Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.Monocytes : subsets, origins, fates and function s [628437]

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.Monocytes : subsets, origins, fates and function s
Simon Y ona and Stef fen J ung
Introducti on
Itwas Ilya Metc hnikof f, in a series of classical studies
spannin
g
from
the
e
chinode
rm
amoe
bocyte
to
the
vertebrate
macrophag
e,
who
a
century
ago
first
fully
comprehen
ded
the
capabiliti
es
of
pha
gocytes
[1
–
4].
Later
in
the
1960s,
van
Furth
and
Cohn
[5]
defin
ed
the
mononuc
lear
phagocyt
e
system
as
a
n
e
twork
of
non-
granulocyt
ic,
myeloi
d
cells,
which
are
now
known
to
collectiv
ely
perfo
rm
im
portant
roles
in
tissue
remod
eling,
homeostas
is
as
well
as
stimulat
ory
and
regul
atory
aspects
of
the
innat
e
and
adaptive
immune
syst
em.
The
mono-
nuclear
pha
gocyte
system
is
curr
ently
divi
ded
into
three
cell
types,
the
termi
nally
differen
tiated
macroph
ages
and
dendriti
c
cells,
whi
ch
them
selves
compris
e
mul
tiple
sub-
populatio
ns,
an
d
monoc
ytes.
Monocy
tes
are
classical
ly
defi
ned
as
circul
ating
blood
cells
that
const
itute
app
roximatel
y
10%
of
perip
heral
leukocytes
in
humans
and
app
roximatel
y
4
%
o
f
leuko-
cytes
in
mi
ce.
Blood
monocytes
de
velop
in
the
bo
ne
marrow
from
a
divi
ding
common
myel
oid
progen
itor
thatis
share
d
with
granulocyt
es.
Monocy
tes
are
subsequen
tly
rel
eased
to
the
periph
eral
circul
ation
as
nond
ividing
cells
[6].Thehalf-lifeofacirculatingmonocytehasbeen
estima
ted
to
be
around
3
days
in
humans
and
1
day
in
mi
ce
[5,7].
Indeed
,
this
short
half-l
ife
has
cultivated
the
no
tion
that
the
blood
acts
as
a
genera
l
reservoi
r
o
f
myeloi
d
precur
sors
enabling
the
con
tinuous
repop
ulation
of
tissue
mac
rophage
s
and
in
particular
the
ephemer
al
dend
ritic
cells
[8
–
10].
Circul
ating
blood
monoc
ytes
were
origina
lly
classifi
ed
by
thei
r
irregular
cell
morpholog
y
and
density
[11
–
13].
How
ever,
these
morp
hologica
l
features
exhibi
t
a
degree
of
heter
ogeneity,
for
exam
ple,
v
ariability
in
siz
e,
nuc
lear
mor
phology
and
granular
ity,
making
it
diffic
ult
to
dis-
ting
uish
them
by
histolo
gical
criter
ia
alone
[14,15
].
Monocyte subsets
Almo st 30 years ago, two disc rete sub populatio ns of
human
blood
monoc
ytes
were
identified
by
mor
phology
and
the
differe
ntial
expressio
n
o
f
the
antigen
ic
markersDepartment of Immunology, The Weizmann Institute of
Science,
Rehovot,
Israel
Correspondence
to
Steffen
Jung,
Ph
D,
Department
of
Immunology,
The
Weizm
ann
Institute
of
Science,
Rehovot
76100,
Israel
Tel:
+972
8
934
2787;
fax:
+972
8
934
4141;
e-mail:
s.jung@weizma
nn.ac.il
Current
Opinion
in
Hema
tology
2010,
17:53
–
5
9Purpo s e o f r eview
The
term
mono-cyte
suggests
this
population
of
cells
consists
of
a
single
homogenous
fraction.
However,
evidence
from
a
number
of
laboratories
indicates
that
monocytes
are
composed
of
several
subsets,
which
differ
in
phenotype,
size,
nuclear
morphology,
granularity
and
gene
profiles.
Most
importantly,
recent
data
suggest
that
monocyte
subsets
are
also
functionally
distinct.
Here
we
summarize
the
recent
advances
in
our
understanding
of
monocyte
subsets
and
their
origins,
fates
and
functions.
Recent
findings
The
recent
past
has
seen
major
progress
in
our
understanding
of
myeloid
differentiation.
Specifically,
the
published
literature
now
suggests
a
dichotomy
that
starts
at
the
stage
of
a
novel
clonotypic
bone
marrow
resident
precursor,
the
macrophage
dendritic
cell
progenitor
(MDP).
Insights
into
differential
origins
of
macrophages
and
dendritic
cells,
linked
with
functional
specifications,
are
likely
to
significantly
change
our
current
view
of
the
mononuclear
phagocyte
system.
Sum
m
ary
Contemporary
studies
have
demonstrated
that
two
subsets
of
monocytes
reside
in
the
peripheral
circulation.
These
subsets
are
surprisingly
distinct;
with
regard
to
their
functions
and
fates,
for
example,
one
subset
might
be
dedicated
to
generate
macrophages
upon
extravasation
from
the
peripheral
circulation,
whereas,
the
other
subset
under
inflammatory
conditions
may
differentiate
into
inflammatory
dendritic
cells.
The
tissue
response
during
pathogenesis
seems
to
differentially
mobilize
these
cells,
thereby
manipulating
the
local
mononuclear
phagocyte
composition
according
to
acute
needs.
Keywords
dendritic
cell,
inflammation,
macrophage,
monocyte
Curr Opin Hemat ol 17:5 3 – 5 9
/C2232010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1065-6251
1065- 6251 /C2232010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/MOH .0b013e32 83324f80

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.CD16 and CD14 [16 – 19]. Thes e data provi ded the first
clues
to
a
potent
ial
exis
tence
of
differe
ntial
phy
siological
activi
ties
of
monoc
yte
subset
s
(for
revi
ew
see
[12,20
]).
Distin
ct
expressio
n
o
f
C
D
1
4
and
CD16
on
human
blood
monoc
ytes
en
abled
the
categori
zation
of
these
cells
into
two
major
subsets:
CD
14țțCD16/C0cells term ed ‘classi-
cal’
because
thei
r
phen
otype
resemb
les
the
origina
l
descr
iption
of
monoc
ytes,
account
ing
for
90%
of
hum
an
blood
monoc
ytes
and
a
less
freque
nt
‘noncl
assical’
CD14țCD16țțsubset [21,22 ]. In addition, human
monoc
ytes
compr
ise
a
slight
populat
ion
of
CD14țț
CD16țcells, which has be en term ed ‘in termediate ’.
Althoug
h
the
heter
ogeneity
of
human
monoc
yte
subset
s
falls
outside
the
scope
of
the
present
revi
ew,
it
should
be
emphas
ized
that
these
cells
differ
in
many
aspects
and
the
discrimin
ation
and
funct
ion
of
these
po
pulations
is
a
matter
of
inte
nse
investigati
on.
Moreover,
monoc
yte
heter
ogenei
ty
is
now
regarded
to
be
a
genera
l
them
e
conser
ved
among
mamma
ls,
wi
th
monoc
yte
subset
s
having
be
en
repor
ted
in
cows
[23,24
],
pigs
[25,26],
rats
[27,28
]
and
mice
[9].
Mouse
bone
mar
row-resi
dent
and
circulati
ng
blood
monoc
ytes
are
defined
primar
ily
by
their
expres
sion
of
CD115
,
F4/80,
CD11b
and
CX 3CR1 [29 – 31]. Phenotypi c
chara
cterization
in
the
mouse
ident
ified
two
discret
e
blood
monocyte
subsets,
according
to
their
expres
sion
of
Ly6C
and
CX 3CR1. Thes e two po pulations were
descr
ibed
as
being
Ly6ChiCX 3CR1loCCR2țCD62Lț
andLy6CloCX 3CR1hiCCR2/C0CD62L/C0blood monoc yte
subset
s
[9,32].
The
ratio
of
these
two
sub
sets
in
the
murine
cir
culation
is
approxim
ately
4
:
6,
Ly6Clocom-
pared
to
Ly6Chimonoc ytes, respec tively; this ratio
rem
ains
relativel
y
const
ant
in
naı
¨
ve
mice
[33].
Followin
g
infe
ction,
a
consid
erable
number
of
Ly6Chimonoc ytes
egres
s
from
the
bone
mar
row
to
the
periph
eral
circulation
in
a
CCR2-dep
endent
fashi
on
[8,9,34
,35].
Chal
lenged
mice
there
fore
ofte
n
have
increase
d
numb
ers
of
circulat-
ing
Ly6Chimonoc ytes.
Impor
tantly,
the
ident
ifica
tion
of
mouse
monoc
yte
sub-
sets
ha
s
allow
ed
studies
into
their
functions
in
a
phy
sio-
logical
contex
t.
Indeed
,
evidenc
e
i
s
emerging
from
adopti
ve
transfer
studies
that
Ly6CloandLy6Chiblood
monoc
ytes
are
surprisingl
y
distinc
t,
with
respec
t
t
o
their
funct
ions
and
fat
es
in
the
pe
riphery.
Thes
e
findi
ngs
are
disc
ussed
be
low.
Monocyte origins
Blood monoc ytes origina te in the bon e marrow from
hemat
opoietic
stem
cells,
via
several
commi
tment
steps
and
progenitor
stag
es.
Thes
e
steps
include
the
common
myelo
id
progen
itor
(CMP)
and
the
granul
ocyte
macro-
phage
progen
itor
(GMP)
[36].
In
2006
Fog
g
et
al
.
[37]
,
descr
ibed
a
n
o
vel
speci
fic
bone
marrow-r
eside
nt
clono
-genic
progeni
tor,
which
in
contrast
to
GM
P
lac
ked
the
pot
ent
ia
l
t
o
dif
fer
ent
iat
e
int
o
g
r
anu
loc
yt
ic
,
lymp
hoi
d,
ert
hro
id
or
meg
aka
ryo
cyt
ic
ce
lls
.
Und
er
the
app
rop
ri
at
e
in-
vit
ro
cul
tur
e
c
o
ndi
ti
ons
or
up
on
tr
ans
fer
int
o
rec
ip
ien
t
mic
e,
the
se
CX 3CR1țCD1 15țCD3 4țCD1 6țlin-cells
exp
and
ed
and
ga
ve
exc
lus
iv
e
r
i
s
e
t
o
sev
era
l
macr
opha
ge
sub
set
s
and
ste
ady
sta
te
den
dri
ti
c
cel
ls
.
H
e
nce
,
Gei
ssm
ann
et
al
.
[9]
,
t
e
r
m
e
d
t
h
e
m
m
a
cro
ph
age
/de
nd
ri
ti
c
cel
l
pro
gen
i-
tor
s
(
M
DPs
).
Int
ra
bon
e
cav
it
y
tran
sf
er
expe
ri
me
nts
of
MD
Ps,
per
for
me
d
b
y
our
lab
or
ato
ry
dem
ons
tra
ted
tha
t
wit
hi
n
the
ir
na
tive
bon
e
mar
row
mic
roe
nvi
ron
men
t
M
D
P
s
dif
fer
ent
iat
e
i
n
t
o
mon
ocy
tes
tha
t
sub
seq
uen
tl
y
e
g
res
s
int
o
the
per
iph
era
l
cir
cul
at
ion
.
T
h
ese
exp
er
ime
nts
defi
ned
MD
Ps
as
the
in-
viv
o
pre
cur
sor
s
o
f
bon
e
m
a
r
r
o
w
and
bl
ood
mon
ocy
te
s
[38
].
Su
rpr
is
ing
ly
,
w
e
als
o
obs
er
ved
tha
t
i
n
t
h
e
abs
enc
e
o
f
infl
am
mat
ion
,
L
y
6
Chiblood mon ocy te s effi –
ci
ent
ly
shu
tt
le
ba
ck
to
the
bon
e
m
a
r
r
ow.
Mor
eov
er
,
the
se
cel
ls
wer
e
fou
nd
to
con
ver
t
wit
hin
3
day
s
int
o
L
y
6
Clo
monocy te s tha t egr ess ed bac k i n t o the per iph era l c i r c ula –
ti
on
(Fig
.
1).
Imp
or
tan
tl
y,
thi
s
fi
n
din
g
c
l
ari
fied
pre
vio
us
obs
erv
at
io
ns
reg
ar
din
g
the
dis
app
ea
ran
ce
of
ado
pt
ive
ly
tr
ans
fer
red
Ly6
Chimonoc yte s f r o m t h e ci rcu la ti on, in
the
abs
enc
e
o
f
infl
amm
ati
on
[9,
39]
.
A
pre
cur
so
r/p
ro
gen
y
rel
ati
ons
hip
of
Ly6
ChiandLy6 Clomonocy tes is fu rth er54 Myeloid biology
Figure 1 Mononuclea r phagocy te develo pment in mice
MDP
Ly6C+
mono c y t eCDP
Pre-cDC
Class i ca l
DCPDCLy6C-
mono c y t e
Mono c y t e-d e r i v e d
DCMacr o p h a geBM
PDCBlo
o
d
Tis
s
u
e
sLy6C+
mono c y t ePre-cDC PDCLy6C-
mono c y t eLoca t i o n
MDPs give rise to Ly6Chimonocytes, and to CDPs. It remains to be
shown
whether
MDPs
give
rise
directly
to
Ly6Clomonocytes (dotted
line).
Ly6Chimonocytes convert in the bone marrow to give rise to Ly6Clo
monocytes . The two monocyte subsets; Ly6ChiandLy6Cloegress from
the
bone
marrow
and
enter
the
peripheral
circulation
.
Under
steady
state
conditions,
Ly-6Clomonocytes might contribut e t o the tissue macro-
phage
compa
rtment.
Ly6Chimonocytes can under inflammatory con-
ditions
give
rise
to
macrophages
and
dendritic
cells.
CDPs
give
in
the
bone
marrow
rise
to
pre-classical
dendritic
cells
and
PDC.
Pre-classic
al
dendritic
cells
circulate
in
blood
and
enter
lymphoid
tissue,
where
they
give
rise
to
classical
dendritic
cells.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.suppor ted by re sul ts obt ain ed fr om par abi oti c ani mal s
th
at
rev
eal
ed
tha
t
L
y
6
Clomonocy te s hav e a co nsi der abl y
lo
nge
r
hal
f-l
if
e
i
n
t
h
e
ci
rc
ula
ti
on
[7]
.
Giv
en
the
pos
si
bi
lit
y
of
mo
noc
yte
co
nver
si
on,
it
rem
ain
s
u
n
cle
ar
wh
eth
er
MDP
s
gi
ve
ri
se
dir
ect
ly
to
Ly6
Clomonoc yte s, whe the r the gen er –
at
io
n
o
f
the
se
cel
ls
re
qui
res
an
obl
ig
ato
ry
Ly
6Chimonoc yte
in
ter
med
ia
te
or
wh
eth
er
the
two
mut
ual
ly
not
exc
lus
iv
e
pa
thwa
ys
exi
st
si
de
by
sid
e
[
3
8].
Fu
tur
e
lin
ea
ge
tra
cki
ng
st
ud
ies
wil
l
ext
end
our
un
der
st
and
ing
in
th
e
dev
el
opm
en-
ta
l
r
e
lat
ion
shi
p
bet
we
en
the
mon
ocy
te
sub
se
ts.
Infl
amma
–
to
ry
con
dit
ion
s
rap
id
ly
mob
ili
ze
bon
e
marr
ow
res
id
ent
mo
noc
yte
s
[9,
40
–
42]
.
A
n
int
ere
st
ing
twi
st
to
th
e
ori
gin
of
rec
rui
ted
mon
ocy
tes
has
bee
n
adde
d
b
y
t
h
e
re
cen
t
id
ent
ifi
cat
io
n
o
f
a
ma
jor
mon
ocy
te
re
ser
voi
r
i
n
the
sub
–
ca
psu
lar
red
pu
lp
of
the
spl
een
in
mic
e
[
4
3/C15/C15].Th e t r an-
sc
ri
pto
me
and
mor
phol
ogy
of
the
se
cel
ls
are
in
dis
ti
ngu
is
h-
ab
le
fro
m
c
i
rcu
la
ti
ng
bl
ood
mon
oc
yte
s.
Fol
low
ing
inj
ury
,
sp
len
ic
res
er
voi
r
mon
ocy
tes
are
mob
ili
zed
to
th
e
sit
e
o
f
in
flam
ma
ti
on
in
an
ang
io
ten
si
n-m
edi
ate
d
m
a
n
n
e
r
[
4
3/C15/C15].
Li
ke
con
ven
ti
ona
l
b
l
ood
mon
ocy
tes
,
spl
eni
c
r
e
ser
voi
r
mo
noc
yte
s
app
ear
to
be
gen
era
te
d
i
n
the
bon
e
m
a
rro
w,
ra
the
r
tha
n
l
o
cal
ly
in
th
e
spl
een.
Monocyte fates
Circulating monoc ytes have an exceedi ngly short half- life,
estima
ted
to
be
abou
t
1
day
in
mice
[7].
This
supported
the
no
tion
that
blood
monoc
ytes
act
as
a
transien
t
reservoi
r
o
f
myeloi
d
precur
sors
enabling
the
continuous
repop
ulation
of
periphe
ral
tissue
macro-
phages
an
d
d
e
ndritic
cells
in
the
steady
state.
The
identifica
tion
of
the
murine
monoc
yte
subset
s
combi
ned
with
the
use
of
tra
nsgenic
labeling
strateg
ies
based
on
reporter
gen
es,
for
example,
the
Cx
3cr1gfpmice [31], has
allowed
this
statem
ent
to
ev
olve,
throug
h
e
x
periment
al
challenge
and
refinem
ent.
Monocyte -derived macrophage
Tissue macroph ages have variou s funct ions in the main-
tenance
of
tissu
e
homeos
tasis,
for
examp
le,
clearanc
e
o
f
senescen
t
cells,
tissue
remod
eling,
repair,
as
well
as
the
genesis
and
resolution
of
the
inflam
matory
respons
e
[44
–
46].
Althoug
h
macrophag
es
wer
e
historical
ly
consi
dered
to
be
derived
from
the
blood
monoc
yte
reservo
ir
[47,48
],
numerou
s
studi
es
have
since
demons
trated
that
under
steady
stat
e
conditio
ns
residen
t
tissue
macroph
age
popu-
lations
are
largel
y
mainta
ined
throug
h
loca
l
prol
iferation.
This
holds
true
for
macrophag
es
as
diverse
as
alve
olar
macrophag
es
[49
–
51],
spleni
c
whi
te-pulp
and
metallo-
philic
macrophag
es
[52]
and
liver
Kupffer
cells
[53]
,
a
s
well
as
brain
mi
croglia
[54]
.
Inflam
matory
insults,
how-
ever,
result
in
the
rapi
d
recr
uitment
of
blood-
borne
precursor
s
t
o
the
respec
tive
tissue
macrophag
e
compa
rt-
ment
[41,42,
47,53,55].
It
remains
to
be
show
n
whether
these
acute
blood-
borne
im
migrants
inte
grate
into
thestea
dy
state
residen
t
mac
rophage
network,
funct
ioning
in
an
identica
l
manner
to
resident
cells.
Below
we
highlight
some
of
the
recent
research
that
speci
fically
addres
sed
the
link
betw
een
the
monoc
yte
compa
rtment
and
tissue
mac
rophage
s.
Em
erging
evidenc
e
suggest
s
that
Ly6Clo,but not Ly6Chi
blood monoc ytes mi ght be dedicated to generate macro-
pha
ges
upon
extr
avasation
from
the
periph
eral
circula-
tio
n.
Stud
ies
from
our
group
invol
ving
adopti
ve
mono-
cyte
transfer
s
into
macrophag
e-
and
de
ndritic
cell-
de
pleted
mice,
indicat
e
that
only
Ly6Clomonoc ytes
harbor
the
im
mediate
potential
to
differen
tiate
into
par-
en
chymal
lung
mac
rophage
s
[51].
In
terestingl
y,
in
these
studi
es
the
genera
tion
of
alveo
lar
macrophag
es
that
resid
e
i
n
the
exter
nal
lung
caviti
es
required
obligat
e
parenc
hymal
lung
macroph
ages
intermed
iate
[56].
In
sup
port
of
this
unique
lin
k
betwee
n
Ly6Clomonoc ytes
and
mac
rophage
s,
transcr
iptional
profil
ing
of
extravas
ated
Ly6Clomonoc ytes retrie ved from the peri toneum follow-
ing
Listeria
monocy
togene
s
infection
revea
led
a
distinc
t
mac
rophage
differe
ntiation
progr
am,
whereas
recruit
ed
Ly6Chimonoc ytes initiated a d e ndritic cell signa ture [57]
(Fig.
1).
In
a
model
of
resol
ving
myoc
ardial
infarctio
n
Nahrendorf
et
al
.
[41]
,
observed
the
specifi
c
early
recruit
ment
of
Ly6Chimonoc ytes during the first 3 days, which exhib-
ite
d
phagocyt
ic,
prote
olytic
and
inflamma
tory
activi
ty.
A
sub
sequent
resol
ving
phase
was
in
contr
ast
dominate
d
b
y
a
second
wav
e
o
f
Ly6Clomonocy tes, which displ ayed
anti
-inflamm
atory
prop
erties.
Thes
e
cells
expres
sed
vas-
cula
r
e
n
dothelia
l
growth
factor
(VEGF)
and
prom
oted
tissue
rem
odeling
and
repair
via
myofibr
oblast
accum
u-
lation,
angio
genesi
s
and
the
depositi
on
of
collagen
.
Arn
old
et
al.,
examined
monoc
yte
subset
recr
uitment
and
differe
ntiati
on
kinet
ics
in
a
model
of
skele
tal
muscle
inj
ury.
Aga
in
the
inju
red
musc
le
earl
y
o
n
selectivel
y
recr
uited
Ly6Chiblood monoc ytes, which displ ayed
an
inflam
matory
profile
exp
ressing
TNF
a
and
IL-
1
b
mR
NA
[42]
.
However
,
i
n
contrast
to
the
Nahr
endorf
study,
the
Ly6Chimonoc yte infil trate differen tiated
during
the
subsequen
t
resolvin
g
phase
withi
n
the
tissue
int
o
pro
lif
era
ti
ng
Ly
6CloF4/80himacrop hag es. The se cel ls
acq
uir
ed
a
more
ant
i-
infl
am
mat
ory
pro
file
and
st
imul
ate
d
memb
ra
ne
rep
ai
r,
myo
gen
esi
s
and
fib
er
gro
wth
to
res
to
re
mus
cl
e
int
egr
it
y
[
4
2].
Us
in
g
a
mo
del
of
spi
na
l
c
o
r
d
inj
ury
,
we
re
cen
tl
y
est
abl
is
hed
an
ess
ent
ia
l
rol
e
o
f
mon
oc
yte
–
der
ive
d
m
a
cro
ph
age
s
i
n
the
rec
ove
ry
pro
ces
s
[
5
8/C15].Ag ain
we
obs
erv
ed
a
rap
id
and
sel
ec
ti
ve
rec
ru
it
men
t
o
f
L
y
6
Chi
blood mon oc yte s t o the le sio n sit e. How eve r, our res ul ts
ind
ic
ate
tha
t
i
n
thi
s
par
ti
cul
ar
ti
ssu
e
set
ti
ng
the
mon
ocy
te
–
der
ive
d
cel
ls
dif
fe
ren
ti
ate
in
to
ma
cro
ph
age
s
wit
h
a
pro
–
noun
ced
ant
i-
infl
amm
ato
ry
phen
ot
ype
tha
t
r
e
gul
at
es
the
det
ri
men
ta
l
act
iva
ted
res
id
ent
mic
rog
lia
pop
ul
ati
on
by
sec
ret
ing
IL
-10
[5
8/C15].Im por tan tl y, our dat a sug ges t t h a tMonocytes : subsets, origins, fates and functions Yona and Jung 55

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.monocy te -de ri ved ma cro ph age s and the res id ent mic ro gli a
hav
e
non
red
un
dan
t
f
u
nct
io
ns.
Atheros
clerosi
s
i
s
characte
rized
by
hyp
ercholest
erole-
mia-a
ssociat
ed
monoc
ytosis,
giving
rise
to
mac
rophage
foam
cells
in
the
atheroma
ta,
a
proces
s
which
is
do
mi-
nated
by
the
sele
ctive
recruitment
of
Ly6Chiblood
monoc
ytes
[59]
.
This
subset
appe
ars
to
be
recruited
into
the
atheroscl
erotic
plaque
primar
ily
in
a
CCR
2-
dep
endent
manner
[20],
althou
gh
o
ther
chemo
kine
recept
ors,
such
as
CX 3CR1 and CCR5 also app ear to
be
involved
in
monocy
te
recruitment
and
retenti
on
[60]
.
Inter
estingly
,
mice
de
ficient
for
eit
her
CX 3CR1 o r its
unique
membrane
-tethere
d
lig
and
CX 3CL1 (fract alkine)
are
rel
atively
prote
cted
from
ather
oscleros
is
develo
p-
ment
.
Notably
,
Cx3Cr1/C0//C0and Cx3Cl1/C0//C0mice show a
sele
ctive
reduct
ion
of
Ly6Clomonoc ytes, which results
from
thei
r
uniqu
e
depende
nce
on
a
C
X3Csurvival signal
[33]
.
Mon
ocy
tes
are
re
cru
it
ed
int
o
s
o
lid
tu
mors
wh
ere
the
y
dif
fer
ent
iat
e
i
n
t
o
tum
or-
as
soc
ia
ted
macr
oph
age
s.
The
se
cel
ls
enh
anc
e
t
u
morg
ens
is
,
for
exa
mp
le,
tum
or
in
vas
io
n
[61
],
the
pro
mo
ti
on
of
the
ang
io
gen
ic
swi
tch
and
th
e
pro
gre
ss
ion
of
ma
lig
nan
cy
[62
,63
].
The
ons
et
of
ang
iog
en-
esi
s
i
s
a
ra
te-
lim
it
ing
fa
cto
r
for
tum
or
gro
wth
.
Mamm
ary
and
gli
oma
tum
or
oge
nes
is
stu
die
s
led
by
Na
ldi
ni,
hav
e
dem
ons
tr
ate
d
tha
t
the
spe
ci
fic
el
imi
nat
ion
of
a
pop
ula
tio
n
of
Tie
2țmonocy tes re duce s tum or ang iog ene si s and sl ows
tum
or
pro
gre
ss
ion
[64
,65
].
In
a
mod
el
of
VEGF
-i
ndu
ce
d
liv
er
ang
iog
ene
si
s
w
e
dem
ons
tr
at
ed
tha
t
adu
lt
neo
vas
cu-
la
riz
ati
on
rel
ies
up
on
the
re
cru
it
men
t
o
f
blo
od
mo
noc
yte
s
[66
].
Mor
e
rec
ent
ly,
we
obs
erv
ed
tha
t
Ly6
Chimonoc yte s
mig
rat
e
t
o
s
i
tes
of
VEG
F-i
nd
uce
d
ang
iog
ene
si
s
whe
re
the
y
d
i
f
f
ere
nti
ate
int
o
Ly6
Clocells to pro mot e and co or-
din
at
e
ang
io
gene
si
s
(un
pub
lis
hed
obs
erv
at
ion
).
Final
ly,
during
the
progr
ession
of
Toxoplas
ma
gondi
infec-
tion
,
wher
e
bacteri
a
d
e
stroy
the
ep
ithelial
laye
r
o
f
the
sma
ll
intestine,
the
speci
fic
recruit
ment
of
Ly6Chimono-
cytes
to
the
lamina
propri
a
forms
an
additiona
l
b
a
rrier
of
prote
ction
by
up-reg
ulating
iNOS,
TNF
a
and
IL-12
to
contr
ol
this
inte
stinal
pathoge
n
[67/C15].Cur iously, these
Ly6Chimonocyte- derived cells lacked classical dendri tic
cell
markers
but
at
the
sam
e
time
act
in
an
inflam
matory
den
dritic
cell
fashion,
up-regu
lating
iN
OS
an
d
TNF
a
[67/C15],adding yet another layer of complexi ty in de fining
these
cells.
Monocyte-deri ved dendritic cells
Dendr itic cells are a heter ogenous populat ion of speci al-
ized
migratory
anti
gen
present
ing
cells
(APCs),
ubiqui
–
tously
distri
buted
both
in
lymphoid
and
nonlymp
hoid
tissues.
Or
iginally
disc
overed
by
Stei
nman
and
Cohn
in
the
1970s,
by
thei
r
unique
morp
hology
and
unriv
alledpotenti
a
l
t
o
s
ti
mula
te
na
ı
¨
ve
T
c
ells
[68],
t
he
latter
attribute
r
emains
the
b
est
c
ri
teria
t
o
d
istinguish
dendri-
ti
c
c
el
ls
f
r
om
their
c
lose
rela
t
i
ve
the
m
a
c
r
o
phage.
T
he
notion
that
b
l
oo
d
m
on
o
c
ytes
possess
t
he
p
o
te
ntial
t
o
differentiate
i
nto
d
endri
t
ic
cells
stem
med
o
riginally
from
a
s
eries
o
f
c
lassical
i
n
-v
itro
studies.
I
solated
b
l
o
od
monocytes
c
ultu
r
e
d
under
t
he
influence
o
f
g
ranulocyte-
macrophage
colony
stimul
a
ting
fa
ct
or
(GM-
CS
F
)
a
n
d
IL-4
produced
‘im
mature’
d
endritic
cells,
w
hi
ch
could
subsequently
be
‘matured’
b
y
t
reatment
wi
th
toll-like
receptor
ligands
or
TNF
a
[69
,
70].
I
n
f
act
bone
marrow-
culture
a
nd
monocyte-cultu
re
deri
ved
d
endritic
cell
s
have
been
u
s
ed
ever
since
a
s
a
convenient
substitute
for
ex
vivo
isolates,
i
n
d
endritic
cell
studies.
H
ence,
i
t
w
as
surprising,
w
hen
w
e
a
nd
others
found
th
a
t
lymphoid
organ-resident
classical
dendritic
cells
in
vivo
ar
e
n
ot
derived
f
ro
m
m
onocytes
[38,
71].
Rather,
c
lassical
d
en-
dritic
cells
were
re
cently
shown
t
o
d
evelop
exclusiv
ely
from
MDPs
via
a
n
a
lternati
v
e
dedicat
ed
cir
c
ulat
ing
precursor
c
ell
p
opulation,
th
e
s
o-
ca
lled
pr
e-
class
i
c
a
l
dendritic
cells
[72/C15].
Under
inflam
matory
cond
itions,
blood
monoc
ytes
can
howev
er
clea
rly
develo
p
many
of
the
phenotypi
c
feat
ures
and
funct
ions
of
de
ndritic
cells.
Most
remarka
bly
in
this
respec
t
are
the
studies
led
by
Eric
Pamer
,
who
esta
b-
lished
that
upo
n
Listeria
challenge
Ly6Chimonoc ytes
enter
the
splee
n
a
n
d
give
rise
to
a
discret
e
popu
lation
of
TNF
a
and
iNOS
expres
sing
den
dritic
cells
(Tip-d
en-
dritic
cells)
that
is
critical
for
pathoge
n
con
trol
[35].
Interest
ingly,
these
studies
als
o
revea
led
the
intrig
uing
requi
rement
of
the
chemo
kine
recept
or
CCR2
for
the
bone
marrow
egres
s
o
f
the
Ly6Chimonoc ytes.
Further
evidenc
e
for
the
fact
that
monoc
ytes
can
differ-
entiate
into
dend
ritic
cells
stems
from
work
of
the
Rando
lph
group.
Thei
r
earlier
studi
es
repor
ted
that
dend
ritic
cells
could
arise
from
monoc
ytes
that
migrate
across
endothelium
in
an
ablumen
al-to-lume
nal
dire
c-
tion,
wher
eas
monoc
ytes
that
rem
ained
in
the
sub
en-
dothel
ial
mat
rix
develo
ped
into
mac
rophage
s
[10,73
].
Subseq
uently,
they
show
ed
that
followi
ng
a
sub
cu-
taneous
injecti
on
of
latex
microsph
eres,
Ly6Chiand
Ly6Cintmonoc ytes, but not Ly6Clocells, were recruited
to
the
site
of
inflamma
tion,
wher
e
they
differe
ntiated
into
dend
ritic
cells
and
migrated
to
the
lymph
nod
es
[74].
Na
kano
et
al
.
[75/C15],rec ent ly rep ort ed the spe ci fic rec rui t-
men
t
o
f
L
y
6
Chiblood mon ocy te s t o l y mph nod es fo llo w-
ing
infl
uen
za
(H
1N1
)
i
n
fec
ti
on
or
imm
un
iza
tion
.
The
se
cel
ls
gav
e
ris
e
t
o
CD1
1cțCD11 bhiLy6ChiCD4 0intmono-
cyt
e-d
eri
ved
den
dri
ti
c
c
e
lls
,
whic
h
pro
du
ce
IL
-12
p70
st
imul
ati
ng
a
TH1respo nse .
We
ourselves
recent
ly
esta
blished
a
dire
ct
link
between
monoc
ytes
and
a
d
e
fined
periphe
ral
tissue
de
ndritic
cell56 Myeloid biology

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.populatio n using adop tive transfers of specific myeloi d
precursor
s
(MD
Ps,
predendr
itic
cells,
monoc
ytes)
into
recipien
t
mice
that
had
been
deplet
ed
of
thei
r
endogen-
ous
den
dritic
cells
using
the
CD
11c-DTR
system
[76].
Interest
ingly,
we
found
that
in
this
experi
mental
system
Ly6Chimonoc ytes gave rise specifical ly to CX 3CR1ț
CD14țlamina propria de ndritic cells in this model ,
whereas
a
second
distinc
t
pop
ulation
of
CD
103țlamina
propria
de
ndritic
cells
was
de
rived
from
pre-c
lassical
dendriti
c
cells
[77/C15/C15].Notab ly, Ly6Clomonoc ytes failed
to
give
rise
to
lamina
propria
de
ndritic
cells
but
diff
er-
entiated
into
cells
in
the
Peyers’
Patche
s
with
a
macrophag
e
morpholog
y.
Finally,
in
a
model
of
ultraviol
et
(U
V)
irradi
ation-in
duced
skin
inflamma
tion,
the
Merad
group
demons
trated
that
Ly6Chimonoc ytes enter the epidermi s and give ris e t o
cells
with
Lang
erhans
’
cell
featu
res
[78]
.
However
,
i
t
remains
to
be
shown
if
these
monoc
yte-d
erived
phago-
cytes
are
ident
ical
to
the
resi
dent
radio-resi
stant
Lang
er-
hans’
cell
po
pulation.
Interest
ingly
in
this
respect,
Langerhans
’cells
are
also
found
loca
ted
within
the
muco-
sal
epithelial
lining
of
the
vaginal
and
oral
cavities.
Thes
e
vaginal
ep
ithelial
den
dritic
cells
are
readily
recons
tituted
by
bo
ne
mar
row-derive
d
precursor
s,
an
d
only
under
inflamma
tory
cond
ition
are
efficiently
repopul
ated
by
Ly6Chimonoc ytes [79] .
Monocyte s functions
Given the plas ticity of monocytes (as discu ssed earl ier) to
give
rise
to
mac
rophage
and
de
ndritic
cell
populatio
ns
with
opposi
te
functions
,
for
exam
ple,
pro-inflam
matory
or
anti-i
nflammat
ory
activi
ties,
the
question
arises
whether
monoc
ytes
have
specifi
c
functions
beyon
d
being
precursor
cells.
Indeed,
we
would
like
to
suggest
that
the
only
de
finitive
funct
ion
of
monoc
ytes
and
thei
r
unique
critical
contr
ibution
to
the
mononuc
lear
pha
gocyte
sys-
tem
lies
in
their
mobi
lity.
Ter
minally
differe
ntiated
macrophag
es
and
den
dritic
cells
are
either
statio
nary
or
harbor
a
limi
ted
migratio
n
potent
ial
to
reach
draining
lymph
nod
es
or
T-cel
l
zones.
In
contrast
,
monoc
ytes
can
reach
an
y
part
of
the
organism
.
More
over,
the
rapi
d
mobilizatio
n
from
bone
marrow
and
splee
n
monoc
yte
reservoirs
upo
n
chal
lenge
can
significa
ntly
modify
the
mononuc
lear
phagocyt
e
compo
sition
of
a
given
tissue
and
thereby
regul
ate
its
acute
needs.
In
add
ition
to
this
feature
recircu
lating
monoc
ytes
appear
to
be
invol
ved
in
surveil
lance
of
the
vascul
ar
surface.
Rece
ntly,
it
was
observed
that
Ly6Clomonoc ytes constantl y patrol and
monitor
blood
vessels,
by
crawl
ing
on
the
luminal
side
of
the
en
dothelium
in
a
C
D
11a
dep
endent
fashi
on.
Curious
ly,
in
response
to
tissue
dama
ge
or
infe
ction
these
patroling
Ly6Clomonoc ytes are rapidly recru ited
to
the
site
of
injury,
precedin
g
the
arrival
of
granul
ocytes
and
Ly6Chimonoc ytes [57] .Conclusion
Mono cytes represen t the most versatile and dynamic cell
po
pulation
within
the
mononuc
lear
pha
gocyte
system,
provi
ding
a
criti
cal
link
between
the
sites
of
hemato-
po
iesis
in
the
bone
marrow
and
peri
pheral
organs.
The
disc
overy
of
dist
inct
monoc
yte
sub
sets,
that
no
t
only
repop
ulate
tissue
macrophag
e
and
de
ndritic
cell
compa
rt-
ment
s
but
als
o
contr
ibute
to
the
esta
blishme
nt
an
d
resolu
tion
of
loca
l
inflam
matory
reac
tions,
and
participat
e
in
the
innat
e-imm
une
survei
llance
of
the
organism
,
has
signifi
cantly
advance
d
our
underst
anding
of
these
cells.
Fur
ther
comprehen
sive
studi
es
are
required
to
fully
elucid
ate
the
link
be
tween
monoc
yte
sub
sets
and
the
pe
ripheral
mac
rophage
and
dend
ritic
cell
pool
in
stea
dy
state
and
unde
r
inflamma
tory
conditio
ns.
Acknowledgemen ts
S.J.is t h e in cu mb en t o f t h e Pa ul in e Rec an at i C a r e e r D e v e l o p m e n t Ch ai r.
S.Y
.
i
s
a
re
cip
ie
nt
of
a
p
o
s
t
d
oc
to
ra
l
f
e
llo
ws
hi
p
f
ro
m
t
h
e
Fe
de
ra
ti
on
of
Eu
ro
p
e
a
n
Bio
ch
em
ic
al
So
cie
ti
es
(F
EB
S)
.
References and recommende d reading
Papers of particular interest , publish ed withi n the annual perio d o f review, have
been
highlighted
as:
/C15
of
special
interest
/C15/C15
of
outstanding
interest
Additi
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references
related
to
this
topic
can
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be
found
in
the
Current
World
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section
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