(Journal of Leukocyte Biology. 2001;69:698-704.)
© 2001
by Society for Leukocyte Biology
Phenotypic and functional change of cytokine-activated neutrophils: inflammatory neutrophils are heterogeneous and enhance adaptive immune responses
Shigeo Yamashiro,
Hidenobu Kamohara,
Ji-Ming Wang,
De Yang,
Wang-Hua Gong and
Teizo Yoshimura
Laboratory of Molecular Immunoregulation, National Cancer Institute at Frederick, Frederick, Maryland
Correspondence: Dr. Teizo Yoshimura, Bldg. 559, Rm. 1, NCI-Frederick, Frederick, MD 21702. E-mail: yoshimur{at}mail.ncifcrf.gov
 |
ABSTRACT
|
|---|
Polymorphonuclear leukocytes (PMN) are the most abundant leukocytes,
comprising about two-thirds of peripheral blood leukocytes, and play
major roles in innate immunity. In addition, PMN play critical roles in
the development of adaptive immunity. Recently, defensins and other
peptides pre-stored in PMN granules were shown to attract monocytes,
dendritic cells, and T cells, leading to the hypothesis that the
release of PMN granular peptides may link innate and adaptive immunity.
During the past several years, we have focused on an alternative
hypothesis that activated PMN further differentiate and acquire new
phenotypes and functions that enable them to link the two responses. To
test our hypothesis, we have taken local and global approaches and have
shown several key findings that support the hypothesis. The findings
include the requirement for priming PMN by cytokines to induce the
delayed expression of MCP-1/CCL2, a signal for mononuclear cells, and
the expression of new cell-surface markers by such cytokine-activated
PMN. In the present manuscript, we focus on the phenotypic and
functional changes that occur during PMN activation with selected
cytokines. The results of our study indicate that inflammatory PMN are
heterogeneous and play roles in not only innate but also adaptive
immunity in response to stimuli released in injured tissues.
Key Words: inflammation • chemokine • chemokine receptor • gene expression
|
INTRODUCTION
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Polymorphonuclear leukocytes (PMN) are the most abundant
leukocytes, comprising about two-thirds of peripheral blood leukocytes.
In humans, circulating PMN have a half-life of only 6–10 h after being
released from the bone marrow (BM) and execute a constitutive,
programmed death, followed by elimination mainly in the liver and
spleen [1
, 2
]. Upon tissue injury,
circulating PMN infiltrate into sites rapidly. The lifespan of
infiltrating PMN is much longer than that of circulating PMN:
Twenty-four h after the onset of an inflammatory reaction, large
numbers of PMN are still present at the sites long after the cessation
of PMN influx, typically noted at 1–4 h [1
,
2
]. These PMN are activated at the sites by a wide
variety of stimuli, including chemotactic factors and cytokines, and
play important roles in innate immunity (Fig. 1
). It is also known that activated PMN are able to produce and
release pro-inflammatory mediators, such as interleukin (IL)-1, IL-1
receptor antagonist, IL-8, and macrophage inflammatory protein (MIP)-1s
[3
]. Thus, activated, tissue-infiltrating PMN are
distinct from resting, circulating PMN.
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Figure 1. PMN play a role in not only acute inflammation (innate immunity) but
also in DTH (adaptive immunity).
|
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In addition to their role in innate immunity, previous in
vivo studies also suggested strongly that PMN could contribute to
the development of adaptive immunity, including delayed-type
hypersensitivity reaction (DTH) [4
5
6
7
8
]. Monocyte
chemoattractant protein-1 (MCP-1)/CCL2 is a CC-chemokine that has a
potent, monocyte-chemotactic activity in vitro and in
vivo [9
, 10
]. Recently, the importance
of MCP-1 in the development of DTH was shown dramatically by studies of
MCP-1-deficient mice. Although similar numbers of PMN infiltrated sites
of injection by a specific antigen in sensitized, wild-type mice or
MCP-1-deficient mice, infiltration of mononuclear cells was decreased
markedly in the MCP-1-deficient mice [11
]. Furthermore,
in a rat-DTH model, MCP-1 was detected largely in association with
early infiltrating PMN but not with other types of cells that are
well-known MCP-1-producing cells in vitro. Neutralization of
MCP-1 activity in these rats inhibited completely the subsequent
infiltration of monocytes and lymphocytes [7
]. These
results indicated clearly an important role of PMN-derived MCP-1 in the
subsequent, enhanced, mononuclear-cell recruitment in DTH. In contrast,
when an acute-type of the inflammatory response was induced by an
intraperitoneal injection of casein in rabbits, infiltrating PMN did
not express significant levels of MCP-1 [12
]. Thus, the
production of MCP-1 by PMN may be one of the important events that
regulate the transition from innate to adaptive immunity. During the
past few years, we investigated the changes in gene expression of
cytokine-activated PMN and learned that activated PMN exhibit
pleotrophic gene expression, potentially contributing to a broad range
of activities. In the present manuscript, we focus on phenotypic and
functional changes induced in cytokine-activated PMN, which reveal PMN
to be heterogeneous. As will be discussed, not all activated PMN
produce MCP-1 but only primed, cytokine-activated PMN, after a delay in
response to cytokine signals. Such PMN heterogeneity may enable PMN to
play crucial roles in innate and adaptive immunity.
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DELAYED EXPRESSION OF MCP-1 BY PRIMED, CYTOKINE-ACTIVATED PMN
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Human PMN were shown previously to express and produce very low
levels of MCP-1 after overnight incubation in a fetal calf serum
(FCS)-containing medium. However, this spontaneous, low-level
expression of MCP-1 did not account for the in vivo
observations that MCP-1 was associated mainly with PMN in chronic
inflammation, including DTH [6
, 7
,
13
], but not in acute inflammation [7
,
12
], leading us to hypothesize that there must be a
unique mechanism up-regulating the expression of MCP-1 in PMN.
This led us to show that human PMN are capable of expressing high
levels of MCP-1 after activation with a cytokine-rich, culture
supernatant of phytohemagglutinin (PHA)-stimulated human peripheral
blood mononuclear cells (PBMC; PHA-sup). The use of the PHA-sup was
relevant because there are numerous stimuli at sites of inflammation,
and presumably, the PHA-sup contains some of these stimuli, including
as yet uncharacterized molecules. It is interesting that unlike IL-8 or
MIP-1
, whose expression levels could reach a peak within a few hours
after activation with tumor necrosis factor (TNF)- or other
cytokines, the expression of MCP-1 was delayed: Sixteen-h incubation
was necessary for the expression level of MCP-1 to reach a peak.
Protein synthesis and tyrosine phosphorylation were involved in the
process [14
].
TNF- in the PHA-sup was found to be an important inducer of MCP-1
mRNA expression because anti-TNF--treated PHA-sup lost most of its
activity. An additional 60-kD factor(s) was required to cooperate with
TNF- to attain maximal MCP-1 mRNA expression in PMN
[15
]. This 60-kD factor(s) alters the responsiveness of
PMN to TNF-, followed by activation with TNF-, increasing the
level of MCP-1 expression to the maximal level within 4 h. The
activation with TNF- was mediated through TNF receptor
(TNFR)-p55, because only a TNF- mutant that had a binding
specificity restricted to TNFR-p55 induced maximal, MCP-1 expression.
However, the expression level of TNFR-p55 was not increased after
overnight culture, suggesting that the 60-kD factor(s) may alter the
post-TNFR-p55 intracellular-signaling pathway. Thus, PMN primed by a
product(s) of PBMC can acquire the capacity to respond fully to TNF-
for maximal expression of MCP-1 (Fig. 2
) [15
].
In our study, the priming 60-kD factor(s) was a PBMC product, raising a
question as to whether such a product(s) is available at the initial
stage of inflammation when PMN infiltrate injured tissues. It is,
however, seen commonly that other cell types residing in tissues, such
as endothelial cells, fibroblasts, mast cells, or macrophages, are
actually the source of molecules identified originally as PBMC
products. Therefore, cells other than PBMC may also produce the 60-kD
factor(s) and enable PMN to amplify DTH. Because MCP-1 produced and
secreted by early infiltrating PMN could contribute to the transition
from acute to chronic inflammation, identification of the 60-kD priming
factor(s) may yield therapeutic approaches to reduce chronic
inflammation, including DTH.
|
COMPARISON OF GENE EXPRESSION BY CYTOKINE-ACTIVATED PMN AND PRIMED,
CYTOKINE-ACTIVATED PMN
|
|---|
The genes expressed by resting, human peripheral granulocytes,
most of which were PMN, were studied previously by analyzing a
3'-directed cDNA library [16
]. Sequencing of 1142
individual clones resulted in the detection of 748 independent
sequences. Approximately 20% of the expressed genes consisted of
nuclear proteins such as DNA-binding proteins, secretory proteins such
as cytokines, and membrane proteins such as major histocompatibility
complex proteins and receptors, indicating that they maintain their
gene expression without further activation. Additionally, after
activation with lipopolysaccharides (LPS),
N-formyl-Met-Leu-Phe (fMLP), or proinflammatory cytokines,
PMN express new genes rapidly, including cytokines and chemokines
[3
]. Thus, activated PMN are functionally distinct from
resting PMN.
As described above, our study demonstrated that PMN primed with a PBMC
product(s) also had the capacity to differentiate and express further a
biologically important chemokine, MCP-1, upon activation with TNF-.
This novel finding led us to another hypothesis: Primed,
cytokine-activated PMN might play a broader role in inflammation by
expressing additional genes not known previously to be expressed by
unprimed, activated PMN. To determine the capacity of primed,
cytokine-activated PMN to express novel genes, we analyzed a profile of
genes expressed after overnight activation with PHA-sup, using cDNA
microarrays containing 588 well-characterized, human cDNAs, and
compared with that after a 4-h activation with TNF-
[14
]. The expression of chemokine genes such as IL-8,
MIP-1, and MIP-1ß was up-regulated markedly in PHA-sup-activated
or TNF--activated PMN. However, the expression of MCP-1 was
up-regulated in only PHA-sup-activated PMN, showing a clear difference
between cytokine-activated and primed, cytokine-activated PMN. The
expression of anti-apoptotic protein A1, cyclin-dependent kinase
inhibitor p21Waf1/Cip1, and receptor tyrosine kinase
discoidin domain receptor 1 (DDR1) was up-regulated in either PMN.
Up-regulation of A1 has been shown to have an important
role in PMN survival [17
], indicating that
activated PMN can prolong their life by expressing genes important for
cell survival and control their fate positively. Induction of
p21Waf1/Cip1 was shown previously to correlate with growth
arrest associated with monocyte-macrophage differentiation
[18
]. Thus, a similar signaling event also occurs during
PMN activation. DDR1 was cloned originally from highly metastatic tumor
cells and suggested to be involved in tumor progression
[19
]. Ligands of DDR1 were later found to be collagens,
components of extracellular matrix (ECM) [20
,
21
], suggesting that DDR1 expressed by PMN may play a
role in the communication between the cells and ECM during
inflammation.
In contrast to the up-regulation of genes, the expression of myeloid
cell nuclear differentiation antigen (MNDA) was down-regulated after
activation with PHA-sup or TNF-. The appearance of MNDA coincides
with cessation of cell proliferation and the final stage of maturation,
and MNDA is expressed in normal, mature granulocytes and differentiated
HL-60 cells [22
]. Although the biological function of
MNDA remains unclear, down-regulation of MNDA in activated PMN suggests
that activated PMN are at a functionally different stage from that of
normal, resting PMN.
Recently, we extended our study by using another cDNA microarray
containing approximately 7000 human cDNAs, including a large number of
expressed sequence tags (ESTs; unpublished results). The expression of
about 400 genes was up-regulated at least twofold in PHA-sup-activated
PMN. These genes included indole 2,3-dioxygenase (IDO), TNF-inducible
protein TSG-6, and MCP-1. Expression of several ESTs was also
up-regulated highly in these cells. Many of the cDNAs were cloned
previously from other types of cells. IDO was cloned originally from
interferon (IFN)-
-activated fibroblasts and converts tryptophan and
other indole derivatives to kinurenine and contributes to the
inhibition of intracellular pathogens, such as Toxoplasma
gondii and Chlamydia psittaci [23
].
TSG-6 was cloned from TNF--activated fibroblasts in a search of
TNF--activated genes. TSG-6 forms a stable complex with components
of the plasma protein inter--inhibitor, and these two proteins
synergize to inhibit plasmin, the major fibrinolytic enzyme in the
clotting system. Plasmin also has an ability to activate matrix
metalloproteinases, which are responsible for most of the extracellular
matrix degradation associated with inflammation, suggesting the role of
TSG-6 in a negative feedback control of the inflammatory response
[24
]. Thus, PMN-derived IDO and TSG-6 can play an
important role in these events. It is interesting to note that PMN play
a role in resistence to T. gondii [25
] and
C. psittaci [26
]. Finally, the biological
functions of the proteins coded by these ESTs need to be defined. Taken
all together, this study reinforced the idea that resting, circulating
PMN are not terminally differentiated cells with the limited capacity
to express genes but can be cytokine-activated or primed and
cytokine-activated to prolong their survival and expand their gene
expression markedly.
|
ROLE OF CHEMOKINE RECEPTORS IN MOBILIZATION AND ACTIVATION OF PMN
|
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Five CXC-chemokine receptors (receptors for CXC-chemokines) and 11
CC-chemokine receptors (receptors for CC-chemokines) have been cloned
to date [27
]. Two of the CXC-chemokine receptors, CXCR1
and CXCR2, were cloned first from PMN as the receptors for IL-8.
Another CXC-chemokine receptor, CXCR4, was also detected on PMN. Thus,
it appeared that PMN expressed only CXC-chemokine receptors. However,
expression of several CC-chemokine receptors, including CCR1, CCR2,
CCR3, and CCR5, was detected recently on PMN that were activated by
cytokines in vitro [28
] or infiltrating
in vivo [29
].
It is now clear that PMN express various chemokine receptors at
different stages of their life, and these chemokine receptors play a
role in the mobilization of PMN (Fig. 3
). Immature and mature PMN in the BM express CXCR1, CXCR2,
and CXCR4. A recent study in CXCR4-deficient mice indicated a critical
role of CXCR4 in the retention of PMN precursors in the BM
[30
], whereas IL-8, a potent ligand for CXCR1 and CXCR2,
appears to play a role in the release of PMN from the BM
[31
]. Circulating PMN express all three chemokine
receptors, and the cells infiltrate injured tissues after recognizing
the production of ELR+ CXC-chemokines through CXCR1 and
CXCR2. In tissue-infiltrating, activated PMN, the expression of CXCR1
and CXCR2 can be down-regulated [32
, 33
],
whereas the expression of CC-chemokine receptors, including CCR1, CCR2,
CCR3, and CCR5 [28
, 29
], can be
up-regulated. The expression of CCR1 was found to be necessary for
mouse neutrophil-mediated host defense [34
], but the
roles of other CC-chemokine receptors on PMN remain unclear.
|
EXPRESSION OF DENDRITIC CELL (DC) PHENOTYPES AND FUNCTIONS BY
CYTOKINE-ACTIVATED PMN
|
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Our cDNA microarray study described above suggested the
up-regulation of another CC-chemokine receptor, CCR6, in
PHA-sup-activated PMN. CCR6 is a unique receptor for liver and
activation-regulated chemokine (LARC) [35
], also known
as MIP-3 [36
] or exodus [37
], and for
ß defensins [38
] and is expressed on DC
[39
], IL-2-stimulated T cells [35
], or
memory T cells and B cells [40
]. In DC, CCR6 is
expressed only at an immature stage, not at a mature stage. Expression
of CCR6 appears to be involved in the trafficking of DC
[41
]. Thus, we hypothesized that PMN expressing CCR6
might be in the process of acquiring features characteristic of DC. It
was indicated previously that cytokine-activated PMN could express
HLA-DR and present antigens, the most important feature of DC
[42
43
44
45
]. Furthermore, highly purified,
lactoferrin-positive, immediate precursors of end-stage PMN could be
reverted in their functional maturation program and driven to acquire
features characteristic of DC [46
].
Among recombinant cytokines, TNF- induced high levels of CCR6 mRNA
expression, whereas IFN- induced low levels. The two cytokines
together exhibited a considerable synergy. Priming was not necessary to
induce CCR6 expression. By a receptor-ligand binding assay using
125I-LARC, approximately 160 binding sites were detected
with the equilibrium dissociation constant (Kd) of 1.6 nM after
activation with TNF- and IFN-. Although the Kd of LARC-PMN
binding was in the range of previously shown Kd values for binding of
LARC to CCR6 [35
, 39
, 47
,
48
], the number of CCR6 on PMN was extremely low compared
with that on DC. Immature DC that were generated in vitro by
incubating human monocytes in the presence of granulocyte-macrophage
colony-stimulating factor (GM-CSF), IL-4, and TGF-ß1 for 7 days
expressed approximately 42,000 binding sites per cell
[48
]. Nevertheless, expressed CCR6 was functional,
because cytokine-activated PMN migrated toward LARC in a dose-dependent
manner. These results indicate that PMN can be induced to express
functional CCR6 after activation with selected cytokines. However, CCR7
that is expressed on mature DC [41
] could not be
detected on PMN up to 4 days, indicating that PMN do not parallel the
maturation program for DC [49
].
DC are characterized by their expression of several cell-surface
molecules, including CD40, CD54, CD80, CD83, CD86, and HLA-DR, some of
which are associated directly with their ability to present antigens to
T cells [50
]. As noted above, the expression of HLA-DR
was detected previously on PMN after activation with GM-CSF. Recently,
we detected additional molecules, including CD40 and CD83, after
activation with selected cytokines [49
]. Detection of
CD83 was particularly interesting because CD83 is a predominant marker
for mature DC [51
]. Although we did not detect the
expression of co-stimulation molecule CD86, a molecule similar to CD80
was detected by others [52
]. Our data from the cDNA
microarray study also suggest the induction of CD54. Thus, PMN are able
to express several cell-surface molecules characteristic of DC during
the course of their activation processes.
The most important function of DC is the ability to present antigens to
T cells. PMN expressing HLA-DR were able to serve as accessory cells in
superantigen-mediated, T-cell activation [45
]. We
investigated whether PMN are capable of presenting foreign antigens to
T cells by examining whether cytokine-activated PMN could stimulate an
allogenic mixed leukocyte reaction (MLR). Although the results
suggested their modest, antigen-presenting activity, it remains unclear
whether PMN are capable of presenting antigens at a considerable level.
There was also no detectable level of IL-12 in the culture supernatants
of the activated PMN, again indicating that the cytokine-activated PMN
are distinct from mature DC.
|
PMN DIFFERENTIATION AND HETEROGENEITY
|
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In the present manuscript, we have described phenotypic and
functional changes induced in resting, circulating, human PMN. Our view
is that the previously shown activity of PMN to initiate the
development of adaptive immunity can be attributed to the functions
they newly acquire after survival and differentiation of the cells in
response to selected cytokines released in a tissue microenvironment.
In this regard, a combination of cytokines that prolong cell survival
and those that activate the transcription of genes plays a crucial role
and determines the fate of inflammatory PMN. So far, we have tested
three representative cytokines, GM-CSF, TNF-, and IFN-, for their
ability to induce cell-surface markers and functions. GM-CSF is a
well-known survival factor for PMN [53
,
54
]. In contrast, TNF- is one of the most potent PMN
activators and induces the expression of many genes. IFN- is known
to potentiate the production of cytokines by PMN [3
].
Using this approach, we have identified three types of PMN (Fig. 4
). GM-CSF-activated cells express HLA-DR and present superantigens
to T cells [45
] but do not express CD40, CD83, or CCR6
(Fig. 4)
. In contrast, PMN activated with TNF- and IFN- express
CD83 but not CD40 or HLA-DR. The lack of HLA-DR expression suggests
that these PMN do not present antigens, including superantigens. When
PMN are activated by a combination of all three cytokines, the cells
express HLA-DR, CD40, and CD83. These cells are likely to present
superantigens. None of the stimuli used in our study induces CD86, an
important co-stimulatory molecule expressed on DC. This may be a reason
why these PMN were not able to activate MLR significantly. Further
activation of the cells with CD40 ligand may result in the expression
of CD86, because CD40 ligand can induce CD86 expression in DC
[55
].
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Figure 4. Phenotypic and functional change of PMN after activation with selected
cytokines. PMN, after emigration, can acquire different cell-surface
markers and functions, suggesting that inflammatory PMN are
heterogeneous.
|
|
As described above, PHA-sup-primed and activated PMN expressed and
produced MCP-1. Neither GM-CSF nor IFN- was responsible for
PHA-sup-induced MCP-1 expression by PMN, because neutralization of
GM-CSF or IFN- activities did not block the priming effect by
PHA-sup [15
]. However, when PMN were activated for
24–48 h in the presence of TNF- and IFN- or GM-CSF, TNF-, and
IFN-, these cells expressed high levels of MCP-1 mRNA and secreted
2–3 ng/ml MCP-1, most of which were secreted between 24 and 48 h.
Kinetics of MCP-1 secretion by those cytokine-activated PMN were
similar to that of PHA-sup-activated PMN. These results suggest that
IFN- and GM-CSF may emulate the priming effect of the 60-kD
factor(s), although they are distinct molecular entities. Because
PHA-sup-primed and activated PMN did not express HLA-DR or CD40,
PHA-sup-primed and activated PMN may be at a similar activation stage
as that of PMN activated with a combination of TNF- and IFN-
(unpublished results). Further study is necessary to determine whether
IFN- and GM-CSF can prime PMN as the 60-kD factor(s). PMN with
potent MCP-1-producing activity can play a role in adaptive immunity by
recruiting large numbers of monocytes and T cells.
All three cytokines we used are available in vivo at sites
of DTH [56
], suggesting the presence and role of
differentiated PMN in DTH. There are other cytokines, including IL-4
and IL-10, which are known to affect the phenotypic and functional
change of PMN. IL-4 and IL-10 have inhibitory effects on
pro-inflammatory cytokine mRNA expression by PMN [3
]. It
will be interesting to determine whether these cytokines can modulate
the differentiation of PMN.
It has been well-established that GM-CSF and M-CSF independently induce
proliferation and maturation of monocytes into distinct subsets of
macrophages with different morphology and functions
[57
]. The differentiation processes can be reversed upon
withdrawal of the cytokines. However, the possibility that
cytokine-activated PMN can be reverted to a resting state and activated
again with different cytokines may be unlikely, because although the
survival of PMN is prolonged after activation with several cytokines,
they subsequently undergo apoptosis.
|
CONCLUSION
|
|---|
Specific roles of PMN in the inflammatory responses have been
investigated by depleting PMN from animals by pre-treating them with
anti-granulocyte antibodies. These in vivo studies have
demonstrated clearly that PMN play crucial roles not only in acute
inflammatory responses caused by bacterial infection or ischemic
reperfusion injury but also in other inflammatory or immune responses
against viruses [58
] and cancers [59
,
60
]. Contributions of PMN in these disease models can be
explained to some extent by their ability to release oxygen radicals,
anti-microbial peptides, and proteolytic enzymes. However, the precise
mechanisms by which PMN mediate these inflammatory responses remain
unclear. Release of anti-microbial peptides from PMN could play a
direct role in adaptive immunity by recruiting PMN, monocytes, DC, and
T cells [38
, 61
]. Acquisition of new
functions by activated PMN may be another mechanism by which PMN play a
role in adaptive immunity. After emigration of circulating PMN into
inflamed tissues, these cells can be activated by numerous stimuli,
including bacterial products, components of ECM such as collagens, and
cytokines. So far, we have tested only a few stimuli to induce
phenotypic and functional changes in PMN. Nevertheless, our studies
have yielded novel findings, which indicate that PMN can undergo
considerable, unique phenotypic and functional changes after activation
with certain cytokines, some of which may be associated with their
roles in adaptive immunity. Our findings also suggest that inflammatory
PMN are heterogeneous depending on the availability of stimuli in a
tissue microenvironment. We will next attempt to define specific roles
of inflammatory PMN in host defense by deleting target genes
specifically in PMN. The knowledge obtained from our studies could be
used to provide opportunities for better treatment and prevention of
chronic inflammation and cancer.
|
ACKNOWLEDGEMENTS
|
|---|
W-H. G. was supported by the Intramural Research Support
Program, SAIC Frederick. The content of this publication does not
necessarily reflect the views or policies of the Department of Health
and Human Services, nor does mention of trade names, commercial
products, or organizations imply endorsement by the U.S. Government.
This project has been funded in part with Federal Funds from the
National Cancer Institute, National Institutes of Health, under
Contract No. NO1-CO-56000. We are grateful to Dr. Joost J. Oppenheim
for his support and critical comments. We are also grateful to Ms.
Nancy Dunlop for her excellent technical assistance.
Received November 30, 2000;
revised January 13, 2001;
accepted January 16, 2001.
|
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TOP
ABSTRACT
INTRODUCTION
