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* Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, School of Medicine, Kumamoto University, Kumamoto, Japan;
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cytokines use complex signaling cascades to elicit their biological effects. Stat proteins are fundamental transcription factors that mediate cytokine signaling and are implicated in a variety of immune responses (10, 11). Although most of the studies to date have focused on the role of Stat proteins in T cells or T cell-related acquired immunity, it is now evident that Stat proteins are also involved in innate immunity. In a murine model of septic peritonitis induced by cecal ligation and puncture (CLP), 3 we have shown that mice deficient in Stat4 and Stat6 are resistant to the lethality by balancing local type-1 and systemic type-2 cytokine responses (12). Stat3 is a key transcriptional factor for several cytokines including anti-inflammatory cytokine IL-10 (13). Recently, we have demonstrated that Stat3 activation in macrophages is indispensable for IL-10 mediated anti-inflammatory responses in a murine model of endotoxin shock (14).
To further identify the functional role of Stat3 in innate immune cells during sepsis, we here used a murine model of sepsis induced by CLP. CLP is a clinically relevant model of intraabdominal sepsis that develops slowly and simulates a polymicrobial enteric insult similar to that seen in patients with colonic perforations (15). In the present study, we demonstrate that mice with Stat3 deficiency in macrophages and neutrophils are highly susceptible to sepsis induced by CLP. The increased lethality resulted from aberrant inflammation, characterized by excessive systemic inflammatory responses with serious multiple organ failure (MOF). The event was accompanied by overzealous production of inflammatory cytokines. Furthermore, we show novel findings that Stat3 activation is fundamental for effective bacterial clearance by innate immune cells. These results suggest a new paradigm for the role of Stat3 in host defense during sepsis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice with a cell type-specific disruption of Stat3 gene in macrophages and neutrophils were generated as described (14). In brief, LysMcre mice in which the cre cDNA was inserted into the mouse lysozyme M gene (a mixed 129/Ola, C57BL/6 and CB.20 background) were crossed to mice heterozygous for a Stat3 null mutation (16), leading to the generation of mice that carried the cre gene and the heterozygous Stat3 null mutation (LysMcre/Stat3+/- mice). LysMcre/Stat3+/- mice were further mated with a mouse in which the Stat3 gene was flanked by two loxP sites (Stat3flox/+ mice) to generate LysMcre/Stat3flox/- mice. LysMcre/Stat3+/+ from these crosses were used as wild-type littermate controls in the experiments. Despite the residual STAT3 protein in peritoneal macrophages, cytokine-induced Stat3 activation was completely abolished in LysMcre/STAT3flox/- mice (14). Female mice (6–8 wk) were used in this study under specific pathogen-free conditions. The animal use committee at the Kumamoto University (Honjo, Japan) approved all studies.
In vivo experimental protocol
The mice were subjected to CLP surgery, as described elsewhere (7, 15, 17). In brief, mice were anesthetized and the cecum was exposed, ligated with a 3–0 silk suture below the ileocecal valve, and punctured through and through once with an 18-gauge needle. In the first set of experiments, CLP mice were monitored for 7 days after CLP to determine mice survival. In the second set of experiments, CLP mice were anesthetized, bled, and euthanized at appropriate intervals after CLP. The peritoneal cavities were washed with 1 ml x 2 of sterile saline, and the lavage fluids were harvested. After taking a 10-µl aliquot for bacteria CFU, the lavage fluids were centrifuged and the resultant cell-free peritoneal fluids were stored at -50°C. Ten microliters of peritoneal lavage fluids and peripheral blood from each mouse were serially diluted with sterile saline. Five microliters of each dilution was aseptically plated on Trypticase Soy Agar (TSA) plates with 5% sheep blood and incubated overnight at 37°C, after which the number of aerobic bacteria colonies was counted. Cell pellets were resuspended in saline and the cell numbers were counted in a hemocytometer. Differential cell analysis was made after Diff-Quik staining of cytospin preparations. The liver and kidney were excised, snap frozen in liquid nitrogen, and stored at -80°C. A part of tissues was fixed in 4% paraformaldehide, embedded in paraffin, and the tissue sections were stained with H&E or masson-trichrome. In other experiments, mice were i.p. inoculated with live bacteria (2 x 108 CFU/mouse) recovered from CLP mice, after which the survival rates were monitored. For this, peritoneal lavage fluids at 24 h after CLP were plated on TSA-blood plates and incubated overnight at 37°C. The resultant aerobic colonies were resuspended in saline and the CFU was titrated.
Clinical chemistry and endotoxin level
Levels of aspartate transaminase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), creatinine, serum amyloid A (SAA), and albumin were measured with human assay systems. Fibrinogen level in plasma was measured by sandwich ELISA using anti-murine fibrinogen IgG (Nordic, Tilburg, The Netherlands) and murine fibrinogen (Molecular Innovations, Southfield, MI). Plasma endotoxin level was assessed with a QCL-1000 kit (Daiichi Pure Chemicals, Tokyo, Japan).
Measurement of cytokines and myeloperoxidase (MPO)
Murine cytokines were measured using a standard method of sandwich ELISA, as described (7, 12). The captured Abs, detection Abs and the recombinant cytokines were purchased from R&D Systems (Minneapolis, MN). The ELISAs used in this study did not cross-react with other murine cytokines available. Measurement of MPO levels in liver extracts was measured by ELISA kit (Calbiochem, San Diego, CA). The livers were homogenized in PBS containing 0.1% TritonX-100 and complete protease inhibitor (Roche, Mannheim, Germany), centrifuged, and the cleared supernatants were obtained. Protein concentrations in the extracts were measured by protein-dye binding assay (Bio-Rad, Hercules, CA).
Western blotting
Leukocytes were dissolved in Laemmli buffer (1 x 106/50 µl), sonicated, boiled, fractionated on SDS-polyacrylamide gel (10 µl), and transferred to a nitrocellulose membrane. After blocking with TBS + 0.1% Tween 20 containing 5% skim milk for 1 h at room temperature, the membrane was incubated with Abs to STAT3 or tyrosine-phosphorylated STAT3 (Cell Signaling, Beverly, MA) overnight at 4°C. After washing with TBS + 0.1% Tween 20, the membrane was incubated with anti-HRP-linked Ab for 1 h at room temperature and visualized with an enhanced chemiluminescence system (Cell Signaling).
In vitro bactericidal activities of leukocytes
Peritoneal cells were harvested from non-treated mice, cultured for 1 h at 37°C (3 x 106/ml) in antibiotic-free RPMI 1640 containing 5% FCS, and the adherent cells were used as resident macrophages. Infiltrating leukocytes were harvested at 18 h after i.p. injection of 1 ml of 4% thioglycollate, washed, and placed in 24-well culture plates (3 x 106/ml) in antibiotic-free RPMI 1640 containing 5% FCS. Most of the cells were alive (>97%, trypan blue exclusion) and consisted of macrophages and neutrophils. The populations were similar between LysMcre/Stat3flox/- mice and LysMcre/Stat3+/+ mice (50–60% neutrophils). Lymphocytes were <5% in total leukocytes. In some experiments, neutrophils were isolated from elicited leukocytes (>94%) by Ficoll gradient centrifugation. To determine in vitro bactericidal activities of cells, a classical CFU assay was used with minor modifications (18). In brief, cells were infected with 1 x 106 CFU of live bacteria recovered from CLP-mice. Control wells contained only bacteria. After a 4-h culture in a 5% CO2 incubator, plates were placed at -80°C for 30 min and cells were lysed by thawing. This did not affect bacteria viability, as determined in control experiments. The lysates were serially diluted, plated on TSA-blood plates, incubated overnight at 37°C, and the number of aerobic colonies were counted. Bactericidal activity was expressed as the percentage of bacteria death = [CFU from control wells (without cells) - CFU from experimental wells)]/[(CFU from control wells (without cells)] x 100.
Cell culture
Resident peritoneal macrophages and infiltrating leukocytes, prepared as described above, were cultured in RPMI 1640 supplemented with 5% FCS, glutamine and antibiotics in a 5% CO2 incubator for 24 and 48 h with a TLR2-ligand, macrophage-activating lipopeptide-2 (MALP-2) (10 ng/ml, Alexis Biochemicals, Montreal, Canada) or a TLR4-ligand, Escherichia coli LPS (100 ng/ml, 0111, B4: Difco, Detroit, MI). The culture supernatants were used for measurements of cytokines and lysosomal enzyme release, which was assessed by measuring 
-glucuronidase activity (19). In other experiments, spleens were excised from CLP-mice post-24 h and spleen cells were dispersed into single-cell suspensions. After lysing RBC, the cells (5 x 106/ml) were suspended in RPMI 1640 supplemented with 5% FCS, glutamine and antibiotics and cultured in a 5% CO2 incubator for 48 h without stimulation.
Statistics
Statistical significance was evaluated by ANOVA. In case of survival curve and CFU count, the data were analyzed by the log-rank test and Mann-Whitney U test, respectively. A p < 0.05 value was regarded as statistically significant. All data were expressed as mean ± SE.
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Results |
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In initial investigations, we examined whether Stat3 was activated in the infiltrating leukocytes during CLP. CLP permitted the recruitment of neutrophils and macrophages in the peritoneum. Lymphocytes were minor populations within 24 h post CLP (<5%). As shown in Fig. 1A, Stat3 in infiltrating leukocytes was tyrosine-phosphorylated in Stat3+/+ control littermates, indicating that the Stat3 was activated during CLP. In contrast, the phosphorylated-Stat3 was completely abrogated in mice with Stat3 deficiency in macrophages and neutrophils despite the negligible Stat3 protein in the infiltrating leukocytes (Fig. 1A).
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Enhanced local inflammation in mice lacking Stat3
In an attempt to identify the mechanism underlying the increased lethality, we first investigated the leukocyte influx in the peritoneum during CLP. The data in Fig. 2 showed that the numbers of infiltrating neutrophils and macrophages were significantly augmented in LysMcre/Stat3flox/- mice, resulting in a 2.3- and 1.7-fold increase, respectively, at 24 h post-CLP as compared with the control mice. Given previous data implicating Stat3 in apoptosis (20), we examined leukocyte apoptosis at 6 and 24 h after CLP. Consequently, most of the leukocytes from LysMcre/Stat3flox/- mice and control mice were alive (>94%) as determined by trypan blue exclusion. DNA ladder pattern was not detected on electrophoresis (data not shown). We then measured peritoneal levels of cytokines during CLP, which showed that LysMcre/Stat3flox/- mice displayed dramatic increases in the peritoneal level of TNF-
, IL-1, IL-12, and IFN-
, relative to the controls (Fig. 3). In addition, levels of IL-6 and IL-10, cytokines using Stat3 in their signaling, were elevated in LysMcre/Stat3flox/- mice. Thus, mice lacking Stat3 in macrophages and neutrophils exhibited an exaggerated local inflammation that was accompanied by increases in the peritoneal level of multiple cytokines, but not associated with apoptosis.
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Plasma cytokine level was next investigated, which demonstrated that levels of circulating TNF-, IL-1, IL-12, IFN-, IL-6, and IL-10 were dramatically increased in LysMcre/Stat3flox/- mice relative to the controls (Fig. 4A). In addition, spleen cells from LysMcre/Stat3flox/- mice that have undergone CLP spontaneously released higher levels of IL-12 and IFN- than did cells from the control mice (Fig. 4B), suggesting that systemic inflammation might be deteriorated in LysMcre/Stat3flox/- mice. Subsequently, the severity of systemic inflammation was examined. Acute phase protein (APP) is a marker of systemic inflammation, in which fibrinogen and SAA are positive APP while serum albumin is a negative APP (21). As shown in Table I, LysMcre/Stat3flox/- mice exhibited increased levels of fibrinogen and SAA while decreasing albumin levels relative to the controls, thereby indicating an exaggerated systemic inflammation in mice lacking Stat3 in macrophages and neutrophils.
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Bacterial burden is tightly associated with the mortality in this model (17, 23). We next investigated bacterial load in these mice, which demonstrated that LysMcre/Stat3flox/- mice contained comparable levels of viable bacteria in the peritoneum as compared with the controls (Fig. 7A). Mice with bacteremia at 24 h post-CLP were 4/13 in LysMcre/Stat3flox/- mice and 3/19 in the control mice (not significant). Plasma endotoxin level released from bacteria was then quantitated, which showed that there was no statistical difference between the groups (Fig. 7B). Furthermore, i.p. inoculation of live bacteria recovered from CLP-mice resulted in 56% lethality in LysMcre/Stat3flox/- mice (9/16 mice) whereas none of the control mice died (0/15 mice) by the treatment (Fig. 7C). Under the conditions, the number of infiltrating leukocytes and levels of cytokines in the peritoneum were much higher in LysMcre/Stat3flox/- mice as compared with the controls (data not shown). Thus, mice lacking Stat3 in macrophages and neutrophils failed to facilitate effective bacterial clearance despite increased numbers of infiltrating leukocytes and enhanced cytokine production. The data also suggest that impaired bacterial clearance is not likely the cause of increased lethality in LysMcre/Stat3flox/- mice.
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We hence examined bactericidal activity of leukocytes. As shown in Fig. 8A, bactericidal activity in resident peritoneal macrophages from LysMcre/Stat3flox/- mice was significantly lower than those from the controls (40 and 63%, respectively), although productions of TNF-, IL-1, IL-12, and IFN- were augmented when cells were stimulated with MALP-2 and LPS (Table II). Similarly, the activity in elicited leukocytes from LysMcre/Stat3flox/- mice was significantly reduced to 25% while it was 52% in the controls (Fig. 8B). When neutrophils were isolated from elicited leukocytes (>94%), the bactericidal activity in cells from LysMcre/Stat3flox/- mice was also lower than the controls (65.3 ± 9.7% vs 86.5 ± 0.9%, p < 0.01). Thus, bactericidal activity appeared to be impaired in both macrophages and neutrophils with Stat3 deficiency. Although the elicited leukocytes lacking Stat3 produced significantly higher levels of inflammatory cytokines than those with Stat3 (not shown), Stat3-deficient leukocytes did not release -glucuronidase (lysosomal enzyme) in response to MALP-2 and LPS whereas it was augmented in the control leukocytes (Fig. 8C). -glucuronidase level in resident macrophages with Stat3 deficiency was also lower than the controls (not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, we have demonstrated that mice with Stat3 deficiency in macrophages and neutrophils are highly susceptible to septic peritonitis induced by CLP. An aberrant inflammation is likely the mechanism underlying the increased lethality. The number of infiltrating leukocytes in the peritoneum was significantly augmented in mice lacking Stat3, which was accompanied by significant increases in peritoneal level of inflammatory cytokines, accounting for the exaggerated local inflammatory response. Furthermore, the mice exhibited dramatic increases in plasma level of multiple cytokines (hypercytokinemia) that include IL-6. IL-6 level is well correlated with a fatal outcome in patients with sepsis, reflecting the clinical severity (27). Hypercytokinemia has been implicated in the development of systemic inflammatory response syndrome (SIRS) or MOF (8). In this model, the mice displayed exaggerated systemic inflammation and organ damage as evidenced by clinical chemistry and histopathology.
Of interest are the findings that Stat3 deficiency exclusively in macrophages and neutrophils has significant impact on the regulation of inflammatory responses during CLP. Stat3 is ubiquitously expressed in other cell types such as endothelial cells, mast cells, dendritic cells and lymphocytes, cells capable of producing and responding to IL-10 (14, 28, 29, 30), and IL-10 level in mice lacking Stat3 was much higher than that in the control. These results suggest that Stat3 expressed in macrophages and neutrophils, but not other cells types, play a key role in modulating local and systemic inflammatory responses during sepsis. Macrophages and neutrophils are major cell populations producing cytokines in various types of inflammation and play pivotal roles in the protective immunity in infection (3, 8). Thus, the present data highlight evidence that these innate immune cells appear to be essential not only for the initiation and development of inflammatory response but also the resolution of the response, playing multifunctional roles in innate immunity during sepsis.
Effective bacterial clearance depends on the accumulation and activation of macrophages and neutrophils (17, 23, 31). Recently, we demonstrated that Stat6 deficient mice facilitated bacterial clearance due to enhanced local inflammatory response (12). We had initially hypothesized that the mice lacking Stat3 in macrophages and neutrophils would exhibit enhanced bacterial clearance, as the mice displayed a polarized immune response toward type-1 response, which is beneficial to infection. In contrast to the assumption, the bacterial clearance was not augmented in mice with Stat3 deficiency, suggesting a possibility that bactericidal activity of leukocytes may be impaired in the mice. Interestingly, the activity was significantly decreased in Stat3-deficient macrophages and neutrophils, which was accompanied by a significant decrease in the release of an effector molecule for bacterial clearance from the cells (lysosomal enzyme) although productions of cytokines were amazingly augmented. Similar data were recently reported, in which NADPH oxidase activity of neutrophils that involved in antimicrobial response was reduced in mice with Stat3 deletion in bone marrow cells (32). Thus, Stat3 appears to be a key mediator for bactericidal activity of innate immune cells. Increased numbers of these cells in mice lacking Stat3 appeared to compensate for the lack of host defense ability of these cells, resulting in an unchanged bacterial clearance in mice during CLP.
The precise mechanism whereby macrophages and neutrophils lacking Stat3 derogate bactericidal activity is unknown. We and others have shown that IFN-, a cytokine with powerful bactericidal activity, also activates Stat3 in neutrophils (33) and macrophages (14), suggesting a possibility that the lack of anti-microbial activity in Stat3-deficient macrophages and neutrophils may be due to the absence of Stat3. However, we have demonstrated that IFN--mediated signaling is not impaired in peritoneal macrophages lacking Stat3 (14). Stat1 is a transcription factor primarily activated by IFN- (34), and Stat1-deficient mice have been shown highly sensitive to microbial pathogens with loss of NO production, an effector molecule for killing pathogens, by macrophages after the stimulation with IFN- (35). These results suggest that the bactericidal activity of IFN- appears to be mediated by Stat1. Possible mechanisms may involve suppressor of cytokine-signaling-1 and -3, which are activated by bacterial component LPS and multiple cytokines including TNF-, and in turn may suppress the activity of several cytokines that include IFN- (36, 37). Studies are ongoing to more fully characterize the mechanism(s).
Taken together, these results clearly demonstrate Stat3 associated with macrophages and neutrophils as an important regulator of innate immunity during sepsis. Lacking Stat3 in these cells caused aberrant inflammation, resulting in an increased lethality. The treatment of sepsis and septic shock remains a clinical conundrum (38). The present results in addition to a murine model of endotoxin shock (14) suggest that increasing Stat3 expression in macrophages and neutrophils at the right time may represent a promising new approach for the treatment of sepsis, especially in a fatal condition known as SIRS. An attractive question is how Stat3 is regulated in patients with SIRS. Stat may be involved in the later phase of infection, as over- or prolonged production of IL-10 accounts for compensatory anti-inflammatory response syndrome (9), a fatal condition in the later stage of sepsis. Another question is whether the Stat3 deletion would affect the innate and adaptive immunity to secondary bacterial infection. Further study will produce important insights into the pathogenesis of sepsis and its treatment strategy.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to: Dr. Akihiro Matsukawa, Department of Pathology, Experimental Medicine, Graduate School of Medical Sciences, School of Medicine, Kumamoto University, 2-2-1, Honjo, Kumamoto 860-8556 Japan. E-mail address: mastu{at}kaiju.medic.kumamoto-u.ac.jp
3 Abbreviation used in this paper: CLP, cecal ligation and puncture; MOF, multiple organ failure; TSA, trypticase soy agar; AST, aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen; SAA, serum amyloid A; MPO, myeloperoxidase; MALP-2, macrophage-activating lipopeptide-2; APP, acute phase protein; SIRS, systemic inflammatory response syndrome.
Received for publication July 7, 2003. Accepted for publication September 30, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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c chain with the interleukin-9 receptor subunit leads to STAT activation and prevention of apoptosis. J. Biol. Chem. 273:9255. in human neutrophils. J. Leukocyte Biol. 65:391.[Abstract]
and LPS receptors during macrophage activation. EMBO J. 17:3660.[Medline]
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, p < 0.05, *, p < 0.01, vs control.
, p < 0.001, vs control.
