/CCL3 on the expression of host’s innate immunities against infectious complications
* Department of Internal Medicine, The University of Texas Medical Branch, Galveston;
Department of General Surgery, Graduate School of Medicine, Chiba University, Japan; and
University of California Davis Medical Center, Sacramento
Correspondence: Fujio Suzuki, Ph.D., The University of Texas Medical Branch, Department of Internal Medicine, 301 University Boulevard, Galveston, TX 77555-0435. E-mail: fsuzuki{at}utmb.edu
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(MIP-1)/CCL3 knockout (CCL3-/-) and severe combined immunodeficiency (SCID) mice. CCL3-/- mice and their littermates (CCL3+/+ mice) treated with anti-CCL3 monoclonal antibodies were susceptible (0–20% survival) to CLP-induced sepsis, and CCL3-/- mice supplemented with recombinant (r)CCL3 (250 ng/mouse) and CCL3+/+ mice were resistant (70–80% survival). The resistance of SCID mice to CLP was markedly improved by the rCCL3 administration (88% survival), and SCID mice treated with saline were shown to be middling resistant to the same CLP (45% survival). However, the resistance of SCID-M mice (SCID mice depleted of the macrophage function) to CLP was not improved by the rCCL3 administration (11% survival), and 41% of SCID-M mice reconstituted with normal peritoneal macrophages and 79% of SCID-M mice inoculated with CCL3-treated peritoneal macrophages survived. In addition, the resistance of SCID-MN mice (SCID mice depleted of functional macrophages and neutrophils) to CLP was improved by the inoculation of CCL3-treated macrophages (78% survival), and all of SCID-MN mice inoculated with CCL3-treated neutrophils died. CCL3 is shown to be essential to the host resistance against bacterial sepsis. Macrophages but not neutrophils are highlighted as the major effector cells when protective innate immunities against sepsis are improved by CCL3.
Key Words: sepsis • SCID mice • CCL3 knockout mice
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Chemokines, a superfamily of small peptides (6–14 kDa) secreted by a variety of cells, play a crucial role in the trafficking and recruitment of effector leukocytes to the primary sites of immune response and inflammation [17 18 19 ]. CCL3, a ß-chemokine, regulates the migration of various effector cells such as monocytes, T cells, neutrophils, eosinophils, basophils, and natural killer cells [17 18 19 ]. Recently, CCL3 has been described as a necessary agent for the clearance of Cryptococcus neoformans or Listeria monocytogenes [20 21 ]. The absence of CCL3 greatly impaired the recruitment of monocytes and neutrophils into infected organs [20 ]. In addition, CCL3 induces activated macrophages capable of killing Escherichia coli, Trypanosoma cruzi, or Klebsiella pneumonia [22 23 ]. All of these observations indicate the importance of CCL3 to the host’s protective immunity against infections. Recently, we demonstrated the decreased production of CCL3 in cultures of peripheral blood mononuclear cells (PBMC) from patients with severe thermal injuries [24 ]. After stimulation with anti-CD3 monoclonal antibodies (mAb), healthy donor PBMC produced 2355–7395 pg/ml CCL3 into their culture fluids. However, CCL3 was not detectable in the culture fluids of PBMC from 90% of thermally injured patients [24 ]. These facts and the previous observations described above led us to ask whether an inability of PBMC to produce CCL3 is associated with infectious complications in severely burned patients.
This study explores the pivotal role of CCL3 on the host’s innate immunities against infectious complications. This ß-chemokine proved to be essential in improving host’s innate resistance against infectious complications in reducing cecal ligation and puncture (CLP)-induced sepsis in CCL3 knockout (CCL3-/-) mice, supplemented with CCL3 and increasing severities of CLP-induced sepsis in CCL3+/+ mice treated with anti-CCL3 mAb. Also, macrophages highlighted as antibacterial effector cells responded to the CCL3 stimulation.
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Reagents and media
Murine recombinant (r)CCL3 and anti-Ly6G mAb were purchased from PharMingen (San Diego, CA). Anti-CCL3 mAb was purchased from R&D Systems (Minneapolis, MN). Carrageenan was purchased from Sigma Chemical Co. (St. Louis, MO). RPMI-1640 medium supplemented with 10% fetal calf serum, 2 mM L-glutamine, antibiotics (culture medium) was used for cultivation of macrophages and neutrophils.
CLP
This study used a CLP technique to induce sepsis. Infectious complications induced by CLP have been described as sepsis similar to that developed in thermally injured patients [25
26
27
]. This laboratory developed a modified procedure to perform a well-controlled cecal ligation and 26-gauge puncture [28
]. To perform CLP, mice were anesthetized with pentobarbital (50 mg/kg, i.p.). To induce the constant severity of CLP, a minimum-sized incision (less than 1.0 cm) to the lower right quadrant of the abdomen was made, and the cecum was drawn out. To avoid dehydration, the exposure of the cecum to air was kept to a minimum. The distal one-third was ligated with silk suture and punctured with a 26-gauge needle. Then, the cecum was returned and placed far away from the incision, and the peritoneal incision was closed using sutures (not surgical glue). All mice were treated with 2 ml sterile saline [subcutaneously (s.c.)] for fluid resuscitation during the postoperative period. Infection induced by this CLP procedure consistently corresponded to 0.1–0.2 LD50.
Preparation of macrophages and neutrophils
Macrophages at a purity of 92% or more were prepared from peritoneal exudate cells of normal BALB/c mice, as described in a previous study [29
]. As required, these macrophages (2x106 cells/ml) were treated in vitro with rCCL3 (10 ng/ml). In some experiments, these macrophages (1x106 cells/mouse) were adoptively transferred to SCID-M mice. As a control, the same numbers of peritoneal macrophages freshly isolated from normal BALB/c mice and not treated with rCCL3 were adoptively transferred to SCID-M mice. Immediately after the macrophage inoculation, all these mice were subjected to CLP. Peripheral blood neutrophils were isolated from heparinized blood by dextran sedimentation followed by Ficoll-Hypaque density gradient centrifugation [30
]. Exposure to hypotonic solution eliminated red blood cells in the neutrophil preparations [30
].
Measurements of macrophage function
The effect of CCL3 on phagocytic and killing activities of macrophages was examined in vitro. To determine these activities of macrophages, Pseudomonas aeruginosa (kindly provided by J. P. Heggers, Ph.D., The University of Texas Medical Branch at Galveston) was used as a target pathogen. Peritoneal macrophages (1x104 cells/ml) prepared from BALB/c mice, CCL3-/- mice, or CCL3+/+ mice were stimulated with 2.5, 10, and 40 ng/ml rCCL3 for 24 h. Then, these macrophages were exposed to 1 x 105 colony-forming units (CFU)/ml P. aeruginosa [an effector:target (E:T) ratio of 1:10] in 96-well fibronectin-coated microtiter plates at 37°C for 30 min. Phagocytic and killing activities of these macrophages were determined as follows: (i) Phagocytic activity, Thirty minutes after incubation, the wells were extensively washed out with warm, complete medium to remove unphagocytized bacteria. Then, the macrophages were lysed with sterile 0.5% Triton X-100. The number of bacteria in the obtained solution was determined by a colony-counting method [31
]. The phagocytic activity of macrophages was expressed as the phagocytic index calculated by the following formula: Phagocytic index = (no. of CFU in tested wells 30 min after cultivation/no. of CFU in control wells 30 min after cultivation). (ii) Killing activity, Thirty minutes after cultivation, the wells were extensively washed out with warm, complete medium to remove unphagocytized bacteria. These macrophages in the wells were further cultured with fresh medium for an additional 2.5 h. Then, macrophages were lysed with 0.5% Triton X-100, and the number of bacteria in the solution obtained was determined by a colony-counting method [31
]. Killing percent was calculated using the following formula: Killing % = [1–(no. of CFU in tested wells 3 h after cultivation/no. of CFU in tested wells 30 min after cultivation)] x 100.
Experimental design
To determine the role of CCL3 on host resistance against infectious complications, a series of in vivo studies was conducted. In the first experiments, CCL3-/- mice, supplemented with rCCL3 (250 ng/mouse, s.c., 2 h before and 12 and 24 h after CLP), and their littermates (CCL3+/+ mice), treated with mAb directed against CCL3 (10 µg/mouse, s.c., 2 h before and just after CLP), were exposed to CLP. As controls, CCL3-/- mice and CCL3+/+ mice were treated with saline or rat immunoglobulin (Ig), respectively. Survival rates of 80–90% were completely reproducible in normal BALB/c mice subjected to our procedure for CLP. In the second experiments, SCID mice treated with rCCL3 (250 ng/mouse, s.c., 2 h before and 12 and 24 h after CLP) or anti-CCL3 mAb (10 µg/mouse, s.c., 2 h before and 12 and 24 h after CLP) were subjected to CLP. Doses and schedules of CCL3 used in in vivo systems were determined in our preliminary studies. In addition, SCID-M mice treated with rCCL3 or anti-CCL3 mAb were exposed to CLP. SCID-M mice were SCID mice-depleted of macrophage function. In the third group of experiments, SCID-M mice, inoculated with peritoneal macrophages previously treated with rCCL3 (10 ng/ml, 18 h), were exposed to CLP. In these experiments, the dose of rCCL3 was determined according to the results displayed (see Fig. 5a
and 5b
). As a control, SCID-M mice inoculated with freshly isolated macrophages were subjected to the same CLP. In the fourth experiments, SCID-MN mice, inoculated with peritoneal macrophages or peripheral blood neutrophils and treated with rCCL3 (250 ng/mouse, s.c., 2 h before and 24 and 48 h after CLP), were exposed to CLP. Macrophages (1x106 cells/mouse) were injected i.v. once to SCID-MN mice 2 h before CLP. The inoculation of SCID-MN mice with 1 x 106 cells/mouse of neutrophils was performed three times just before the rCCL3 administration. As a control, SCID-MN mice, inoculated with macrophages or neutrophils and treated with saline, were subjected to the same CLP. SCID-MN mice were SCID mice-depleted of functional macrophages and neutrophils. We observed all of these mice daily to determine their morbidities [mean survival day (MSD)] and mortalities (percent survival, 10 days after CLP).
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Figure 5. Phagocytic and killing activities of macrophages stimulated with various doses of rCCL3. (a) Phagocytic activity: Peritoneal macrophages treated with various doses of rCCL3 were mixed with P. aeruginosa at an E:T ratio of 1:10. Thirty minutes after cultivation at 37°C, the number of phagocytized bacteria was determined by a colony-counting method. The phagocytic activity of macrophages was expressed as a phagocytic index, as described in text. (b) Killing activity: Peritoneal macrophages stimulated with various doses of rCCL3 were mixed with P. aeruginosa at an E:T ratio of 1:10. Thirty minutes after cultivation at 37°C, unphagocytized bacteria was removed, and these macrophages were recultured with fresh medium for an additional 2.5 h. Then, macrophages were lysed with 0.5% Triton X-100, and the number of bacteria in the solution obtained was determined by a colony-counting method. The killing activity of peritoneal macrophages was calculated by the formula as described in text. *P < 0.05; **P < 0.01; ***P < 0.0005.
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(MIP-1) knockout mice (CCL3-/- mice) and their littermates (CCL3+/+ mice) were subjected to well-controlled CLP. CLP is known as a sepsis model that is more clinically relevant and acceptable for studying the systemic responses [25
26
27
]. This model induces polymicrobial peritonitis by leakage of mixed intestinal flora and presents serologically close to that of humans [25
26
27
]. The severity of CLP routinely performed in our laboratory corresponded to 0.1– 0.2 LD50 in BALB/c normal mice. Less than 20% of these BALB/c normal mice died consistently until 10 days of CLP. As shown in Figure 1a
, all of CCL3-/- mice treated with saline died within 5 days of CLP, and 70% of CCL3-/- mice supplemented with rCCL3 (250 ng/mouse) 2 h before and 12 and 24 h after CLP survived (P<0.005). Conversely, CCL3+/+ mice treated twice with anti-CCL3 mAb (2 h before and just after CLP, 10 µg/mouse) were susceptible (17% survival) to CLP-induced sepsis, and CCL3+/+ mice treated with rat Ig (2 h before and just after CLP, 10 µg/mouse) were resistant (83% survival; P<0.005; Fig. 1b
). These results indicate that improved, protective innate immunity against CLP-induced sepsis requires CCL3.
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Figure 1. Importance of CCL3 on the resistance of mice to CLP-induced sepsis. (a) CCL3-/- mice were treated s.c. with rCCL3 (250 ng/mouse, open circles, 10 mice) or saline (0.2 ml/mouse, solid circles, 10 mice) 2 h before and 12 and 24 h after CLP. *P < 0.005 compared with the control. (b) CCL3+/+ mice were exposed to CLP in combination with s.c. treatment by anti-CCL3 mAb (10 µg/mouse, open circles, six mice) or rat Ig (10 µg/mouse, solid circles, six mice) 2 h before and just after CLP. *P < 0.005 compared with the control.
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Figure 2. Effect of CCL3 on the resistance of SCID mice exposed to CLP-induced sepsis. SCID mice exposed to CLP were treated s.c. with rCCL3 (250 ng/mouse, open circles, eight mice, 2 h before and 12 and 24 h after CLP), anti-CCL3 mAb (10 µg/mouse, open boxes, 10 mice, 2 h before and immediately after CLP), or saline (0.2 ml/mouse, solid circles, 11 mice, 2 h before and 12 and 24 h after CLP). *P < 0.05 compared with SCID mice treated with saline.
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Figure 3. Importance of CCL3 and CCL3-stimulated macrophages on the resistance of SCID-M mice subjected to CLP-induced sepsis. (a) SCID-M mice subjected to CLP were treated s.c. with rCCL3 (250 ng/mouse, open circles, nine mice) or saline (0.2 ml/mouse, solid circles, 14 mice) 2 h before and 12 and 24 h after CLP. SCID-M mice were SCID mice-depleted of a macrophage function (see text). (b) SCID-M mice (open circles, 14 mice) were inoculated with 1 x 106 cells/mouse of peritoneal macrophages that were previously treated with rCCL3 (10 ng/ml); then, they were exposed to CLP. In addition, SCID-M mice (open triangles, nine mice) inoculated with normal peritoneal macrophages were subjected to CLP. These mice were then treated with anti-CCL3 mAb (10 µg/mouse). As a control, SCID-M mice, inoculated with freshly isolated peritoneal macrophages, were subjected to CLP and treated with saline (solid circles, 17 mice). *P < 0.05 compared with SCID-M mice inoculated with normal macrophages.
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Figure 4. Effect of macrophages and neutrophils on the CCL3-stimulated, innate immunity of SCID-MN mice against CLP-induced sepsis. (a) SCID-MN mice inoculated with 1 x 106 cells/mouse of peritoneal macrophages were subjected to CLP; then, they were treated with rCCL3 (250 ng/mouse, open circles, 18 mice, 2 h before and 24 and 48 h after CLP). Macrophages were injected once to SCID-MN mice 2 h before CLP. SCID-MN mice were SCID mice-depleted of functions of macrophages and neutrophils (see Materials and Methods). SCID-MN mice (solid triangles, 10 mice) and SCID-MN mice inoculated with peritoneal macrophages and treated with saline (0.2 ml/mouse, solid circles, 10 mice) were served as controls. *P< 0.001 compared with SCID-MN mice inoculated with macrophages and treated with saline. (b) SCID-MN mice inoculated with 1 x 106 cells/mouse of peripheral blood neutrophils were subjected to CLP; then, they were treated with rCCL3 (250 ng/mouse, open boxes, 12 mice, 2 h before and 24 and 48 h after CLP). The inoculation of neutrophils to SCID-MN mice was performed three times just before the CCL3 administration. SCID-MN mice (solid triangles, 10 mice) and SCID-MN mice inoculated with neutrophils and treated with saline (0.2 ml/mouse, solid boxes, 10 mice) were served as controls.
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Table 1. The Effect of rCCL3 on the Phagocytic Activity of Macrophages Derived from CCL3-/- Mice or their Littermates
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In our study, the phagocytic and antibacterial killing functions of macrophages were directly enhanced by CCL3, suggesting that CCL3 may be an activator of macrophages. In addition, effects of CCL3 on tumor necrosis factor (TNF-) production by macrophages were tested. Although significant amounts of TNF- were not detected in culture supernatants of normal macrophages (<10 pg/ml), peritoneal macrophages cultured with 10 ng/ml rCCL3 produced 322 pg/ml TNF- into their culture fluids [35
]. TNF- has already been reported as a critical, protective component for host antibacterial responses [36
]. These results shown in our earlier studies indicate that CCL3 has a capability to expand the antibacterial functions of macrophages, directly or indirectly. These effects of CCL3 on the function of macrophages may also be important when infectious complications are suppressed in individuals treated with CCL3 or when an innate immunity against sepsis is expressed by CCL3.
A key role of mast cells in innate immunity against sepsis with gram-negative bacteria has been described [37
38
]. The beneficial role of mast cells on the protective innate immunity is facilitated by their limited and piecemeal releases of inflammatory mediators, including histamine, TNF-, and leukotrienes, as well as by their capacities to phagocytize bacteria [37
38
]. CCL3 is implicated in the degranulation and recruitment of mast cells [38
]. Through the induction of TNF- from mast cells, CCL3 has the capability to activate neutrophils and macrophages [38
], suggesting that CCL3 may play a role on mast cell-associated host resistance against sepsis. Conversely, multiple organ failure, a major reason for the high mortality rates of patients with sepsis, has been observed when sepsis-associated lymphocyte apoptosis developed throughout the body [39
]. The administration of caspase inhibitors to animals with CLP-induced sepsis has been shown to prolong the lifespan of these animals [40
]. A mixture of ß-chemokines [CCL3, CCL4 (MIP-1ß), and CCL5 (regulated on activation, normal T expressed and secreted)] has recently been reported to inhibit apoptosis induced by pokeweed mitogen or staphylococcal enterotoxin B in cultures of T cells from AIDS patients [41
]. In addition, anti-CD3-triggered apoptotic death of T cells has been inhibited by the same mixture of ß-chemokines [41
]. The facts that CCL3 inhibits the apoptotic death of lymphocytes suggest that CCL3 may have a capability to regulate the multiple organ failure. In addition, CCL3 was shown to be required when IL-12 was produced by macrophages [42
]. IL-12 is a key cytokine in promoting differentiation of naive T cells into T helper cell type 1 (Th1) cells, and it functions as a costimulus for maximal interferon-
(IFN-) production by already differentiated Th1 cells [43
44
45
]. In fact, a representative Th1 cytokine (IFN-) was not induced by the anti-CD3 mAb stimulation in cultures of PBMC from burned patients with an inability to produce IL-12 [46
]. Th1 cytokines are needed to convert macrophage functions from resting to bacteriocidal [47
]. In addition, IL-12 has been shown to inhibit death of T cells by the regulation of caspase processing [48
]. All facts described above suggest an important role of CCL3 when the host resistance against sepsis is expressed.
Using various mouse models, this study identified CCL3 as essential when the protective innate immunity against sepsis is improved. Miller et al. [49 ] reported previously that CCL3 is protective against multiple organ dysfunction syndrome (MODS) induced by zymosan A. Mice treated with zymosan A are useful models of MODS, which is not caused by infection. With MODS, a mortality rate of CCL3-/- mice treated with zymosan A was 60%, and a 15% mortality rate was shown in CCL3+/+ mice. This fact indicates the importance of CCL3 on the host resistance against MODS. This finding supports our results. Macrophages were highlighted as the major antiseptic effector cells activated by CCL3. As the beneficial protective effects of rCCL3 are demonstrated in CCL3 knockout mice exposed to CLP-induced sepsis, studies to examine the therapeutic potential of CCL3 to treat infectious complications are in progress. These studies will be performed in SCID mice inoculated with PBMC from patients with severe thermal injuries. Previous studies show that PBMC from burned patients, who are very susceptible to infections, cannot produce CCL3 [50 ].
Received December 7, 2001; revised August 5, 2002; accepted August 7, 2002.
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(MIP-1) is required for the effector phase of pulmonary cell-mediated immunity to a Cryptococcus neoformans infection J. Immunol. 159,318-327[Abstract] in vivo J. Immunol. 162,5423-5428, and MIP-1ß induce trypanocidal activity in human macrophages via nitric oxide Infect. Immun. 66,4690-4695 in SCID mice inoculated with burned patient’s PBMC J. Allergy Clin. Immunol. 107,S82(abstract) (MIP-1) display anti-bacterial activities in vitro and in vivo. FASEB J. 15,A651(abstract), interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis Proc. Natl. Acad. Sci. USA 88,7011-7015 (MIP-1) Abstract of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy ,73 (MIP-1) induces the IL-12 production and improves the polarization of Th1 responses in thermally injured mice J. Allergy Clin. Immunol. 107,S81(abstract) production and type 1 cytokine responses Immunity 4,471-481[Medline] dramatically alter the mortality from zymosan-induced multiple organ dysfunction syndrome (MODS): C5a contributes to MODS while MIP-1 has a protective role Mol. Immunol. 33,1135-1137[Medline] J. Immunol. 169,4460-4466This article has been cited by other articles:
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