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* Department of Immunology, Klinikum der Universität Greifswald, Sauerbruchstrasse, Germany;
Molecular Immunology, Robert Koch-Institute, Berlin, Germany;
Centre National de la Recherche Scientifique Institut Transgenose, Orleans, France;
Infectious Disease Division, University of Massachusetts, Worcester, MA 01655; and
¶ Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the involvement of LBP and CD14 in innate defense, we
have generated LBP- and CD14-deficient mouse lines and used them to
show that both genes are essential for survival in an i.p.
Salmonella infection (6, 7). LBP is thought to
function by transferring LPS released from the outer membrane of
Gram-negative bacteria to CD14 and by so doing to initiate the signal
cascade involving TLR4, myeloid differentiation protein 2, myeloid
differentiation factor 88, and NF-
B, which results in the
synthesis and release of proinflammatory mediators from macrophages
(8). The observation that both CD14- and TLR4-deficient
mice are much more susceptible to a Salmonella infection is
in line with the notion that this pathway is a necessary component of
innate defense against the pathogen (7). Indeed, the
requirement for LBP can be entirely replaced by exogenous application
of the proinflammatory mediator TNF, suggesting that the essential
nonredundant function of the LBP in these mice is to initiate an
inflammatory response (9).
An inflammatory response involves a complex set of events which include changes in the structure of the cytokine network, rearrangement of innate immune cell populations, and changes in the activation status of these cells. In many infection systems, neutrophil activation plays a central role in innate defense. This is certainly the case with an i.p. Salmonella infection since it has recently been shown that neutrophil depletion abrogates the mouse’s capacity to mount an adequate defense (10). In this study, we have examined the role of LBP and CD14 in inducing neutrophil influx in response to an infection with Salmonella.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Salmonella enterica var typhimurium (S. typhimurium) (ATCC 14028s) transfected with green fluorescent protein (GFP) was a gift from Dr. H. Hensel (Max von Pettenkofer Institut, Munich, Germany). Mid-log phase cells were collected by centrifugation and washed with PBS. Numbers of CFU injected were estimated from the OD at 550 nm and checked by plating aliquots of the inoculum. Mice were injected i.p.
Mice
LBP-deficient mice carrying the NRAMP-1R allele derived from strain CBA were as previously described (9). LBP-deficient animals were backcrossed to strain CBA for four backcross generations and LBP+/- heterozygotes were then crossed inter se. LBP-/- male progeny were then crossed to their LBP+/+ littermates to generate heterozygotes or to their LBP-/- littermates to expand the number of LBP-deficient animals. CD14-/- (11) and CD14+/- animals carrying the CBA-derived NRAMP-1R allele were generated in the same way. Genotyping of these animals by PCR was as previously described (7). Mice deficient for the TNF gene (12) on a C57BL/6 background were reared in the animal facility in Orleans, France. Animals of strain BALB/c, C57BL/6, and CBA were purchased from Charles River Breeding Laboratories (Sulzfeld, Germany). Mice were used at 8–12 wk of age.
Bacterial load in the peritoneum
Mice were infected with Salmonella and 24 h
later sacrificed by cervical dislocation and the peritoneal cavity was
washed with 10 ml of cold sterile PBS. The preparation of the mice and
the peritoneal wash require 
5 min. Because of this, control animals
infected and immediately processed are equivalent to an i.p. infection
of 5–10 min. Appropriate dilutions of the peritoneal wash were plated
in duplicate. Plates were incubated for 16 h at 37°C and
colonies were counted.
Assay of IL-6 and TNF in the peritoneum of infected animals
Groups of animals were infected with 5000 CFU of
Salmonella and 0.5, 1.0, and 2.0 h later they were
sacrificed. The peritoneal cavity was washed with 1 ml of PBS and the
recovered peritoneal wash (0.5 ml) was centrifuged at 500 x
g to remove cells. The cell-free supernatant was assayed for
IL-6 and TNF by ELISA using kits from BD PharMingen (Heidelberg,
Germany). The values for the amount of detected cytokines are given as
picograms per peritoneum.
Preparation of peritoneal wash cells
Groups of six animals were injected i.p. with 100 µl of Salmonella suspended in sterile pyrogen-free saline. Since injection of PBS or saline at 4°C also results in a substantial neutrophil influx into the peritoneum, all solutions were prewarmed to 37°C before injection. At the appropriate time points, animals were sacrificed by cervical dislocation and the peritoneum was washed with 10 ml of sterile PBS. Recovered cells were pelleted by centrifugation at 300 x g for 10 min at 4°C and resuspended in 500 µl of PBS. Cell number was determined using a counting chamber. Although in general more cells are recovered from larger animals than from smaller ones, there is no significant strain-dependent difference between the total number of peritoneal cells recovered from the strains used in this study (C57BL/6, BALB/c, and CBA).
FACS analysis
The fraction of neutrophils in the population of peritoneal wash cells was determined by FACS analysis using FITC-labeled mAb RB6-8C5 (BD PharMingen, Heidelberg, Germany). This Ab detects an epitope on the Ly6G molecule which is highly expressed on neutrophil lineage cells and to a lower extent on a population of CD8+ T cells (13). 7-azo-actinomycin D was used as a nuclear stain to define the living cells and within this gate the Ly6Ghigh cells were counted as neutrophils. In preliminary experiments, the identity of the cells flooding into the peritoneum after infection was checked by examining smears of the isolated peritoneal cells. There was no significant difference between the numbers of neutrophils estimated by FACS analysis using mAb RB6-8C5 and by morphological criteria. The fraction of macrophages was determined using FITC-labeled anti-F4/80 (Caltag Laboratories, Burlingame, CA). Statistical comparisons of the responses of the animals were conducted using the Mann-Whitney U test.
Confocal microscopy
Initial attempts to study phagocytosis of Salmonella by peritoneal wash cells using confocal microscopy were frustrated by the fact that the cytospin procedure which we used resulted in a flattening of the neutrophils and macrophages on the slides. We therefore adopted a different approach designed to maintain the three-dimensional structure of the cells. Peritoneal wash cells were surface stained in suspension, fixed, and dropped onto indented slides. The staining procedure was as follows: 2 x 105 peritoneal wash cells in 50 µl of FACS-PBS (PBS supplemented with 2.5% FCS and 0.01% NaN3) were incubated on ice with 4 µl of unlabeled RB6-8C5 (20 µg/ml) for 30 min. The cells were then washed twice in 200 µl of FACS-PBS. The cell pellet was resuspended in 50 µl of FACS-PBS containing 7.5 µg/ml anti-rat Ig-Cy3 (Dianova, Hamburg, Germany). After incubation on ice for 30 min, the labeled cells were washed twice with FACS-PBS, resuspended in 50 µl of PBS, and treated with 50 µl of 4% formaldehyde. Fixation was for 20 min at room temperature. The fixed cells were washed twice with FACS-PBS, resuspended in 50 µl of FACS-PBS supplemented with 0.2% saponin (Sigma-Aldrich, St. Louis, MO) containing TOTO-3 iodide (Molecular Probes, Eugene, OR) at a final concentration of 0.2 µM, and incubated at room temperature for 15 min. Cells were then washed once with FACS-PBS, resuspended in 10 µl of Citifluor AF1 (PLANO, available at www.plano-em.com), and stored at 4°C before analysis. The labeled cells were transferred to indented glass slides and examined in a Zeiss model LSM510 confocal microscope (Zeiss, Oberkochen, Germany) using a x63 water immersion lens. Single cells were analyzed in three dimensions by creating a stack of images at overlapping Z levels. Orthogonal sections were cut through the Z-stack with the help of the LSM510 image analysis software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously shown that LBP and CD14 are required for mice
to survive an i.p. infection with Salmonella (6, 7). Since it is well established that in this infection model
neutrophils play an essential role in innate defense (10),
we have asked whether neutrophil influx into the peritoneum following
infection is altered in the absence of LBP or CD14. To follow changes
in the neutrophil population, we have used the mAb RB6-8C5
(13). In an uninfected LBP+/-
heterozygous mouse, granulocytes (Ly6Ghigh cells)
make up 1% or less of the peritoneal wash cell population. Injection
of PBS alone does not cause neutrophil influx (Fig. 1
B). However, injection of
5000 CFU of Salmonella results in a rapid influx of cells so
that within 2 h a substantial fraction of the population of
peritoneal wash cells is composed of neutrophils and by 24 h up to
50% of the peritoneal cell population consists of neutrophils. A
typical result is shown in Fig. 1. This is not due to some peculiarity
of our LBP+/- animals since the same result is
reproducibly seen with BALB/c mice (Fig. 2) as well as for CBA and C57BL/6 animals
(data not shown).
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). This relatively small increase in the size of the total
peritoneal population is matched by a dramatic increase in the number
of neutrophils. In uninfected animals neutrophils make up <1% of the
total peritoneal cell population. Twenty-four hours after i.p.
infection with 3000 CFU of Salmonella, they are 50% of
the peritoneal cells. Thus, a 2-fold increase in the total peritoneal
cell population reflects a >50-fold increase in the neutrophil
subpopulation. When the infection is initiated with as few as 30 CFU,
the effects are smaller but even here a substantial neutrophil influx
takes place (Fig. 2). Peritoneal neutrophils in LBP-/- and CD14-/- mice
To determine what role LBP and CD14 may play in the host response
to the infection, we investigated the kinetics of neutrophil influx
into the peritoneum in LBP+/-,
LBP-/-, and CD14-/-
mice. Animals were infected i.p. with 3000 CFU of Salmonella
and after 24 h the influx of neutrophils was determined by FACScan
analysis. In all three lines, a considerable neutrophil influx was
evident following infection, showing that neither LBP nor CD14 is
essential for this to occur (Fig. 3A). Nevertheless, when
earlier stages of the infection were examined, we found that the
absence of either CD14 or LBP delays the neutrophil influx. Two hours
after infection, many neutrophils have entered the peritoneum of the
control animals (Fig. 3B) but no such influx is apparent in
the CD14-/- or LBP-/-
animals (Fig. 3B). By 4 h after infection, however,
neutrophil influx into the peritoneum is apparent even in the
LBP-/- and the
CD14-/- animals (Fig. 3C).
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Delayed influx of neutrophils is accompanied by expansion of Salmonella
We next asked whether differences in the number of bacteria are
detectable 2–4 h after infection. As shown in Fig. 4, LBP-/-
animals, both at 2 and 4 h after infection, have a small but
significant (p < 0.05, Mann-Whitney
U test) deficiency in their capacity to clear the infection
and hold the multiplication of the pathogen in check. Indeed, a
substantially increased number of Salmonella are detected in
the peritoneum and in peripheral organs of LBP-deficient animals 24–72
h after infection (6, 9). Thus, a delayed influx of
neutrophils into the peritoneum might provide an opportunity for the
Salmonella to expand and overwhelm the innate defense
system.
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In wild-type mice, a peritoneal Salmonella infection is
followed by a rapid inflammatory response measured as an increase in
serum IL-6. The serum IL-6 increase is already evident 2 h after
infection. This inflammatory response, which is essential for survival,
is not detected in LBP-/- animals
(9). Since neutrophil influx into the peritoneum following
infection is by this time already apparent, we asked whether an
inflammatory reaction could be detected in the peritoneum at early time
points. Groups of three LBP-/-,
CD14-/-, and control mice were infected with
5000 CFU of Salmonella and after 0.5, 1.0, and
2.0 h the titer of the proinflammatory cytokines IL-6 and TNF in
the peritoneum was measured by ELISA. As shown in Fig. 5, both IL-6 and TNF are readily
detectable in the peritoneum 1 h after infection in the control
animals but are not detectable in the CD14-/-
or in the LBP-/- mice.
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Since an early proinflammatory response involving TNF is of
central importance in surviving a peritoneal Salmonella
infection, we asked whether injection of TNF alone would stimulate
neutrophil influx in uninfected mice. As shown in Fig. 6 injection of 800 ng of recombinant
human TNF (9) into LBP+/- animals
indeed resulted in a substantial influx of neutrophils measured 2 and
4 h later.
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The fact that exogenously applied TNF is able to induce neutrophil
influx raises the possibility that TNF may play a major role in vivo in
organizing neutrophil influx early in the infection. To test this
hypothesis, we have made use of TNF-deficient animals. As shown
in Fig. 7, the animals carrying a
targeted deletion of the TNFgene do mount a neutrophil influx in response to
Salmonella infection but the response is significantly less
than that seen in the controls injected with the same number (800 CFU)
of Salmonella. We have tried as an alternative approach to
reduce the available TNF in the mice by injecting 1.25 mg (63 mg/kg) of
recombinant human TNFR2-IgG1-Fc H chain (Enbrel; Immunex, Seattle,
WA) at the same time as the Salmonella. In contrast
to the result with the TNF KO mice, there is no reduction in the
neutrophil influx in Enbrel-treated animals.
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To determine whether the neutrophils which move into the
peritoneum late are competent to phagocytose the Salmonella,
we have conducted confocal microscopy of peritoneal cells recovered
after peritoneal infection with Salmonella expressing GFP.
To be able to detect sufficient phagocytosed bacteria, we injected
1 x 107 CFU of Salmonella and
examined the peritoneal wash 2–4 h after infection. After recovery
from the peritoneum, the neutrophils were surface stained using the mAb
RB6-8C5. The staining procedure was optimized to maintain the
three-dimensional structure of the cells for confocal microscopy (see
Materials and Methods). A preliminary examination in the
confocal microscope at low magnification showed that 20% of
neutrophils in LBP-/-,
CD14-/-, and
LBP+/- controls were associated with
Salmonella. This may well be an underestimate since the GFP
fluorescence seems to be rather rapidly lost after phagocytosis.
Neutrophils staining positive for the GFP label of the bacteria were
subjected to confocal serial optical sectioning to determine whether
the associated Salmonella were inside the cell or merely
bound on the surface. In three independent experiments, a total of
seven LBP-/- neutrophils, five
CD14-/- neutrophils, and seven neutrophils
from the LBP+/- controls were examined in
this way. Typical results shown in Fig. 8 demonstrate that not only
neutrophils from LBP+/- mice (Fig. 8A) but also those from both
CD14-/- (Fig. 7B) and
LBP-/- (Fig. 8C) animals were able
to ingest the bacteria in vivo. Thus, these neutrophils, although
delayed in their influx kinetics, are phagocytosis competent once they
reach the peritoneal cavity.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One of the earliest responses to a peritoneal infection with
Salmonella which we have so far been able to detect involves
the release of proinflammatory mediators, including IL-6 and TNF. The
rapid release of TNF is a hallmark of mast cell activation since these
are the only cells in the body that store preformed TNF (15, 17). Although bone marrow-derived mast cells do not express
CD14, they do express TLR4 and are competent to respond to LPS with the
release of proinflammatory mediators (18). Whether they
require soluble CD14 to do this has not yet been established. An early
consequence of the proinflammatory response involves a rapid and
massive influx of neutrophils into the peritoneum. Within a few hours
sufficient neutrophils flow in to double the size of the peritoneal
population. One of the most astonishing aspects of this response is
that it can be triggered by as few as 30 CFU (Fig. 2).
It has previously been shown in a peritoneal Klebsiella pneumonia infection in WBB6F1 mice that removal of TNF reduces but does not abolish neutrophil influx. It was concluded that TNF plays a major role in stimulating neutrophil influx but that other mediators may also be involved (15). The results we obtained in the Salmonella model are strikingly similar. The neutrophil influx at 2 h was substantially reduced but not to the same extent as was seen in the LBP-/- or CD14-/-animals. This suggests that in this infection model the proinflammatory response initiated via LBP and CD14 generates mediators other than TNF which can also, albeit less efficiently, organize the influx of neutrophils into the peritoneum. In this respect, it is interesting that the attempt to abrogate neutrophil influx using Enbrel was not successful even though the human TNFR2 is known to bind mouse TNF and the 62.5-mg/kg dose used is substantial in comparison to the 0.4 mg/kg routinely used in the treatment of human patients with polyarticular-course juvenile rheumatoid arthritis. One possible explanation might be that in this infection model the level of TNF required to induce neutrophil influx is very low, lower than can be reached by entrapment with the soluble TNFR. Were this to be the case it might help explain why there is only a moderate increase of the risk of serious infection in patients treated with this drug (19).
The low but significant level of neutrophil influx discernible in the TNF KO mice 2 h after infection indicates that TNF-independent processes are able to initiate neutrophil influx. In line with this is the observation that loss of either LBP or CD14 does not lead to a complete failure to recruit neutrophils into the peritoneal cavity. Indeed, 24 h after infection there is no discernible difference between the KO animals and the controls in the number of peritoneal neutrophils. Clearly, systems other than LBP-CD14-TLR4 are also able to induce an influx of phagocytosis competent neutrophils in response to a Salmonella infection. However, in the absence of the LPS detection system, there is a short but crucial delay in the recruitment of neutrophils.
Since any single recognition system may eventually be evaded by the
pathogen, it is likely that the host relies on a spectrum of detection
systems for its defense. Indeed, recent evidence indicates that there
are multiple possibilities for the mouse to detect an incipient
peritoneal infection with Salmonella. Like all other
bacteria, Salmonella produces lipoproteins capped with the
N-acyl-S-diacylglyceryl cysteine element
necessary for interaction with TLR2 (20, 21). The LPS
detection system, consisting of LBP, CD14, and TLR4, provides a second
possibility (6, 22). A third possibility may be offered by
the fact that Salmonella is a flagellated bacterium whose
flagellin is a potent activator of TLR5 (23). Beyond these
TLR-based systems, complement activation provides a further innate
means of sensing a peritoneal infection (24). It is likely
that many, perhaps all, of these systems play a role in defense against
a peritoneal Salmonella infection. In the race between the
host and pathogen, survival of the host depends on achieving maximal
advantage from an integrated set of defense strategies. Incapacitation
of any of the host’s defenses may tip the balance in favor of the
pathogen. Loss of the LPS detection system through ablation of LBP
(6) or of CD14 (11) results in a failure to
induce an early inflammatory response, leading to a delayed recruitment
of neutrophils into the peritoneum. It would seem unlikely that the
modest increase in bacterial numbers which this delay permits (Fig. 4)
would be sufficient to explain the central importance of LBP and CD14
in defense against Salmonella. However, this pathogen is
known to adapt to life within the host by a reorganization of its gene
expression pattern (25, 26). The delayed response may give
the pathogen a short but crucial window of opportunity in which to
complete this adaptation process, thus enhancing its capacity to
overrun the remaining defense systems. In this way an apparently minor
delay in neutrophil recruitment in the initial hours of the infection
may make the difference between life and death a week later. We are
currently attempting to clarify this issue by extending our analysis of
the development of the infection beyond the first 24 h.
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Footnotes |
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2 K.K.Y. and B.G.D. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Robert S. Jack, Institut für Immunologie und Transfusionsmedizin, Klinikum der Universität Greifswald, Sauerbruchstra
e, D-17489 Greifswald, Germany. E-mail address: jack{at}mail.uni-greifswald.de
4 Abbreviations used in this paper: LBP, LPS-binding protein; TLR, Toll-like receptor; GFP, green fluorescent protein.
Received for publication February 25, 2002. Accepted for publication July 31, 2002.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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D. D. Bannerman, M. J. Paape, W. R. Hare, and E. J. Sohn Increased Levels of LPS-Binding Protein in Bovine Blood and Milk Following Bacterial Lipopolysaccharide Challenge J Dairy Sci, October 1, 2003; 86(10): 3128 - 3137. [Abstract] [Full Text] [PDF]
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 P. A. Thompson, P. S. Tobias, S. Viriyakosol, T. N. Kirkland, and R. L. Kitchens Lipopolysaccharide (LPS)-binding Protein Inhibits Responses to Cell-bound LPS J. Biol. Chem., August 1, 2003; 278(31): 28367 - 28371. [Abstract] [Full Text] [PDF]
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J.-W. Lee, M. J. Paape, T. H. Elsasser, and X. Zhao Recombinant Soluble CD14 Reduces Severity of Intramammary Infection by Escherichia coli Infect. Immun., July 1, 2003; 71(7): 4034 - 4039. [Abstract] [Full Text] [PDF]
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