Neuronal

Chemokines

Versatile

Messengers

In

Central

Nervous

System

Cell

Interaction

Whereas

chemokines

are

well

known

for

their

ability

to

induce

cell

migration

only

recently

it

became

evident

that

chemokines

also

control

a

variety

of

other

cell

functions

and

are

versatile

messengers

in

the

interaction

between

a

diversity

of

cell

types

In

the

central

nervous

system

-LRB-

CNS

-RRB-

chemokines

are

generally

found

under

both

physiological

and

pathological

conditions

Whereas

many

reports

describe

chemokine

expression

in

astrocytes

and

microglia

and

their

role

in

the

migration

of

leukocytes

into

the

CNS

only

few

studies

describe

chemokine

expression

in

neurons

Nevertheless

the

expression

of

neuronal

chemokines

and

the

corresponding

chemokine

receptors

in

CNS

cells

under

physiological

and

pathological

conditions

indicates

that

neuronal

chemokines

contribute

to

CNS

cell

interaction

In

this

study

we

review

recent

studies

describing

neuronal

chemokine

expression

and

discuss

potential

roles

of

neuronal

chemokines

in

neuron

astrocyte

neuron

microglia

and

neuron

neuron

interaction

Introduction

Chemokines

are

small

proteins

that

are

able

to

induce

a

chemotactic

response

in

cells

expressing

the

corresponding

chemokine

receptors

Since

the

discovery

of

the

first

protein

with

chemotactic

activity

-LSB-

-RSB-

the

chemokine

family

has

expanded

to

approximately

chemokines

-LSB-

-RSB-

and

receptors

-LSB-

-RSB-

Chemokines

have

been

divided

into

four

groups

based

on

the

position

of

four

conserved

cysteine

residues

in

the

N-terminal

region

of

the

protein

The

two

largest

groups

are

CXC

and

CC

The

first

two

cysteines

in

the

CXC

group

are

separated

by

one

amino

acid

residue

whereas

the

first

two

cysteines

in

the

CC

group

are

adjacent

to

each

other

-LSB-

-RSB-

The

two

small

groups

are

the

C

chemokines

with

only

one

cysteine

in

the

N-terminal

region

and

the

chemokine

where

the

first

two

cysteines

are

separated

by

three

amino

acid

residues

-LSB-

-RSB-

Chemokine

receptors

are

designated

according

to

the

chemokine

group

they

preferentially

bind

For

example

CC

chemokines

bind

to

CC

receptors

and

so

on

There

has

yet

only

been

one

exception

reported

namely

that

in

addition

to

also

binds

to

-LSB-

-RSB-

All

chemokine

receptors

belong

to

the

family

of

G-protein

coupled

receptors

-LRB-

GPCRs

-RRB-

In

general

GPCRs

can

bind

many

different

G-proteins

allowing

for

a

great

variety

of

intracellular

signaling

pathways

-LRB-

for

excellent

review

see

-LSB-

-RSB-

-RRB-

The

majority

of

chemokine-induced

responses

are

inhibited

by

pertussis

toxin

-LRB-

PTX

-RRB-

indicating

that

mediate

many

effects

-LSB-

-RSB-

Chemokine

receptors

can

activate

intracellular

targets

like

adenylcyclase

phospholipases

GTPases

like

Rho

Rac

and

and

pathways

of

major

kinases

like

mitogen-activated

protein

kinase

-LRB-

MAPK

-RRB-

and

phosphatidyl

kinase

-LRB-

-RRB-

-LSB-

-RSB-

This

diversity

of

intracellular

signaling

shows

that

chemokine

receptors

in

addition

to

pathways

involved

in

cell

migration

also

activate

other

pathways

and

may

in

that

way

control

a

great

spectrum

of

cellular

functions

-LSB-

-RSB-

Chemokines

are

well-known

regulators

of

peripheral

immune

cell

trafficking

under

both

physiological

and

pathological

conditions

-LRB-

reviewed

by

-LSB-

-RSB-

-RRB-

In

addition

to

chemo-attraction

of

immune

cells

chemokines

have

been

implicated

in

a

variety

of

cell

functions

such

as

early

development

formation

of

secondary

lymphoid

organs

wound

healing

angiogenesis

and

angiostasis

regulation

of

adhesion

molecule

expression

development

of

profiles

tumor

growth

and

metastasis

-LSB-

-RSB-

Thus

from

being

molecules

thought

to

solely

orchestrate

immune

cell

migration

chemokines

are

now

considered

versatile

messengers

with

the

ability

to

control

the

interaction

between

a

wide

diversity

of

cell

types

In

addition

to

their

presence

in

the

periphery

numerous

studies

have

demonstrated

that

chemokines

are

also

expressed

in

the

central

nervous

system

-LRB-

CNS

-RRB-

where

they

play

a

crucial

role

in

physiological

and

pathological

conditions

such

as

development

synaptic

transmission

homeostasis

injury

and

disease-associated

neuroinflammation

-LSB-

-RSB-

Although

astrocytes

and

microglia

are

the

primary

source

of

chemokines

there

is

evidence

that

neurons

express

and

secrete

chemokines

as

well

indicative

of

a

neuronal

contribution

to

chemokine

signaling

In

this

paper

we

review

recent

studies

describing

neuronal

chemokine

expression

and

discuss

the

potential

roles

of

neuronal

chemokines

in

neuron

astrocyte

neuron

microglia

and

neuron

neuron

interaction

Neuronal

Chemokine

Expression

Approximately

studies

describe

chemokine

expression

in

neurons

under

physiological

and

pathological

conditions

-LRB-

see

Table

-RRB-

These

studies

of

which

the

majority

is

published

in

the

last

years

are

reviewed

in

the

following

sections

Table

chemokine

-LSB-

-RSB-

Spinal

cord

ALS

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

rBrain

-LSB-

-RSB-

Brain

cranial

nerve

injury

-LSB-

-RSB-

Brain

ischemia

-LSB-

-RSB-

Retina

ischemia

-LSB-

-RSB-

Spinal

cord

peripheral

nerve

injury

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

mBrain

ischemia

-LSB-

-RSB-

Spinal

cord

ALS

model

-LSB-

-RSB-

Monoculture

West

Nile

virus

-LSB-

-RSB-

AD

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

rRetina

ischemia

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

mMonoculture

-LSB-

-RSB-

-LSB-

-RSB-

rRetina

ischemia

-LSB-

-RSB-

mMonoculture

-LSB-

-RSB-

-LSB-

-RSB-

mMonoculture

-LSB-

-RSB-

-LSB-

-RSB-

Trigeminal

neuron

culture

-LSB-

-RSB-

ischemia

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Neonatal

hippocampal

slice

culture

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

HIV

-LSB-

-RSB-

Mixed

brain

culture

-LSB-

-RSB-

macBrain

HIV

-LSB-

-RSB-

rBrain

ischemia

-LSB-

-RSB-

mBrain

entorhinal

cortex

lesion

-LSB-

-RSB-

Brain

West

Nile

virus

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

-LSB-

-RSB-

HIV

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

rBrain

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

mBrain

ischemia

-LSB-

-RSB-

Brain

LPS

injection

-LSB-

-RSB-

Mixed

brain

culture

-LSB-

-RSB-

MS

-LSB-

-RSB-

Brain

HIV

-LSB-

-RSB-

Spinal

cord

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Cell

line

a

-LSB-

-RSB-

macBrain

-LSB-

-RSB-

rBrain

and

spinal

cord

EAE

-LSB-

-RSB-

Spinal

cord

peripheral

nerve

injury

-LSB-

-RSB-

Brain

LPS

injection

-LSB-

-RSB-

Brain

KA

injection

-LSB-

-RSB-

Monoculture

a

-LSB-

-RSB-

mBrain

-LSB-

-RSB-

Brain

prion

disease

-LSB-

-RSB-

Brain

LPS

injection

-LSB-

-RSB-

Brain

KA

injection

-LSB-

-RSB-

Brain

EAE

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

h

Human

mac

macaque

r

rat

m

mouse

ALS

amyotrophic

lateral

sclerosis

AD

Alzheimer

's

disease

HIV

human

immunodeficiency

virus

MS

multiple

sclerosis

EAE

experimental

autoimmune

encephalomyelitis

LPS

lipopolysaccharide

KA

kanaic

acid

present

present

without

change

in

mentioned

conditions

present

with

increase

in

mentioned

conditions

present

with

decrease

in

mentioned

conditions

aIncrease

in

soluble

and

decrease

in

membrane-bound

CC

Chemokines

is

currently

the

most

extensively

described

neuronal

chemokine

The

majority

of

reports

describing

neuronal

expression

are

focused

on

pathological

conditions

An

induction

of

neuronal

expression

was

described

upon

ischemia

-LSB-

-RSB-

after

axonal

injury

-LSB-

-RSB-

and

in

motoneurons

of

patients

with

amyotrophic

lateral

sclerosis

-LRB-

ALS

-RRB-

and

in

mouse

models

for

ALS

-LSB-

-RSB-

Interestingly

neuronal

expression

in

response

to

ischemia

was

detectable

within

h

whereas

expression

in

astrocytes

was

detected

only

after

days

-LSB-

-RSB-

Although

most

reports

show

induction

of

neuronal

expression

under

pathological

conditions

a

recent

study

has

shown

constitutive

expression

in

neurons

throughout

the

rat

brain

-LSB-

-RSB-

This

study

demonstrated

that

depending

on

the

brain

region

up

to

of

the

neurons

were

positive

for

-LSB-

-RSB-

was

mainly

detected

in

neuronal

cell

bodies

and

costaining-depicted

colocalization

with

various

neurotransmitters

and

neuropeptides

corroborating

a

population-specific

expression

of

-LSB-

-RSB-

Constitutive

neuronal

expression

was

also

shown

in

a

human

neuronal

cell

line

-LSB-

-RSB-

and

during

human

CNS

development

-LSB-

-RSB-

and

At

present

there

is

only

one

study

describing

neuronal

expression

in

situ

depicting

protein

expression

in

adult

human

brain

-LSB-

-RSB-

Further

expression

of

and

was

described

in

cultured

forebrain

neurons

derived

from

human

first

trimester

embryos

These

chemokines

showed

increased

expression

after

exposure

to

immunological

stimuli

-LSB-

-RSB-

and

expression

were

induced

in

mouse

cerebellar

granule

neurons

after

infection

with

Toxoplasma

gondii

-LSB-

-RSB-

as

was

expression

after

viral

infections

-LSB-

-RSB-

In

a

middle

cerebral

artery

occlusion

-LRB-

MCAO

-RRB-

mouse

model

of

brain

ischemia

cortical

neurons

rapidly

expressed

in

the

penumbra

of

the

ischemic

core

Because

control

brain

tissue

did

not

express

was

assumed

to

be

specifically

expressed

in

endangered

neurons

-LSB-

-RSB-

In

accordance

with

the

in

vivo

findings

expression

was

induced

in

cortical

neurons

in

vitro

within

h

after

excitotoxicity

-LSB-

-RSB-

The

expression

in

endangered

neurons

was

rather

surprising

as

is

well

known

for

its

constitutive

expression

in

secondary

lymphoid

organs

controlling

the

homing

of

mature

dendritic

cells

and

naïve

T

cells

-LSB-

-RSB-

and

is

therefore

generally

considered

a

homeostatic

chemokine

linked

to

the

development

and

maintenance

of

secondary

lymphoid

organs

-LSB-

-RSB-

The

rapid

expression

in

endangered

neurons

after

injury

indicates

a

brain

specific

role

of

This

assumption

is

corroborated

by

findings

in

transgenic

mice

in

which

was

expressed

ectopically

in

various

tissues

expression

in

the

brain

induced

a

massive

brain

inflammation

that

killed

the

animals

within

days

after

the

expression

onset

-LSB-

-RSB-

whereas

expression

in

the

skin

induced

the

formation

of

secondary

lymphoid

structures

-LSB-

-RSB-

Other

CC

Chemokines

A

single

study

has

demonstrated

a

constitutive

and

inducible

expression

of

in

rat

cerebellar

granule

neurons

in

vitro

which

was

suggested

to

play

a

role

in

neuronal

apoptosis

-LSB-

-RSB-

Expression

of

other

CC

chemokines

has

not

yet

been

observed

in

neurons

CXC

Chemokines

expression

was

first

described

in

cortical

neurons

in

rat

in

response

to

MCAO-induced

brain

ischemia

-LSB-

-RSB-

Remarkably

neuronal

expression

was

transient

and

appeared

rapidly

after

stroke

-LRB-

within

h

-RRB-

whereas

expression

in

astrocytes

was

detectable

later

and

persisted

up

to

days

after

MCAO

-LSB-

-RSB-

Correspondingly

neurons

also

showed

a

rapid

expression

after

entorhinal

cortex

lesion

-LSB-

-RSB-

Further

neuronal

expression

and

release

was

induced

after

viral

infection

in

vitro

and

in

vivo

-LSB-

-RSB-

The

gene

contains

three

splice

variants

termed

stromal

cell-derived

-LRB-

-RRB-

α

β

and

γ

was

cloned

from

rat

brain

and

showed

constitutive

neuronal

mRNA

expression

with

almost

no

change

in

level

after

peripheral

nerve

injury

-LSB-

-RSB-

In

addition

showed

neuronal

mRNA

expression

with

almost

no

change

in

level

after

brain

ischemia

or

intracerebral

LPS

injection

-LSB-

-RSB-

In

contrast

β

mRNA

expression

was

not

detected

in

neurons

-LSB-

-RSB-

As

little

is

known

about

the

role

of

SDF

splice

variants

and

most

studies

did

not

specify

the

splice

variants

is

used

for

all

SDF

splice

variants

henceforth

Like

but

in

contrast

to

most

of

the

other

neuronal

chemokines

is

expressed

constitutively

in

specific

neuronal

populations

Neuronal

expression

in

vitro

was

observed

in

cultured

cortical

hippocampal

and

cerebellar

neurons

from

human

rat

and

mouse

-LSB-

-RSB-

Neuronal

expression

in

vivo

was

studied

in

detail

in

the

adult

rat

brain

showing

mRNA

and

protein

expression

in

cholinergic

dopaminergic

and

vasopressin

containing

neurons

throughout

the

brain

-LSB-

-RSB-

Other

CXC

Chemokines

Studies

describing

the

expression

of

other

CXC

chemokines

in

neurons

are

limited

Most

notably

in

vitro

neuronal

mRNA

expression

of

-LSB-

-RSB-

-LSB-

-RSB-

and

-LSB-

-RSB-

has

been

illustrated

Expression

of

other

CXC

chemokines

has

not

yet

been

described

in

neurons

was

the

first

chemokine

shown

to

be

expressed

in

neurons

-LSB-

-RSB-

Because

microglia

were

shown

to

express

the

corresponding

receptor

a

role

of

signaling

in

neuron

microglia

interaction

was

suggested

-LSB-

-RSB-

is

constitutively

expressed

in

human

macaque

rat

and

mouse

neurons

in

vitro

and

in

vivo

with

high

expression

in

cerebral

cortex

hippocampus

caudate

putamen

thalamus

and

olfactory

bulb

-LSB-

-RSB-

appears

to

be

the

only

chemokine

with

a

higher

expression

level

in

brain

than

in

peripheral

organs

-LSB-

-RSB-

It

is

membrane

bound

and

can

be

cleaved

from

the

cell

surface

by

proteases

of

the

A

Disintegrin

and

Metalloprotease

-LRB-

ADAM

-RRB-

family

-LSB-

-RSB-

The

neuronal

mRNA

expression

remained

relatively

stable

in

response

to

both

neuron-damaging

stimuli

in

vitro

-LSB-

-RSB-

and

during

neuroinflammation

in

vivo

-LSB-

-RSB-

whereas

in

vitro

neurons

released

protein

after

glutamate-induced

damage

-LSB-

-RSB-

Furthermore

concentrations

higher

than

pg/mg

were

described

in

aqueous

extracts

of

the

brain

-LSB-

-RSB-

indicating

that

can

be

cleaved

from

the

neuronal

membrane

and

released

into

the

extracellular

environment

It

is

yet

unknown

which

ADAM

protease

cleaves

in

neurons

and

whether

protein

expression

changes

during

in

vivo

neuroinflammation

or

degeneration

Potential

Roles

of

Neuronal

Chemokines

in

Neuron

Astrocyte

Neuron

Microglia

and

Neuron

Neuron

Interaction

Astrocytes

microglia

and

neurons

have

been

shown

to

express

chemokine

receptors

in

vitro

under

physiological

and

pathological

conditions

and

in

vivo

These

would

include

for

for

and

for

and

for

Studies

describing

the

expression

of

these

chemokine

receptors

on

astrocytes

microglia

and

neurons

-LRB-

see

Table

-RRB-

and

studies

indicating

a

role

for

these

chemokine

chemokine

receptor

pairs

in

CNS

cell

interaction

are

discussed

in

the

following

sections

on

neuron

astrocyte

neuron

microglia

and

neuron

neuron

interaction

Table

receptor

expression

in

astrocytes

microglia

and

neuronsChemokineReceptorCell

MS

HIV

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

macMonoculture

-LSB-

-RSB-

rBrain

EAE

LPS

injection

-LSB-

-RSB-

microgliahBrain

MS

HIV

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Glia

culture

-LSB-

-RSB-

rBrain

tumor

LPS

injection

NMDA

injection

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

mSpinal

cord

peripheral

nerve

injury

-LSB-

-RSB-

neuronhBrain

HIV

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

rBrain

and

spinal

cord

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

MS

HIV

-LSB-

-RSB-

Astrocyte

culture

-LSB-

-RSB-

Mixed

glial

culture

-LSB-

-RSB-

macMonoculture

-LSB-

-RSB-

mMonoculture

-LSB-

-RSB-

microgliahMonoculture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

rCell

line

-LSB-

-RSB-

mBrain

various

infectious

agents

axotomy

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

neuronhBrain

AD

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

macBrain

HIV

-LSB-

-RSB-

rMonoculture

-LSB-

-RSB-

HIV

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

macMonoculture

-LSB-

-RSB-

rBrain

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

mMonoculture

-LSB-

-RSB-

microgliahBrain

and

spinal

cord

HIV

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

babMonoculture

-LSB-

-RSB-

rBrain

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

mCell

line

-LSB-

-RSB-

neuronhBrain

HIV

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Mixed

brain

culture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

macBrain

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

rBrain

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

MS

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

macMonoculture

-LSB-

-RSB-

rMonoculture

-LSB-

-RSB-

mMonoculture

-LSB-

-RSB-

microgliahBrain

MS

-LSB-

-RSB-

Brain

HIV

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

rBrain

ischemia

prion

disease

cranial

nerve

injury

EAE

-LSB-

-RSB-

Brain

LPS

injection

KA

injection

-LSB-

-RSB-

Spinal

cord

peripheral

nerve

injury

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

Brain

LPS

injection

KA

injection

-LSB-

-RSB-

mMonoculture

-LSB-

-RSB-

neuronhMonoculture

-LSB-

-RSB-

Cell

line

-LSB-

-RSB-

rBrain

LPS

injection

KA

injection

-LSB-

-RSB-

Monoculture

-LSB-

-RSB-

mBrain

prion

disease

-LSB-

-RSB-

Brain

LPS

injection

KA

injection

-LSB-

-RSB-

h

human

mac

macaque

bab

baboon

r

rat

m

mouse

MS

multiple

sclerosis

HIV

human

immunodeficiency

virus

EAE

experimental

autoimmune

encephalomyelitis

LPS

lipopolysaccharide

NMDAN-methyl-d-aspartatic

acid

AD

Alzheimer

's

disease

KA

kainic

acid

present

present

without

change

in

mentioned

conditions

present

with

increase

in

mentioned

conditions

present

with

decrease

in

mentioned

conditions

Neuron

Astrocyte

Interaction

Astrocytes

comprise

the

largest

group

of

CNS-residing

cells

and

are

not

only

essential

in

development

homeostasis

maintenance

of

the

blood

brain

barrier

and

regulation

of

central

blood

flow

but

are

also

involved

in

the

immune

defense

of

the

CNS

Furthermore

astrocytes

are

considered

to

be

involved

in

neuronal

information

processing

-LSB-

-RSB-

It

is

becoming

clear

that

astrocytes

play

an

active

role

in

the

intricate

chemokine

network

of

the

CNS

Not

only

has

it

been

shown

that

astrocytes

express

a

wide

variety

of

constitutive

and

inducible

chemokines

in

vivo

and

in

vitro

there

is

also

extensive

evidence

that

they

express

a

repertoire

of

chemokine

receptors

under

physiological

and

pathological

conditions

-LRB-

see

reviews

-LSB-

-RSB-

-RRB-

Neuronal

Chemokines

Induce

Calcium

Transients

in

Astrocytes

The

activation

of

intracellular

calcium

transients

is

a

hallmark

in

chemokine

receptor

signaling

a

mechanism

that

also

holds

true

for

astrocytes

-LSB-

-RSB-

Activation

of

GPCRs

including

chemokine

receptors

results

in

a

rapid

release

of

calcium

from

the

endoplasmatic

reticulum

-LRB-

ER

-RRB-

through

the

activation

of

receptors

on

the

ER

membrane

One

of

the

first

chemokines

described

to

induce

calcium

transients

in

astrocytes

is

-LSB-

-RSB-

concentrations

ranging

from

to

ng/ml

-LSB-

-RSB-

or

nM

-LSB-

-RSB-

induced

calcium

fluxes

in

in

vitro

human

rat

and

mouse

astrocytes

In

all

cases

calcium

mobilization

was

PTX-sensitive

indicating

that

this

process

is

Gαi-protein

mediated

Similar

results

were

found

for

-LSB-

-RSB-

-LSB-

-RSB-

and

-LSB-

-RSB-

In

astrocytes

intracellular

calcium

transients

not

only

function

as

a

second

messenger

in

multiple

intracellular

signaling

pathways

but

are

also

implicated

in

astrocyte

astrocyte

signal

propagation

astrocyte

neuron

synaptic

transmission

and

neurotransmitter

release

-LRB-

see

reviews

-LSB-

-RSB-

-RRB-

Recent

findings

corroborate

that

chemokines

could

also

be

involved

in

astrocyte-mediated

neurotransmitter

release

induced

calcium-dependent

release

of

glutamate

from

astrocytes

in

human

and

rat

astrocyte

cultures

and

rat

hippocampal

slice

cultures

-LSB-

-RSB-

Moreover

reports

that

investigated

the

effects

of

on

the

electrophysiological

properties

of

neurons

in

brain

slice

cultures

suggest

that

effects

on

neurons

at

least

partly

depend

on

astrocytic

glutamate

release

-LSB-

-RSB-

Whether

this

astrocytic

glutamate

release

was

induced

by

activation

or

via

other

pathways

was

not

investigated

Neuronal

Chemokines

Induce

Astrocyte

Proliferation

and

Migration

in

Vitro

Implications

for

Astrogliosis

Astrocytes

respond

to

CNS

injury

or

neuroinflammation

by

enhanced

GFAP

expression

proliferation

and

possibly

migration

a

process

known

as

astrogliosis

-LRB-

see

review

-LSB-

-RSB-

-RRB-

In

these

reactive

astrocytes

enhanced

expression

of

chemokine

receptors

has

been

described

under

various

pathological

conditions

such

as

multiple

sclerosis

-LRB-

MS

-RRB-

human

immunodeficiency

virus

-LRB-

HIV

-RRB-

infection

ischemia

and

neoplasm

-LSB-

-RSB-

Under

these

conditions

was

mainly

found

in

reactive

astrocytes

in

the

proximity

of

the

lesion

sites

suggesting

that

induction

of

expression

in

astrocytes

is

limited

to

damaged

areas

of

the

brain

-LSB-

-RSB-

A

comparable

induction

of

expression

was

found

in

reactive

astrocytes

in

MS

patients

-LSB-

-RSB-

Interestingly

both

and

are

implicated

in

astrocyte

proliferation

in

vitro

-LSB-

-RSB-

In

addition

has

been

shown

to

induce

astrocyte

proliferation

in

vitro

a

process

that

is

dependent

on

activation

of

extracellular

signal-regulated

kinases

and

-LSB-

-RSB-

Both

astrocyte

proliferation

and

activation

was

inhibited

by

PTX

and

wortmannin

suggesting

that

they

are

dependent

on

upstream

activation

of

Gαi

proteins

and

-LSB-

-RSB-

As

chemokines

are

primarily

known

for

their

capacity

to

induce

cell

migration

migration

assays

have

been

used

to

determine

chemokine

receptor

functionality

in

astrocytes

-LSB-

-RSB-

Accordingly

astrocyte

migration

was

demonstrated

in

vitro

in

response

to

and

-LSB-

-RSB-

Thus

reactive

astrocytes

express

various

chemokine

receptors

and

activation

of

these

receptors

in

vitro

induces

proliferation

and

migration

cellular

reactions

that

are

generally

involved

in

astrogliosis

Therefore

it

is

tempting

to

speculate

that

chemokines

are

involved

in

the

regulation

of

astrogliosis

upon

CNS

injury

or

neuroinflammation

Whether

neuronal

chemokines

are

indeed

responsible

for

either

proliferation

or

migration

of

astrocytes

in

vivo

is

yet

unknown

Neuron

Microglia

Interaction

Microglia

in

the

healthy

CNS

are

ramified

cells

that

continually

survey

their

environment

by

moving

their

processes

Upon

injury

they

quickly

protrude

their

processes

toward

the

damaged

site

and

subsequently

transform

into

amoeboid

cells

reflecting

a

fast

activation

-LSB-

-RSB-

Activated

microglia

form

a

first

line

of

defense

in

CNS

injury

through

their

capacity

to

migrate

proliferate

secrete

inflammatory

and

neurotrophic

factors

phagocytose-damaged

cells

and

debris

and

present

antigens

-LSB-

-RSB-

Although

activated

microglia

were

initially

considered

to

be

detrimental

in

CNS

injury

recent

findings

indicate

a

prominent

neuroprotective

activity

as

well

suggesting

a

balance

between

neurotoxic

and

neuroprotective

microglia

activity

-LRB-

see

for

recent

review

-LSB-

-RSB-

-RRB-

Therefore

it

is

of

particular

interest

to

gain

insight

into

the

process

of

microglia

activation

Until

now

it

is

largely

unknown

which

environmental

signals

mediate

microglia

surveillance

and

activation

Almost

years

ago

chemokines

were

indicated

as

promising

candidates

for

neuron

microglia

signaling

-LSB-

-RSB-

Because

then

various

studies

have

described

constitutive

chemokine

expression

in

neurons

and

rapid

changes

in

expression

levels

upon

injury

Parallel

to

this

corresponding

chemokine

receptors

were

described

in

resting

and/or

activated

microglia

In

addition

there

is

increasing

evidence

that

neurons

play

an

important

role

in

microglia

activity

which

is

at

least

partly

mediated

by

chemokines

Microglia

Activity

Upon

Neuronal

Damage

Upon

CNS

injury

activated

microglia

retract

their

protrusions

transforming

into

amoeboid

cells

with

migratory

and/or

proliferative

capacities

-LSB-

-RSB-

It

is

known

that

damaged

neurons

are

accompanied

by

prominent

activated

microglia

within

hours

after

injury

suggesting

that

neurons

emit

signals

that

attract

microglia

-LSB-

-RSB-

Several

findings

support

the

notion

that

these

signals

are

primarily

chemokines

Microglia

express

various

chemokine

receptors

and

cell

migration

is

induced

upon

exposure

to

chemokines

in

vitro

-LSB-

-RSB-

Moreover

damaged

neurons

in

culture

express

and

release

chemokines

like

-LSB-

-RSB-

-LSB-

-RSB-

and

-LSB-

-RSB-

all

of

which

are

able

to

induce

microglia

migration

-LSB-

-RSB-

In

accordance

with

this

inhibition

of

chemokine

function

diminished

microglia

migration

in

response

to

supernatants

from

damaged

neurons

-LSB-

-RSB-

Thus

in

vitro

results

suggest

a

role

of

neuronal

chemokines

in

neuron

microglia

activation

The

issue

of

chemokine-mediated

neuron

microglia

activation

has

been

further

investigated

using

genetically

modified

mice

Mice

deficient

for

either

-LSB-

-RSB-

and

-LSB-

-RSB-

have

been

studied

in

various

CNS

injury

and

neuroinflammation

models

Although

deficiency

did

not

influence

microglia

activity

in

response

to

facial

nerve

lesion

-LSB-

-RSB-

deficiency

was

uniformly

associated

with

higher

levels

of

microglia

activity

in

LPS-induced

neuroinflammation

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridin-induced

neurotoxicity

and

in

the

of

motoneuronal

death

in

the

spinal

cord

-LSB-

-RSB-

Interestingly

enhanced

microglia

activity

in

the

last

three

models

was

accompanied

by

increased

neuronal

death

indicating

that

in

wild-type

mice

neurotoxic

microglia

activity

is

inhibited

by

signaling

-LSB-

-RSB-

These

findings

are

corroborated

by

several

in

vitro

findings

Exposure

of

a

neuron

microglia

coculture

to

reduced

inflammation-related

neuronal

death

accompanied

by

suppressed

nitric

oxide

and

proinflammatory

cytokine

production

-LSB-

-RSB-

In

conjunction

with

these

findings

inhibition

of

endogenous

increased

neuronal

cell

death

in

cocultures

-LSB-

-RSB-

Moreover

in

vitro

exposure

to

supported

microglia

survival

under

basal

culture

conditions

and

reduced

Fas-ligand

induced

apoptosis

considerably

-LSB-

-RSB-

Thus

exposure

of

microglia

to

reduced

microglia

toxicity

and

protected

microglia

from

apoptosis

under

inflammatory

conditions

In

contrast

to

these

results

deficiency

reduced

the

infarct

volume

and

mortality

after

transient

focal

cerebral

ischemia

-LSB-

-RSB-

However

microglia

activity

in

and

wild-type

mice

was

not

compared

in

this

study

making

it

difficult

to

determine

whether

disturbed

neuron

microglia

signaling

was

responsible

for

the

differences

-LSB-

-RSB-

Increased

microglia

toxicity

by

and

its

ligands

and/or

is

suggested

by

findings

derived

from

the

entorhinal

cortex

lesion

-LRB-

ECL

-RRB-

model

in

which

deficiency

was

associated

with

reduced

microglia

activity

and

reduced

loss

of

secondary

neurons

in

the

hippocampal

formation

-LSB-

-RSB-

An

interesting

aspect

of

chemokines

in

neuron

microglia

signaling

is

acknowledged

in

the

ECL

model

In

this

paper

microglia

activity

is

specifically

found

within

the

midmolecular

layer

of

the

dentate

gyrus

which

is

the

projection

site

of

the

transected

neurons

-LRB-

see

for

review

-LSB-

-RSB-

-RRB-

The

microglia

activity

at

a

site

distant

from

the

primary

lesion

indicates

transport

of

the

chemokine

signal

Recent

data

reinforced

this

notion

showing

that

that

was

induced

in

dorsal

root

ganglion

-LRB-

DRG

-RRB-

neurons

after

peripheral

nerve

injury

was

transported

to

afferent

terminals

in

the

spinal

cord

-LSB-

-RSB-

Moreover

in

vitro

neuronal

was

sorted

into

vesicles

transported

into

neuronal

processes

and

even

reached

presynaptic

terminals

-LSB-

-RSB-

The

finding

of

protein

in

neuronal

vesicles

is

a

strong

indication

that

neuronal

chemokines

may

be

the

signals

responsible

for

microglia

activity

at

sites

distant

from

the

primary

lesion

a

phenomenon

that

has

been

observed

also

in

humans

-LSB-

-RSB-

A

role

of

in

microglia

activity

after

neuronal

death

is

suggested

by

a

delayed

microglia

activity

in

the

thalamus

of

mice

in

response

to

cortical

injury

-LSB-

-RSB-

The

delayed

microglia

activity

was

accompanied

by

a

transient

improvement

of

neuron

survival

in

the

thalamus

which

may

indicate

that

is

involved

in

neurotoxic

microglia

activity

-LSB-

-RSB-

However

it

is

not

yet

clear

if

this

effect

is

due

to

disturbed

neuron

microglia

interaction

Damaged

neurons

are

capable

to

express

as

was

found

after

axotomy

in

sympathetic

ganglia

-LSB-

-RSB-

and

facial

nerve

lesion

-LSB-

-RSB-

but

cortical

injury

predominantly

induced

mRNA

expression

in

astrocytes

-LSB-

-RSB-

Whether

interference

with

signaling

would

affect

microglia

activity

in

the

first

two

models

has

not

yet

been

investigated

It

is

clear

that

the

assumption

that

neuronal

chemokines

are

involved

in

neuron

microglia

signaling

is

no

longer

based

on

the

finding

that

damaged

neurons

rapidly

alter

chemokine

expression

patterns

and

that

microglia

express

the

corresponding

receptors

-LSB-

-RSB-

Studies

now

show

that

microglia

activation

is

reduced

in

mice

with

genetically

disturbed

chemokine

function

indicating

an

important

role

of

chemokines

in

microglia

activation

Recent

data

even

suggest

that

neurosupportive

and

neurotoxic

microglia

activity

are

associated

with

chemokine

receptor

expression

-LSB-

-RSB-

The

ultimate

effects

of

neuronal

chemokines

are

likely

dependent

on

injury

type

brain

region

and

disruption

of

the

blood

brain

barrier

-LSB-

-RSB-

Whereas

the

exact

role

of

neuronal

chemokines

in

neuron

microglia

signaling

remains

obscure

their

importance

in

regulating

damage

responses

is

becoming

apparent

Neuron

Neuron

Interaction

Various

reports

indicate

that

chemokines

influence

neuronal

development

differentiation

-LSB-

-RSB-

survival

-LSB-

-RSB-

electrophysiological

properties

-LSB-

-RSB-

and

synaptic

transmission

-LSB-

-RSB-

Because

neurons

can

express

numerous

chemokines

autocrine

and

paracrine

contributions

of

neuronal

chemokines

are

likely

Neuroprotection

Neuronal

cell

death

the

ultimate

consequence

of

all

neuroinflammatory

conditions

has

been

studied

extensively

in

vitro

However

there

are

relatively

few

in

vitro

models

that

can

be

extrapolated

to

pathological

conditions

leading

to

neuronal

death

in

vivo

One

of

the

most

prominent

models

is

glutamate

or

NMDA-induced

neurotoxicity

a

model

for

excitotoxicity

which

is

most

likely

involved

in

various

neurodegenerative

diseases

β-amyloid-induced

neuronal

death

serves

as

a

model

that

may

explain

the

loss

of

neurons

in

Alzheimer

's

disease

whereas

exposure

of

neuronal

cultures

to

HIV

proteins

or

HIVtat

are

aimed

to

elucidate

neuronal

death

in

HIV-dependent

neurodegeneration

-LSB-

-RSB-

Several

reports

indicate

that

neuronal

chemokines

may

protect

neurons

from

these

toxic

conditions

In

vitro

is

known

to

protect

neurons

from

glutamate-induced

toxicity

-LSB-

-RSB-

neuronal

death

-LSB-

-RSB-

and

death

induced

by

deprivation

of

trophic

support

-LSB-

-RSB-

Similar

to

exposure

is

shown

to

protect

neurons

from

glutamate

and

HIV-tat-induced

neurotoxicity

-LSB-

-RSB-

However

exposure

was

not

protective

in

β-amyloid-dependent

neuronal

death

-LSB-

-RSB-

As

exposure

of

neuronal

cells

to

chemokines

is

known

to

activate

the

putatively

neuroprotective

MEK/ERK

and

signaling

pathways

-LSB-

-RSB-

it

is

reasonable

to

argue

that

chemokine-dependent

protection

is

mediated

by

these

pathways

Indeed

inhibition

of

both

pathways

completely

abolished

the

neuroprotective

effects

of

in

and

glutamate-induced

neurotoxicity

in

hippocampal

neurons

-LSB-

-RSB-

Interestingly

in

case

of

glutamate-dependent

neurotoxicity

the

involvement

of

MEK/ERK

and

signaling

pathways

was

only

evident

when

was

applied

together

with

glutamate

-LSB-

-RSB-

exposure

was

shown

to

be

protective

even

when

the

chemokine

was

applied

up

to

h

after

the

glutamate

stimulus

However

an

inhibition

of

MEK/ERK

and

pathways

did

not

affect

the

protective

activity

of

delayed

exposure

indicating

that

may

activate

additional

pathways

in

neurons

that

lead

to

neuroprotection

-LSB-

-RSB-

The

effect

of

on

neuronal

death

is

contradictory

Although

several

reports

indicate

that

exposure

may

protect

neurons

from

neuronal

death

most

papers

describe

a

toxic

effect

of

in

neuronal

cultures

-LRB-

see

below

-RRB-

-LSB-

-RSB-

Neurotoxicity

Approximately

of

HIV-infected

patients

develop

associated

dementia

-LRB-

HAD

-RRB-

It

has

been

shown

that

the

viral

protein

itself

is

neurotoxic

-LSB-

-RSB-

indicating

that

the

neuronal

loss

in

HAD

is

not

only

due

to

inflammation

occurring

after

the

virus

enters

the

brain

but

also

because

of

direct

toxic

effects

of

viral

proteins

-LRB-

see

for

recent

review

-LSB-

-RSB-

-RRB-

It

was

shown

in

that

the

neurotoxic

effect

of

is

mediated

via

the

chemokine

receptor

-LSB-

-RSB-

findings

that

have

been

corroborated

in

subsequent

years

by

various

groups

-LSB-

-RSB-

The

viral

protein

binds

and

activates

the

main

coreceptor

utilized

by

to

infect

T

cells

has

subsequently

become

the

best

investigated

chemokine

receptor

with

respect

to

neurotoxicity

and

its

involvement

in

neurotoxic

signaling

has

been

demonstrated

by

use

of

the

specific

antagonist

-LSB-

-RSB-

The

HIV-derived

protein

shows

agonist

activity

on

and

therefore

it

is

not

surprising

that

its

ligand

has

also

been

described

to

be

neurotoxic

-LSB-

-RSB-

Currently

there

is

little

information

on

intracellular

signaling

pathways

that

are

activated

by

and

subsequently

lead

to

neuronal

death

One

recent

report

indicates

the

involvement

of

Src

activity

in

apoptosis

in

a

neuronal

cell

line

whereas

apoptosis

in

these

cells

was

independent

of

Src

activity

-LSB-

-RSB-

Interestingly

and

had

different

effects

on

ERK

activation

in

neurons

and

astrocytes

-LSB-

-RSB-

indicating

that

signaling

exerts

both

ligand

and

cell-type

specific

effects

The

effect

of

is

further

complicated

by

matrix

which

was

shown

to

remove

the

first

four

amino

acids

of

resulting

in

a

truncated

form

of

-LSB-

-RSB-

This

truncated

form

was

found

to

be

highly

neurotoxic

compared

to

the

full-length

which

remarkably

was

not

mediated

by

but

by

a

yet

unknown

PTX-sensitive

receptor

-LSB-

-RSB-

Because

has

also

been

described

in

HIV-infected

patients

it

is

reasonable

to

assume

that

truncated

may

be

a

neurotoxic

player

in

HAD

-LSB-

-RSB-

is

not

the

only

neuronal

chemokine

that

exerts

neurotoxic

effects

Neuronal

cell

lines

and

primary

human

neurons

respond

to

high

concentrations

of

with

intracellular

calcium

transients

caspase

activity

and

apoptosis

-LSB-

-RSB-

The

direct

involvement

of

was

demonstrated

by

the

use

of

an

antibody

that

prevents

the

activation

of

and

subsequently

inhibited

neurotoxicity

-LSB-

-RSB-

Chemokinergic

Effects

on

Synaptic

Transmission

Recent

data

show

that

activation

by

either

or

significantly

enhanced

giant

depolarizing

potentials

-LRB-

GDP

-RRB-

in

rat

neonatal

hippocampus

-LSB-

-RSB-

These

GDPs

only

occur

in

the

developing

hippocampus

and

are

involved

in

growth

and

synapse

formation

These

data

may

explain

why

HIV

infections

have

a

greater

impact

in

the

developing

brain

than

in

adults

-LSB-

-RSB-

and

show

that

neuronal

chemokines

may

change

the

electrophysiological

properties

of

neurons

thereby

corroborating

earlier

findings

-LSB-

-RSB-

The

electrophysiological

properties

of

neuronal

chemokine

receptors

have

predominantly

been

studied

in

cultured

primary

neurons

or

neuronal

cell

lines

and

brain

slice

cultures

-LSB-

-RSB-

Remarkably

in

cultures

of

DRG

cerebellar

granule

or

Purkinje

neurons

and

hippocampal

pyramidal

cells

chemokines

induced

changes

in

the

electrophysiological

properties

of

only

of

the

neurons

-LSB-

-RSB-

In

addition

several

effects

of

chemokines

in

neurons

were

not

sensitive

to

PTX

in

contrast

to

hematopoietic

cells

suggesting

that

chemokine

receptors

in

neurons

although

generally

accepted

are

not

solely

coupled

to

Gαi

proteins

-LSB-

-RSB-

Whether

these

chemokinergic

PTX-insensitive

effects

are

mediated

by

neuronal

Gz-subunits

is

yet

unclear

-LSB-

-RSB-

Cultured

cerebellar

and

DRG

neurons

respond

to

various

chemokines

with

intracellular

calcium

transients

-LSB-

-RSB-

In

DRG

neurons

exposure

to

and

also

increased

their

excitability

-LSB-

-RSB-

Although

chemokinergic

effects

of

and

in

neurons

have

been

reported

to

modulate

the

frequency

of

both

spontaneous

and

activity-dependent

neuronal

firing

a

direct

effect

on

the

induction

of

action

potentials

has

not

yet

been

described

-LSB-

-RSB-

Similar

to

the

effects

on

isolated

neurons

and

also

affected

neuronal

signaling

in

brain

slice

cultures

-LSB-

-RSB-

However

the

presence

of

glia

cells

-LRB-

astrocytes

microglia

and

oligodendrocytes

-RRB-

in

these

slice

cultures

makes

it

difficult

to

determine

whether

the

electrophysiological

effects

of

chemokines

are

mediated

by

chemokine

receptors

on

neurons

and/or

on

glia

cells

as

glia

cells

may

also

induce

electrophysiological

changes

in

neurons

-LSB-

-RSB-

Whether

the

effects

of

in

brain

slice

cultures

are

mediated

via

chemokine

receptors

on

neurons

and/or

on

glia

cells

may

depend

on

the

concentration

as

concentrations

up

to

nM

caused

a

direct

decrease

in

peak

and

discharge

frequency

of

evoked

action

potentials

in

neurons

and

concentrations

higher

than

nM

activated

an

indirect

GABA-mediated

hyperpolarization

of

neurons

-LSB-

-RSB-

Future

Directions

As

discussed

here

neuronal

chemokines

appear

to

be

versatile

messengers

in

CNS

cell

interaction

However

several

important

issues

need

to

be

addressed

in

future

studies

To

begin

with

neuronal

expression

in

vivo

remains

controversial

Immunohistochemical

analysis

revealed

positive

neurons

in

mouse

brain

sections

with

little

changes

under

pathological

conditions

-LSB-

-RSB-

whereas

neuronal

expression

was

never

described

in

studies

using

genetically

modified

mice

in

which

cells

are

also

positive

for

EGFP

-LSB-

-RSB-

Different

microscopic

techniques

and

models

of

neurodegeneration

have

been

explored

in

these

mice

demonstrating

only

expression

in

resting

and

activated

microglia

-LSB-

-RSB-

An

explanation

may

be

that

neuronal

expression

is

at

such

a

low

level

that

detection

is

difficult

to

achieve

with

microscopic

techniques

This

may

also

be

the

case

for

expression

in

microglia

Although

expression

has

yet

not

been

described

in

microglia

in

vivo

functional

evidence

derived

from

mice

strongly

indicates

that

microglia

do

express

in

vivo

-LSB-

-RSB-

Therefore

it

seems

appropriate

that

future

experiments

concerning

the

expression

of

chemokine

receptors

in

CNS

cells

in

vivo

also

include

functional

analysis

Another

issue

that

needs

to

be

addressed

in

more

detail

regards

cellular

localization

Neurons

are

highly

polarized

cells

as

their

function

is

largely

dependent

on

their

morphology

and

contacts

with

other

cells

-LRB-

e.g.

synapses

with

other

neurons

-RRB-

Although

neuronal

signaling

molecules

such

as

neurotransmitters

neuropeptides

and

neurotrophins

are

generally

found

at

specific

sites

most

reports

describing

neuronal

chemokine

expression

did

not

address

this

issue

Interestingly

a

few

recent

publications

do

suggest

a

localized

expression

of

chemokines

comparable

to

other

neuronal

signaling

molecules

Our

group

demonstrated

that

neuronal

is

transported

in

vesicles

reaching

presynaptic

terminals

in

cortical

neurons

in

vitro

-LSB-

-RSB-

In

subsequent

studies

these

vesicles

appeared

to

be

of

the

large-dense

core

type

in

which

other

neuronal

peptides

are

also

found

-LRB-

e.g.

neurotrophins

Stanulovic

et

al.

manuscript

in

preparation

-RRB-

Moreover

it

has

been

described

for

several

neuronal

populations

in

vivo

that

and

colocalize

with

other

neurotransmitters

and

neuropeptides

in

synaptic

regions

-LSB-

-RSB-

Like

neuronal

chemokine

expression

a

site-specific

expression

of

chemokine

receptors

may

exist

as

is

suggested

by

redistribution

in

the

axonal

and

dendritic

compartment

of

hippocampal

neurons

after

prolonged

exposure

-LSB-

-RSB-

Because

a

localized

expression

of

chemokines

and

their

receptors

may

have

a

consequence

for

their

role

in

cell

interaction

future

studies

on

neuronal

chemokine

expression

may

address

this

issue

At

last

as

all

reports

indicating

that

chemokine

exposure

alters

the

excitability

of

neurons

used

exogenous

chemokines

it

is

yet

unknown

whether

chemokines

released

from

neurons

have

similar

effects

Conclusion

Knowledge

on

the

spatial

and

temporal

expression

of

neuronal

chemokines

and

their

regulation

under

physiological

and

pathological

conditions

is

increasing

rapidly

As

CNS

cells

can

express

the

corresponding

chemokine

receptors

contribution

of

these

neuronal

chemokines

to

CNS

cell

interaction

is

conceivable

This

assumption

is

corroborated

by

various

in

vitro

and

in

vivo

studies

For

example

the

following

effects

of

neuronal

chemokines

were

observed

in

vitro

in

astrocytes

proliferation

and

migration

in

microglia

migration

and

neurotoxic

and

neuroprotective

activity

and

in

neurons

electrophysiological

changes

neurotoxicity

and

neuroprotection

Further

the

synaptic

transmission

between

neurons

seems

to

be

influenced

by

the

action

of

neuronal

chemokines

on

neurons

and/or

glia

cells

In

vivo

studies

support

the

important

role

of

chemokines

in

migration

and

neurotoxic

and

neuroprotective

activity

of

microglia

upon

CNS

injury

and

neuroinflammation

Further

exploration

of

the

roles

of

neuronal

chemokines

in

CNS

cell

interaction

is

needful

as

insight

into

the

role

of

neuronal

chemokines

in

CNS

injury

and

neuroinflammation

may

contribute

to

the

development

of

therapeutic

strategies

O B O O O O B I I B I O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B I I O B O O B O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O B O O O O O O O O B O O O O O O O B O O O O O O B O O O O O O O O O B O O B B I O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O B O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O B O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O B O O O O O O O O O O O O O O O O O O B B I O O O O O O O O O O O O O B O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O B O O O O O O O O O B O O O O O O O O B O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O B O O O O O O O O O B O B O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O B O O O O B O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O B O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O B O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O B O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O B B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O B O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O B O B B I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O B O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O B O B O O O O O O O O O O O O B O O O O O O O O B O B O O O O O O O O O O O B O B B I O O O O O O O O O O B O B O O O O O O O O O O O O

cns
central nervous system
neurons
astrocytes
microglia
chemokines
cell interaction