Homeostasis 3

Árpád Dobolyi

Laboratory of Molecular and Systems Neurobiology,

Department of Physiology and Neurobiology, Eötvös

Loránd University

Outline of the lecture

1. Internal environment of living organisms

2. Homeostatic regulations – the endocrine system

3. Examples of homeostatic regulations not

requiring the nervous system

4. Homeostatic regulations – nervous system

5. Examples of regulations involving the brain

– Water balance

– Body temperature regulation

6. Homeostatic regulations – immune system

7. The role of the nervous system in immune

regulations

Heat produced by basal metabolism

Energy produced by basal metablism leaves the body in the form of

heat. It depends on the size of the animals:

- Heat produced by bigger animals is larger

- Heat produced per body weight decreases with the size of the

animal

Rubner’s surface area law: heat produced by the basal metabolism

of animals is proportional with their surface area rather than their

body weight.

More precisely: Heat produced by basal metabolism is proportional

to W0.75 , where W is the body weight. Thus, heat production is 290

KJ/W0.75, and does not depend on the individual or the species.

Factors determining heat balance of animals

Animals with

constant body

temperature thrive for

heat balance:

Heat loss =

heat taken from the

environment + heat

produced by the body

Red color:

controlability

1. In response to small alterations from set point body temperature, animals first change the circulation of the skin:

• If ambient temperature decreases, skin arterioles contract thereby decreasing heat dissipation

• If ambient temperature increases, skin arterioles dilatate thereby increasing heat dissipation

Body temperature control 1.

In response to larger alterations from set point body temperature:

A. In cold environment

• Heat production by the brown adipose tissue is activated

• Muscle contraction can further increase heat production

(shivering)

• Activation of thyroid hormone production increases metabolism

by enhancing cellular oxidation

• Appropriate behavioral changes

B. In warm environment

• Enhanced ventillation of the lung

• Sweating starts, water evaporates from the skin

• Appropriate behavioral changes

Body temperature control 2.

Mechanism of heat production in brown adipose tissue

If the inner membrane of mitochondrium leaks H-ions then heat is produced instead of ATP

If previous measures were insufficient and body

temperature alteration is life-threatening:

A. In cold environment

• Due to the activation of stress axis, cellular metabolism is

further increased

B. In hot environment

• Heart frequency and blood circulation increases

Body temperature control 3.

Slower adaptations to changes of long-time

alterations of ambient temperature:

1. Alterations of thermal insulation:

- adiposity depos build up

- Changes of outer integument

(e.g. seasonal changes of hair, feather)

2. Appropriate behavioral changes

Body temperature control 4.

Temperature receptors: transients receptor potential (TRP) channels

Etain A. Tansey, and Christopher D. Johnson Advan in Physiol Edu 2015;39:139-148.

Temperature receptors (TRP channels) are located

on free (or bare) nerve terminals in the skin

Thin myelinated (Aδ) or

unmyelinated axons (C)

A

C

A A

A termosensitive (cold) fibers

termination: lamina I

lamina IIa

lamina V

C termosensitive (warm) fibers

termination : lamina IIb

Termination of heat-

sensitive primary

afferents in the

spinal cord

Pathways of heat sensation and heat

localization (only ascending)

- spinothalamic tract

- trigeminothalamic tract

Thermoregulatory pathways

- ascending and descending

Pathways of thermal stress (only descending)

Neuronal pathways carrying temperature

information

The ventral

posterolateral

nucleus of the

thalamus (VPL)

relays sensory

inputs from the

body to the

cerebral cortex

Thermoregulatory

pathways

DH: dorsal horn of spinal cord

LPB: lateral parabrachial nucleus

POA: preoptikus terület

MnPO: median preoptic nucleus

MPA: medial preoptic area

CVC: cutaneous vasoconstrictor

W-S: warm-sensitive

DMH: dorsomedial hypothalamic nucleus

rRPA: rostral raphe pallidus

VH: ventral horn of spinal cord

IML: intermediolateral cell column

BAT: brown adipose tissue

Lateral parabrachial nucleus (LPBN)

scp: superior cerebellar peduncle = brachium superior

Heat-sensitive neurons in the preoptic region of the hypothalamus

•: Cells reacting to central and peripheral change of temperature

Summation of peripheral and central input on heat-

sensitive neurons of the medial preoptic area

a, b: activation of peripheral warm-sensitive receptors

c-d: activation of central warm-sensitive receptors

e: activation of central cold-sensitive receptors

Thermoregulatory

patyways

DH: dorsal horn of spinal cord

LPB: lateral parabrachial nucleus

POA: preoptikus terület

MnPO: median preoptic nucleus

MPA: medial preoptic area

CVC: cutaneous vasoconstrictor

W-S: warm-sensitive

DMH: dorsomedial hypothalamic nucleus

rRPA: rostral raphe pallidus

VH: ventral horn of spinal cord

IML: intermediolateral cell column

BAT: brown adipose tissue

Location of the dorsomedial nucleus in the

hypothalamus and the raphe pallidus in the medulla

In response to larger alterations from set point body temperature:

A. In cold environment

• Heat production by the brown adipose tissue is activated

• Muscle contraction can further increase heat production

(shivering)

• Activation of thyroid hormone production increases metabolism

by enhancing cellular oxidation

• Appropriate behavioral changes

B. In warm environment – neuronal pathways are not known

• Enhanced ventillation of the lung

• Sweating starts, water evaporates from the skin

• Appropriate behavioral changes

Body temperature control 2.

Neuroendocrine and

descending

thermoregulatoy

pathways controlling

the secretion of

thyroid hormones

If previous measures were insufficient and body

temperature alteration is life-threatening:

A. In cold environment

• Due to the activation of stress axis, cellular metabolism is

further increased

B. In hot environment

• Heart frequency and blood circulation increases

Body temperature control 3.

Pathways of heat

stress

When the set point of body temperature

regulation in increased: fever

• The effects of fever:

– Proliferation of bacteria and viruses decreases

– T–cell proliferation increases

– Lymphocyte transformation is enhanced

– Gamma-interferon production is elevated

Pyrogenes

• Any substance that leads to fever

• Endogenous pyrogenes:

- Some cytokines produced by macrophages:

Interleukin 1 (α és 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 result in the production of prostaglandin E2-t (PGE2). PGE2 acts on the hypothalamus to increase the set point. Consequently, the body produces heat and decreases its dissipation.

Humoral and neuronal

hypothesis of fever

pirogene

citokynes

C5a

IL-1

TNF-

IL-6

Endothel /

microglia

PGE2

Prosztaglandin E receptor 3

in preoptic neuros

Dorsomedial

hypothalamus

(DMH)

Thermogenesis

Het loss (vasokonstriction

a bőrben)

Synthesis of Prosta-

glandin E2 (PGE2)

• From arachidonic acid

• Using the following enzymes:

– phospholipase A2 (PLA2),

– cyclooxygenase-2 (COX-2),

– prostaglandin E2 synthase

• Pyrogenes stimulate the

enzymes thereby inducing

PGE2 synthesis

Anti-fever drugs inhibit these

enzymes

Location of the

action of PGE2

within the

thermoregulatory

pathway

Tr. spinothalamicus

Outline of the lecture

1. Internal environment of living organisms

2. Homeostatic regulations – the endocrine system

3. Examples of homeostatic regulations not

requiring the nervous system

4. Homeostatic regulations – nervous system

5. Examples of regulations involving the brain

– Water balance

– Body temperature regulation

6. Homeostatic regulations – immune system

7. The role of the nervous system in immune

regulations

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

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

33

AFR

Inflammatory processes can be divided

into 2 steps

Step 1: inflammation Step 2: acute phase reaction (APR)

Immediate Starts with a latency

Local Systemal

Without threshold

Goal: separation and elimination of damages tissue, regeneration

Goal: maintain inflammation but also prevent its spreading

Above threshold

Initiation (0-6 hours)

Bleeding

Thrombo-

cyte

activation

IL-1

Bacteria

Complement

activation

C5a C3a

Necrosis

Phagocyte

activation

ROI

TNF-, IL-1

lipids

IL: interleukin; ROI: reaktíve oxygen intermedier, TNF: tumor nekrosis factor

Virus-infected

cell

Machanisms how bacteria can activate 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

Phagocytes are resident macrophages

and arriving granulocytes.

Their response to activation:

1. Phagocyte bacteria

2. Production of cytokines

©Fülöp AK 2010 37

Cytokines produced by macrophages and their functions

©Fülöp AK 2010 38

Mast cell activation

results in:

1. degranulation

2. lipid mediators

3. cytokine production

Consequences:

- Vasodilatation

- Increase of tissue

permeability

- Pain

- Activation of

additional cells

! ! !

Vasodilatory effect of histamine

Leukocyte infiltration to the site of inflammation

Transendothelial Migration

Vessel Lumen

Firm Adhesion

Activated Integrin

Rolling Adhesion

VCAM Selectin

Expression

Leukocyte

Selectin

Resting State

Inactive Integrin

Selectin Counter-receptor

Endothelial Cell

Subendothelial Matrix

Inflammatory Stimulus

Cytokine receptors

Signal transduction of IL-1

Progression (6-12 hours)

Early mediators

Targets:

Phagocytes,

endothel,

fibroblast,

mast cell,

keratinocyte,

TH2

Systemic

cytokines:

TNF,

IL-1,

IL-6

INFg

Liver

Bone

marrow

Adipose

tissue

CNS

Production of

proteins

Leukocytosis

Lipid

mobilisation

Anti-

inflammation

Inflammation Acute phase reaction (APR)

Adaptive response

Outline of the lecture

1. Internal environment of living organisms

2. Homeostatic regulations – the endocrine system

3. Examples of homeostatic regulations not

requiring the nervous system

4. Homeostatic regulations – nervous system

5. Examples of regulations involving the brain

– Water balance

– Body temperature regulation

6. Homeostatic regulations – immune system

7. The role of the nervous system in immune

regulations

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

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

Paraventricular nucleus in the anterior hypothalamic region

Paraventricular hypothalamic nucleus

Corticotropin-releasing hormon (CRH)-expressing neurons in the PVN

Initiation of CNS acute phase reaction: activation of

PVN neurons by IL-1 as compared to other stressors

Paraventricular nucleus (PVN) – c-Fos immunolabeling

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 NO

Foszfolipase A2

Ciklooxygenase2

Prostaglandins,

leukotriens

Adhesion molecules Reduced migration

Induction of

endonucleases

Apoptosis

(limfocytes, leukocytes)

4,000-

2,000-

400-

300-

100-

10,000-

Neutrophil granulocytes

Lymphocytes

Eozinophils

Monocytes

Basophils

6 h 12 h 24 h

Sejt

/mm

3

The effect of glucocorticoids on the

number of leukocytes

To eliminate unwanted immune response:

- Allergy

- Autoimmune diseases

- Organ transplant

a, Antigene-specific immune suppression – selective tolerance

b, Not-antigene- specific

• Corticosteroids (in supraphysiological, pharmacological doses)

• CY-A, FK 506, Rapamycin (T cell proliferation inhibitor)

• Radiation therapy

• Cytostatics

Immunosuppression therapy

O

OH

O O

O

O

Cortizon

Prednizon

(4x more effective

than Cortizon)

Cortisol

Prednizolon

Synthetic products:

Natural and artificial glococorticoids

CH2OH

C=O OH

CH2OH

C=O OH

CH2OH

C=O OH

CH2OH

C=O OH

O

Anti-inflammatory mechanism of glucocorticoids

GRE: glucocorticoid receptor element

Sites of action of cytokines in the CNS

- Through circumventricular organs and also through viscerosensory nerves

- It may depend on the type of mediator and its concentration

Circumventricular organs – humoral inputs

The effect of

IL-1 on

neuronal

activation

(c-fos

expression)

in different

brain areas

Activity of the vagal nerve in response to IL-1

injection

IL-1

The role of nociceptive sensory

system in inflammation

• Tryptase released by mast cells stimulates

nociceptive sensory terminals, which contributes to

the activation of HPA axis.

In additon:

• Substance P is released from the sensory terminals

upon inflammation

• G-protein coupled receptor of substance P is

present in macrophages, through which substance P

increases inflammation

Innervation of the immune system

Hypothalamo-spinal tract and other

descending pathways regulating vegetative

functions

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

Adrenerg

receptor

Target

organ

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

©Fülöp AK 2010

Neuro-

modulation of

inflammation

1. sensory

terminal

(stimulatory)

2. sympath.

(inhibitory)

3. parasymp.

(inhibitory)

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

Systemic inflammatory mediators reduce appetite by

acting on hypothalamic food intake regulatory neurons

Additional effect of inflammatory hormones on energy

homeostasis

LPL: Lipoprotein lipase, NF: nuclear factor

Immune activation produces sickness behaviors,

symptomes that resemble to depression

Thank you for your

attention!