receptors located
on macrophages
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An additional way how the nervous system can influence the
immune system: direct (autonomic) innervation of organs
specifically involved in immune response
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Stages of microglial activation
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Model of focal ischemia in brain:
middle cerebral artery occlusion (MCAO)
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TGF-β1-positive microglia in the penumbra 1 day after MCAO
TGF-β1 in situ hybridisation histochemistry + Hsp70 immunolabeling (penumbra marker)
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Microglial cell in the infarct area 3 days after lesion
TGF-β1 in situ hybridisation histochemistry + GFAP immunolabeling (astrocyte marker)
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Acute phase reaction of the central
nervous system
Systemic cytokines activate the hypothalamus
– Systemic inhibition of the
immune system
• HPA axis
• Vegetative nervous system
– Fever
– Behavioral effects:
• No appetite
• Drowsiness
• Lack of exploratory and
sexual behaviors
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Systemic inflammatory mediators reduce appetite by
acting on hypothalamic food intake regulatory neurons
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Immune activation produces sickness behaviours,
symptomes that resemble to depression
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Outline of homeostasis
1. Internal environment of living organisms and the principles of
homeostatic regulations
2. Homeostatic regulations – the endocrine system
3. Examples of physiological parameters regulated by the endocrine system
– Potassium ion level of blood plasma
– Calcium ion level of blood plasma
4. Examples of regulations involving the endocrine as well as the nervous
system
– Water balance
– Body temperature regulation
5. Homeostatic regulations by the immune system
6. The role of the nervous and the endocrine systems in immune
regulations
7. Principles of the behavioural control of homeostasis
– Feeding behaviour
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Factors, which determine behaviour
Motivation (or drive):
The state of the brain, as to what degree an individual wants (or will) perform a particular behavioural element.
Capability:
The state of the organism whether, and to what degree an individual is able to perform a particular behavioural element.
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The COM-B model: the behaviour is formed as a
result of the interaction of 3 necessary conditions
Physical or psychological
Conscious or autonomous mechanisms,
which activate or inhibit a particular type
of behaviour
Physical or social environment,
which allows a particular behaviour
Michie et al (2011) Implementation Science
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Basic motivations:
- Physiological demands (where the goal of the behaviour is to
maintain homeostasis): e.g. hunger, thirst, feeling warm, pain,
sleepiness
- Social motivations: e.g. sexual, maternal behaviours, belonging
to a group, being understood by a conspecific
Higher order motivations:
- Emotions: e.g. fear, happiness, sadness, disgust, surprise,
curiosity, angriness
- Social emotions: e.g. proudness, jealousy, enviness, love
- Cognitive motivations: e.g. desire for knowledge, understanding
- Social cognitive motivations: e.g. teaching
Types of motivations
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Drive theory based on the temporal
alteration of basic motivations - Hull, 1952
Basic motivations, such as physiological demands (hunger,
thirsts, sexual desire) increase gradually until consummation,
during which they suddenly drop
• Deprivation of physiological demands enhances motivation,
which energetizes the organism and leads to so-called
appetitive (goal directed) behaviours.
• Reaching the goal allows consummatory behaviours, which
fulfill the physiological demand and decrease the particular
motivation.
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Time course of motivation, appetitive and
consummatory behaviours determined by the
reward according to the drive theory
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Assessing motivation in animal experiments 1.
Measuring the intensity of appetitive behaviours
Measuring the intensity of - lever pressing
- nose poke
Skinner box
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The effect of small rewards applied
experimentally in the Skinner box on the
motivation and consummatory behaviours
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Assessing motivation in animal experiments 2.
Measuring conditioned place preference
The ratio of stay in the reward-associated compartment
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Neurobiological approach to the drive
theory
Critiques of the theory:
• Not all motivation derives from physiological demand,
and more complex motivations may not decrease
during consummation (e.g. curiosity).
Testing the theory in neurobiology
• Does the theory has any neurobiological correlation
in the brain?
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Outline of homeostasis
1. Internal environment of living organisms and the principles of
homeostatic regulations
2. Homeostatic regulations – the endocrine system
3. Examples of physiological parameters regulated by the endocrine system
– Potassium ion level of blood plasma
– Calcium ion level of blood plasma
4. Examples of regulations involving the endocrine as well as the nervous
system
– Water balance
– Body temperature regulation
5. Homeostatic regulations by the immune system
6. The role of the nervous and the endocrine systems in immune
regulations
7. Principles of the behavioural control of homeostasis
– Feeding behaviour
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Ghrelin is an orexigenic (food intake
increasing) hormone
• Ghrelin is a peptide hormone comprising of 28 amino
acids
• Its receptor is the growth-hormone-secretagogue
receptor (GHS-R)
• Injection causes hunger in humans, the only such
hormone known
• Increased food intake in both human and animal
models following both peripheral and central
administration
• It is released from the stomach as soon as food is
removed from the stomach while the presence of food
inhibits its secretion
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Ghrelin serum level in human in relation
to the meals
Neil R Carlson, 2013, Physiology of Behavior
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• Blood levels of ghrelin rise in starvation and decrease
postprandially (that is after having eaten)
• Ghrelin injection in human induces hunger and increases food
intake in animals and human, too.
• Mice lacking either ghrelin or its receptor are protected from diet-
induced obesity (although the feeding behaviour does not differ
from control mice under normal feeding conditions arguing for the
existence of other important mechanisms of feeding)
Since ghrelin is the only hormone with hunger-inducing properties, it
may qualify as the orexigenic hormone responsible for
motivation of feeding.
Ghrelin, the hormone responsible for feeling hungry
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Tuberal hypothalamic region
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Target neurons of ghrelin in the arcuate nucleus
of the hypothalamus
HYPOTHALAMUS
ARCUATE NUCLEUS
NPY/AgRP
POMC/CART
+ -
GHRELIN
GHRELINRECEPTOR
OTHERNEURONS
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Thank you for your
attention!