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*
Department of Medical Microbiology, Division of Clinical Immunology, Lund University, Lund, Sweden; and
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, 48109
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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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The epithelial chemokine response to infection has been extensively studied in vitro 3, 4, 5 using cultured epithelial cells. Mucosal pathogens stimulate epithelial cells to secrete C-X-C and C-C chemokines. In the transwell model system, pioneered by Madara et al. 6 , IL-8 has been shown to support neutrophil migration across uroepithelial cell layers infected with Escherichia coli. Monoclonal and polyclonal anti-IL-8 Abs completely blocked the infection-induced increase in neutrophil migration. The effect was due to cell-bound rather than soluble IL-8 and was made possible by a parallel increase in IL-8 receptor expression by the infected cells.
Urinary tract infections (UTI)5 are accompanied by a neutrophil response. Indeed, "pyuria" is one of the classical diagnostic tools in UTI. IL-8 has also been implicated as a major neutrophil chemoattractant in the human urinary tract 1, 3 . Recent studies have shown that urine IL-8 levels increase in patients with UTI, especially during acute pyelonephritis, and that urine IL-8 can support neutrophil migration in vitro 7, 8 . The kinetics of the mucosal IL-8 response were studied in human volunteers after deliberate intravesical inoculation with bacteria. The urine IL-8 concentrations increased rapidly and correlated with urine neutrophil numbers in individual patients 3 . These in vitro and in vivo observations strongly suggested that IL-8 is involved in the mucosal neutrophil responses and that IL-8 of epithelial origin directs neutrophil migration across epithelial barriers.
Macrophage inflammatory protein (MIP)-2 is one of the IL-8 homologues in the mouse. The aim of this study was to examine the C-X-C chemokines and especially the MIP-2 response to experimental UTI and the contribution of MIP-2 to the neutrophil recruitment during UTI.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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E. coli 1177 of serotype O1:K1:H7, was isolated from a child with acute pyelonephritis 9 . The strain was previously shown to cause infection in the mouse UTI model and to evoke a strong inflammatory response 10 . It expressed P and type 1 fimbriae but was hemolysin negative. Bacteria were maintained in deep agar stabs sealed with sterile paraffin. For infection, bacteria were grown overnight in static Luria broth and harvested by centrifugation at 4000 rpm for 10 min. The pellet was resuspended in 0.01 M of PBS, pH 7.2, at a concentration of 1–2 x 109 CFU/ml. The bacterial concentration was confirmed by viable counts.
Experimental UTI
C3H/HeN mice were bred in the animal facilities of the Department of Medical Microbiology, University of Lund (Lund, Sweden). Female mice were used at 9–13 wk of age. Mice were anesthetized, and 0.1 ml of an E. coli 1177 suspension was injected into the bladder through a soft polyethylene catheter (outer diameter 0.61 mm; Clay Adams, Parsippany, NJ) 11 . The catheter was immediately removed, and the mice were allowed food and water ad libitum.
Animals were sacrificed after 2, 6, and 24 h under anesthesia by cervical dislocation. Kidneys and bladders were removed and homogenized in sterile disposable plastic bags using a laboratory blender (Stomacher 80 homogenizer, Seward Medical, UAC House, London, U.K.). The homogenates were diluted in sterile PBS, and 0.1 ml of each dilution was plated on tryptic soy agar. The number of colonies was scored after overnight culture at 37°C.
Urination was induced by gentle pressure on the mouse abdomen, and urine was collected at the urethral orifice into sterile tubes. Urine samples collected before infection were cultured to ensure that the mice were uninfected and were examined for a preexisting neutrophil response. Urine samples collected at 2, 6, and 24 h postinfection were used for neutrophil counts and to quantify the local chemokine response.
Chemokine responses
Murine MIP-2 12 , keratinocyte (KC) 13 , MIP-1
14
monocyte chemoattractant protein-1, MCP-1 (JE) 15 , eotaxin
16 , and human epithelial neutrophil activating peptide-78
(ENA-78) 17, 18 recombinant chemokines were used for the generation
of Abs. Standards for ELISA were purchased from R & D Systems
(Minneapolis, MN). Polyclonal anti-murine and anti-human
chemokine antisera were produced by immunization of rabbits with
chemokines at multiple intradermal sites with CFA. Polyclonal
anti-human ENA antiserum cross-reacts with the murine
equivalent 17 .
Murine MIP-2, KC, ENA, MIP-1, JE, and eotaxin in the urine and MIP-2
in the kidneys and bladders were quantitated by a modification of a
double ligand method 19 . Urine samples were centrifuged and the
supernatant stored at -20°C for chemokine analysis. Kidneys and
bladders were removed, immediately snap frozen, and stored at -70°C.
Kidneys or bladders were homogenized in 3 ml of lysis buffer containing
0.5% Triton X-100, 150 mM NaCl, 15 mM Tris, 1 mM CaCl2,
and 1 mM MgCl2, pH 7.40, using a tissue homogenizer
(Dremel, Racine, WI). Homogenates were incubated on ice for 30 min,
then centrifuged at 1500 x g for 10 min. Supernatants
were collected, passed through a 0.45-mm filter (Gelman Sciences, Ann
Arbor, MI), and used in the ELISA.
Assessment of the neutrophil response
The number of neutrophils migrating across the mucosa into the urine was quantified in uncentrifuged urine, using a hemocytometer chamber. Earlier studies have shown that 99% of the inflammatory cell infiltrate consists of neutrophils 1 .
Tissue neutrophils were quantitated using the myeloperoxidase (MPO) assay 20 . Kidneys and bladders were homogenized in 2 ml of 50 mM potassium phosphate, pH 6.0, with 5% hexadecyl-trimethylammonium bromide and 5 mM EDTA. The homogenate was sonicated and centrifuged at 12,000 x g for 15 min. The supernatant was mixed 1:15 with assay buffer and read at 490 nm. MPO units were calculated as the change in absorbance over time.
Inhibition of neutrophil recruitment
RB6-8C5, a rat IgG2b mAb specific for murine neutrophils and eosinophils 21, 22, 23 was a kind gift from Dr. A. Sjöstedt (Umea University, Sweden), Dr. W. Conlan (Trudeau Institute, Saranac Lake, NY), and Dr. R. Coffman (DNAX Research Institute, Palo Alto, CA). mAb RB6-8C5 was purified from hybridoma supernatants by ammonium sulfate precipitation or by protein G-Sepharose (Pharmacia Biotech, Uppsala, Sweden). The Ig concentration of the purified mAb was determined by ELISA. The mAb or control rat IgG (0.25 mg diluted in 0.5 ml of pyrogen-free saline) were injected i.p. into mice 24 h and again 2 h before bacterial inoculation.
Polyclonal rabbit anti-murine MIP-2 Abs were generated by immunization of rabbits with murine MIP-2 (R & D Systems) 19, 12 . Mice were injected i.p. with anti-MIP-2 antiserum or preimmune serum, (500 µl/mouse), 2 h before intravesical infection.
Histology and immunohistochemistry
Histology and immunohistochemical analysis was performed on kidneys and bladders obtained from mice sacrificed at 0, 2, 6, and 24 h after inoculation 24 . Tissues were cut to 3 x 4 x 5 mm pieces, embedded in OCT compound (Tissue Tek, Miles, Elkhart IN), rapidly frozen in liquid nitrogen, and kept at -80°C until examined. Sections were cut with a steel knife (6 µm) and mounted on poly-L-lysine-coated glass slides. Urine samples were harvested at 6 h postinfection and were spun onto poly-L-lysine-coated glass slides in a Cytospin 11 cytocentrifuge (Shandon Southern Product, Chesire, U.K.) at 300 rpm for 5 min. Samples were fixed in freshly prepared 4% paraformaldehyde in PBS, pH 7.4, for 15 min, rinsed in PBS, and air dried. Sections were stained with hematoxylin and eosin for histology observation. The samples were treated with 0.1% saponin (Sigma, St. Louis, MO) in PBS (PBS-Sap) containing 5% normal mouse serum for 60 min in room temperature to reduce nonspecific binding. After washing in PBS-Sap three times, the samples were incubated with a 1:100 dilution of rabbit anti-mouse MIP-2 antiserum or preimmune serum overnight at 4°C. After washing in 0.1% saponin in Tris-buffered saline (TBS-Sap), alkaline phosphate-conjugated goat anti-rabbit Igs (Dako, Copenhagen, Denmark) were added at a 1:50 dilution’s in TBS-Sap and left to incubate for 60 min at room temperature in a moist chamber. After washes in TBS-Sap, the Fast-Red substrate containing levamisole (Dako) was prepared according to the manufacturer’s recommendations, added to the samples, and left to incubate for 20 min at room temperature. Thereafter, the samples were washed in TBS, pH 7.6, and counterstained with Mayer hematoxylin (Kebo Laboratories, Stockholm, Sweden) for a few seconds, washed in distilled water, and mounted with Mount-quick "AQUEOUS" (Daido Sangyo, Tokyo, Japan). The samples were investigated under a light microscope (Microphot, Nikon, LRI Instruments AB, Tokyo, Japan).
Statistical analysis
Differences between samples were analyzed with the Mann-Whitney U test (two-tailed) and the Spearman rank correlation test. Differences were considered significant for values of p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The C-C and C-X-C chemokine response to intravesical E.
coli 1177 infection was examined in urine samples obtained 2, 6,
and 24 h after infection (Fig. 1
).
KC and JE increased rapidly with peak levels after 2–6 h. MIP-2 and
eotaxin had increased by 2 h but reached peak levels after 6
h. ENA-78 increased slowly, with the highest concentrations after
24 h. MIP-1 was also elevated before infection and showed no
significant change over time. These results demonstrated that E.
coli elicits a diverse chemokine response involving both the C-C
and the C-X-C chemokine families.
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The neutrophil response to intravesical E. coli 1177
infection was quantitated in urine samples obtained at various times
after infection (Fig. 2). Urine
neutrophil numbers had increased after 2 h (66 ± 12
cells/ml), reached a peak by 6 h (238 ± 31 cells/ml), and
remained elevated at 24 h after infection (129 ± 22
cells/ml) (Fig. 2A).
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). Neutrophils were scattered throughout
the renal tissue, adjacent to the pelvic epithelium, and were seen in
the lumen of the renal pelvis. The density of neutrophils in bladder
tissue was lower than in the kidneys.
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Urine chemokine concentrations were examined for possible
correlations with neutrophil numbers in individual urine samples.
Samples in which the neutrophil numbers and the chemokine
concentrations had been determined were included in the analysis.
Positive significant correlations were found for MIP-2
(r = 0.6183, p < 0.005) but not for KC
(r = 0.1615, p = 0.4867), ENA-78
(r = 0.0803, p = 0.7365), MIP-1
(r = 0.2200, p < 0.5588), JE
(r = 0.0847, p = 0.7302), or eotaxin
(r = 0.0102, p = 0.9660). This suggests
that MIP-2 was involved in the infection-induced neutrophil
recruitment.
MIP-2 is produced in the kidney and by recruited PMNs
The site of MIP-2 production in the urinary tract was examined
using kidney and bladder homogenates from infected and control mice
(Fig. 4). Kidney MIP-2 levels increased
to about 40 ng/ml, while bladder levels remained below 10 ng/ml. Kidney
MIP-2 levels increased before a detectable neutrophil response but the
later kinetics followed the neutrophil influx (Fig. 4A).
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). Renal
pelvic mucosal cells showed strong intracellular and surface staining
for MIP-2 after infection (Fig. 5b), but no staining before
infection (Fig. 5a). There was no evidence of MIP-2 staining
in the bladder epithelium, but neutrophils on their way through the
epithelial barrier stained brightly (Fig. 5d). MIP-2 was
also detected in urine neutrophils (Fig. 5f).
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C).
Control Ab had no inhibitory effect.
MIP-2 concentrations in kidneys and bladders of control mice and
RB6-8C5 treated mice are shown in Fig. 4B. MIP-2 levels were
similar at 2 h in both groups of mice, suggesting that the early
response was independent of neutrophils. At 6 h, the
neutrophil-depleted mice had significantly lower tissue MIP-2 levels
than control mice, suggesting that the recruited neutrophils accounted
for the increase at this time. At 24 h after infection, similar
MIP-2 levels were observed in both neutrophil-depleted and control
animals, suggesting that MIP-2 originated from the tissues. MIP-2
concentrations in bladder tissue were low (Fig. 4A).
Inhibition of neutrophil recruitment into the urine following anti-MIP-2 Ab treatment
Pretreatment of the mice with polyclonal anti-MIP-2 Abs
inhibited infection-induced neutrophil migration into the urine (Fig. 2B). Intraperitoneal injection with 500 µl of
anti-MIP-2 antiserum 2 h before intravesical infection with
E. coli 1177 caused a decrease in urine neutrophil numbers
to background levels after 2 h, and neutrophil numbers remained
lower than the control after 6 and 24 h. Preimmune serum had no
effect. These levels confirmed that MIP-2 was involved in
infection-induced neutrophil recruitment.
Difference in localization of tissue neutrophils between RB6-8C5- and anti-MIP-2-treated mice
The neutrophil infiltrate into the tissues of RB6-8C5- or
anti-MIP-2 Ab-treated mice is shown in Fig. 6, A and B,
respectively, using histology and immunohistochemistry. Pretreatment
with RB6-8C5 Ab completely inhibited the neutrophil influx into the
kidney tissue and into the urine (Fig. 6A). Pretreatment
with anti-MIP-2 Ab did not decrease neutrophil recruitment into the
kidneys. In contrast, the density of neutrophils in the kidneys of
anti-MIP-2-treated mice was higher than that in mice treated with
the preimmune serum. The neutrophils accumulated under the mucosal
barrier, but did not cross the urothelium into the urine (Fig. 6B).
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). Mice pretreated with RB6-8C5 Ab had
low kidney MPO activity at 6 and 24 h, confirming the inhibition
of neutrophil recruitment. Anti-MIP-2 Ab-treated mice showed no
difference in tissue MPO levels compared with controls, suggesting that
neutrophil recruitment into the kidney was unchanged. The bladder MPO
activity remained at background levels at 6 and 24 h after
infection in all groups.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chemokines are commonly assigned to two subgroups depending on the
position of the first two cysteines and disulfide bridges. The C-X-C
group contains a single amino acid insert between the first two
cysteines, which are adjacent in the C-C group 25 . Several members of
both groups have been identified in the mouse; MIP-2, KC, ENA-78
(C-X-C), JE, MIP-1, and eotaxin (C-C). In this study, experimental
UTI was shown to trigger a broad mucosal chemokine response including
members of both the C-C and C-X-C families. The chemokines showed
slightly different response kinetics, with KC and JE increasing most
rapidly and ENA-78 most slowly. These results confirm in vitro studies
of epithelial chemokine responses to different infectious agents.
Kagnoff et al. showed that human colonic epithelial cells
constitutively express IL-8, growth related oncogen (GRO),
GROß, GRO
, ENA-78, MCP-1, MCP-1, MIP-1ß, and RANTES 26 .
Uropathogenic E. coli triggers the production of IL-8,
GRO, GROß, GRO, ENA-78, inflammatory protein 10,
Mig, monocyte chemoattractant protein-1, RANTES,
MIP-1, and MIP-1ß in human kidney cell lines (G. Godaly et al.,
unpublished observations). This broad mucosal chemokine repertoir in
both mice and humans suggests that there is a need for mucosal
chemokine diversity. We propose that this diverse chemokine repertoir
provides a basis for specialized recruitment of diverse cell
populations to mucosal sites.
The cellular origin of MIP-2 was examined by quantitation in tissue homogenates and by immunohistochemistry using the MIP-2 antiserum. MIP-2 levels in kidney homogenates increased by 2 h after infection and reached a peak after 6 h. Immunohistochemistry showed MIP-2 staining localized to epithelial cells lining the renal pelvis. These results are consistent with the localization of IL-8 in human kidney biopsies. The epithelial lining of the human urinary tract is rich in IL-8 24 , and human epithelial cells in culture respond to bacterial stimulation and secrete IL-8 both apically and basolaterally. Apical secretion may contribute to the increase in urine IL-8 concentrations during infection. Basolaterally secreted IL-8 is likely to bind the epithelial cells and support neutrophil recruitment. Cell-bound IL-8 of epithelial origin has been shown to support neutrophil passage across the epithelial layer 27 . This study showed a similar role of epithelial MIP-2 for neutrophil passage across the epithelium in the mouse urinary tract mucosa.
MIP-2 staining was also detected in the neutrophils that migrated into renal tissue and into the urine. The relative contribution to the MIP-2 response of kidney epithelial cells and neutrophils, respectively, was analyzed in mice after depletion of neutrophils by pretreatment with RB6-8C5. The kidneys were also shown to produce significant amounts of MIP-2 in the depleted mice. Kinetics suggested that the kidney epithelium was the main source of MIP-2 chemokine during the early stages of infection, but that peak 6-h levels were produced mainly by recruited neutrophils. These observations illustrated the sequential nature of the early inflammatory response, with a first "wave" of mediators produced by the local tissue in response to infection and a second "wave" following the recruitment and activation of specialized inflammatory cells.
The results in the bladder mucosa differed between human and mouse. While IL-8 staining is found in human bladder epithelium, no intracellular epithelial MIP-2 staining was seen in the mouse bladder. The cells with strong MIP-2 staining in the bladder lumen were neutrophils. Tissue sections did not show large neutrophil numbers at any time point, and bladder MPO levels were low. After treatment with anti-MIP-2 Ab, there was no build up of neutrophils under the bladder epithelium. These observations suggested that most of the neutrophils in the infected urinary tract were recruited through the kidneys rather than the bladder or that chemokines other than MIP-2 exert this function in the bladder mucosa.
Important differences were noted between the two Abs used to inhibit neutrophil migration. Both Abs caused a significant reduction in urine neutrophil numbers, but only the RB6-8C5 Ab blocked neutrophil migration into the kidneys. Histology revealed the virtual absence of neutrophils in RB6-8C5-treated mice, and kidney MPO levels were low. MIP-2 Ab treatment blocked neutrophil migration into the lumen, but had no effect on the neutrophil recruitment into the kidneys. Mice pretreated with anti-MIP-2 Ab had adequate tissue neutrophil levels but kidney MPO-levels increased after infection to the same levels as in the control mice. This apparent paradox was explained by immunohistochemistry. In anti-MIP-2 Ab-treated mice, neutrophils accumulated on the tissue side of the pelvic epithelium, suggesting that MIP-2 is required to support neutrophil migration across the urothelium into the urine. This is consistent with in vitro studies showing that IL-8 supports neutrophil migration across E. coli-stimulated human uroepithelial cells layers and that Abs to IL-8 block tissue epithelial neutrophil migration 28 .
Neutrophils are essential effector cells of the antimicrobial host defense at systemic infection sites 21, 24, 27 . Defects that influence the inflammatory response to infection impair bacterial clearance. In a parallel study, we examined the role of the neutrophils for bacterial clearance from the urinary tract. Mice depleted of neutrophils with the RB6-8C5 Ab were highly susceptible to infection with 1000-fold more bacteria in the kidneys than control mice after 24 h. In contrast, anti-MIP-2 Ab-treated mice were able to clear bacteria from the kidneys. This suggested that the neutrophils that accumulate under the epithelium remain fully functional as antibacterial effector cells, despite their inability to cross the epithelial barrier. While these studies clearly demonstrate the importance of neutrophils for host resistance to mucosal infection, they also provide evidence for complexity and redundancy in the mechanism of neutrophil recruitment. Our results suggest that neutrophils cross epithelial cell barriers in a highly regulated manner in response to chemotactic gradients elaborated at this site.
Epithelial cell chemokine production may have evolved to serve physiologic functions unrelated to the antimicrobial defense. Aging neutrophil cells need to be eliminated from the circulation and the tissues. If transported to the mucosa in response to a suitable gradient, they can leave the body with their granular content intact and be destroyed in the lumen, where the toxic products do little damage to the host. It may be speculated that the diversity and apparent hierarchy of mucosal chemokine responses have evolved to support such functions and not only for the defense against mucosal pathogens.
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Acknowledgments |
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Footnotes |
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2 Present address: Department of Urology, Children’s Hospital Medical Center Fukuoka, 2-5-1 Toujin-mati, Chyuo-ku, Fukuoka, 810, Japan.
3 Present address: Division of Rheumatology, Immunology and Allergy, Lymphocyte Biology Section, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115.
4 Address correspondence and reprint requests to Dr. Catharina Svanborg, Department of Medical Microbiology, Division of Clinical Immunology, Lund University, Sàlvegatan 23, S-223-62, Lund, Sweden. E-mail address:
5 Abbreviations used in this paper: UTI, urinary tract infection; MIP, macrophage inflammatory protein; MPO, myeloperoxidase; KC, keratinocyte; JE, monocyte chemoattractant protein-1, MCP-1; ENA, epithelial neutrophil activating peptide; Sap, saponin; TBS, Tris-buffered saline.
Received for publication July 10, 1998. Accepted for publication December 3, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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–) and bladder (–
–) homogenates from mice infected
with E. coli 1177. Urine neutrophil numbers (–
–)
are shown for comparison. Numbers are means ± SE of 5–8 mice per
time point. B, MIP-2 levels in urine of mice treated
with mAb RB6-8C5 (–
–). Numbers are
means ± SE of 5–8 mice per time point.
