[show abstract][hide abstract] ABSTRACT: In our previous studies, peripheral blood lineage(-)CD34(+)CD31(+) cells (CD31(+) IMC) appearing in severely burned patients have been characterized as inhibitor cells for the production of β-defensins (HBDs) by human epidermal keratinocytes (NHEK). In this study, the effect of glycyrrhizin on pseudomonal skin infections was studied in a chimera model of thermal injury. Two different chimera models were utilized. Patient chimeras were created in murine antimicrobial peptide-depleted NOD-SCID IL-2rγ(null) mice that were grafted with unburned skin tissues of severely burned patients and inoculated with the same patient peripheral blood CD31(+) IMC. Patient chimera substitutes were created in the same mice that were grafted with NHEK and inoculated with experimentally induced CD31(+) IMC. In the results, both groups of chimeras treated with glycyrrhizin resisted a 20 LD50 dose of P. aeruginosa skin infection, while all chimeras in both groups treated with saline died within 3 days of the infection. Human antimicrobial peptides were detected from the grafted site tissues of both groups of chimeras treated with glycyrrhizin, while the peptides were not detected in the same area tissues of controls. HBD-1 was produced by keratinocytes in transwell-cultures performed with CD31(+) IMC and glycyrrhizin. Also, inhibitors (IL-10 and CCL2) of HBD-1 production by keratinocytes were not detected in cultures of patient CD31(+) IMC treated with glycyrrhizin. These results indicate that sepsis stemming from pseudomonal grafted site infections in a chimera model of burn injury is controllable by glycyrrhizin. Impaired antimicrobial peptide production at the infection site of severely burned patients may be restored after treatment with glycyrrhizin.
PLoS ONE 01/2014; 9(1):e83747. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Antimicrobial peptides are major host defense effectors against Pseudomonas aeruginosa skin infections. Due to the lack of such peptide production, severely burned hosts are greatly susceptible to P. aeruginosa burn wound infection. β-Defensin (HBD) production by normal human epidermal keratinocytes (NHEK) was inhibited by lineage(-)CD34(+) cells isolated from peripheral blood of severely burned patients. Lineage(-)CD34(+) cells obtained from severely burned patients were characterized as CD31(+), while healthy donor lineage(-)CD34(+) cells were shown to be CD31(-) cells. Lineage(-)CD34(+)CD31(-) cells did not show any inhibitory activities on HBD-1 production by NHEK. CCL2 and IL-10 released from lineage(-)CD34(+)CD31(+) cells were shown to be inhibitory on the peptide production by NHEK, while these soluble factors were not produced by lineage(-)CD34(+)CD31(-) cells. After treatment with a mixture of mAbs for CCL2 and IL-10, the culture fluids of lineage(-)CD34(+)CD31(+) cells did not show any inhibitory activities on HBD-1 production by NHEK. Lineage(-)CD34(+)CD31(+) cells that appear in association with burn injuries play a role on the inhibition of antimicrobial peptide production by skin keratinocytes through the production of CCL2 and IL-10.
PLoS ONE 01/2014; 9(2):e82926. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with 10-30 days postburn injury are greatly susceptible to infections. M1M (IL-10(-)IL-12(+) M) are essential cells in host antibacterial innate immunity against MRSA infections. However, these effector cells are not easily generated in hosts who are carriers of M2bM (IL-12(-)IL-10(+)CCL1(+)LIGHT(+) M). M2bM are inhibitory on M1M generation. In this study, the antibacterial resistance of mice, 10-30 days postburn injury against MRSA infection, was improved by the modulation of M2bM activities. Unburned mice inoculated with M preparations from mice, 10-30 days after burn injury, were susceptible to MRSA infection, whereas unburned mice, inoculated with M preparations from the same mice that were previously treated with CCL1 antisense ODN, were resistant to the infection. M2bM, isolated from Day 15 burn mice, lost their M2bM properties 3 days after cultivation under frequent medium changes, whereas their M2bM properties remained in the same cultures supplemented with rCCL1. In cultures, M preparations from Day 15 burn mice treated with CCL1 antisense ODN did not produce CCL1 and did convert to M1M after heat-killed MRSA stimulation. Also, Day 15 burn mice treated with the ODN became resistant against MRSA infection. These results indicate that CCL1 released from M2bM is essentially required for the maintenance of their properties. The increased susceptibility of mice, 10-30 days after burn injury to MRSA infection, may be controlled through the intervention of CCL1 production by M2bM appearing in association with severe burn injuries.
Journal of leukocyte biology 06/2012; 92(4):859-67. · 4.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: The influence of whole-body gamma-irradiation on the antibacterial host defense against Enterococcus faecalis translocation was investigated. Mice irradiated with or without 5 Gy [(137)Cs] gamma-rays were orally infected with 10(6) CFU/mouse E. faecalis. The pathogen was detected in the mesenteric lymph nodes (MLNs) of irradiated mice 1-4 d postinfection, whereas E. faecalis was not isolated from MLNs of normal mice. All irradiated mice died within 5 d of infection, whereas no mortality was shown in normal mice infected with the pathogen. Irradiated mice inoculated with normal mouse MLN macrophages (M) were shown to be resistant against the infection, although the same mice inoculated with irradiated mouse MLNM (I-MLNM) died postinfection. I-MLNM were identified as IL-10(+)IL-12(-)CCL1(+)LIGHT(+) M (M2bM) and were shown to be inhibitory on M conversion from resident M to IL-10(-)IL-12(+)M (M1M). M2bM were demonstrated in MLNs of mice 10-35 d after gamma-irradiation. M1M were not induced by E. faecalis Ag in cultures of I-MLNM, whereas normal mouse MLNM were converted to M1M in response to the Ag stimulation. After treatment with CCL1 antisense oligodeoxynucleotides, M2bM disappeared in MLNs of irradiated mice, and M1M were generated in MLNs of these mice following E. faecalis stimulation. These results indicate that M2bM presented in the I-MLNM populations were responsible for the impaired resistance of mice irradiated with gamma-rays to bacterial translocation and subsequent sepsis. E. faecalis translocation and subsequent sepsis may be controlled immunologically by the intervention of M2bM present in MLNs.
The Journal of Immunology 06/2012; 189(1):296-303. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Immunosuppressive neutrophils (PMN-II) appearing in association with burn injury have a role on the increased susceptibility of burn patients to various infections. In the present study, the role of PMN-II on the production of human β-defensins (HBDs), important molecules on host antimicrobial innate immunities, by human keratinocytes was studied. Normal human epidermal keratinocytes (NHEKs) were cultured with neutrophils (PMNs) isolated from burn patients or healthy volunteers in dual-chamber transwells. Culture fluids harvested 24 h after cultivation were assayed for HBDs using enzyme-linked immunosorbent assay. Also, these culture fluids were assayed for their antimicrobial activities by a standard colony-counting method using Pseudomonas aeruginosa. In the results, PMNs isolated from peripheral blood of burn patients were confirmed as PMN-II, because these cells produced CC-chemokine ligand 2 (CCL2), but not interleukin (IL)-12 and CC-chemokine ligand 3 (CCL3). Culture fluids of NHEK transwell-cultured with healthy PMNs exhibited strong killing activities against P. aeruginosa (96% inhibition), however, the growth of bacteria was not dramatically inhibited by the culture fluids of NHEK transwell-cultured with burn-patient PMNs (36% inhibition). IL-12 and CCL3 containing culture fluids of healthy PMNs stimulated with the bacterial antigen or rCCL3 and rIL-12 enhanced the production of HBD2 and HBD3 by NHEK, whereas CCL2 containing culture fluids of burn-patient PMN stimulated with the antigen or rCCL2 inhibited the HBD production by NHEK. These results indicate that PMN-II appearing in association with burn injury contribute to the decreased production of HBDs in thermally injured patients.
Immunology and Cell Biology 03/2012; 90(8):796-801. · 3.93 Impact Factor
[show abstract][hide abstract] ABSTRACT: Severely burned mice are susceptible to sepsis stemming from Enterococcus faecalis translocation due to the impaired generation of M1 macrophages (M1MΦs) in local translocation sites. In our previous studies, CCL2 has been characterized as a major effector molecule on the burn-associated generation of M2MΦs, an inhibitor cell type for resident MΦ conversion into M1MΦs. In this study, we tried to protect burned mice orally infected with E. faecalis utilizing CCL2 antisense oligodeoxynucleotides (ODNs). We show that M2MΦs in mesenteric lymph nodes (MLNs) were not demonstrated in burned mice treated with CCL2 antisense ODNs. M1MΦs were not induced by heat-killed E. faecalis from resident MΦs transwell-cultured with mesenteric lymph node macrophages (MLN-MΦs) from burned mice, while M1MΦs were induced by the same antigen from resident MΦs transwell-cultured with MΦs which were isolated from burned mice treated with CCL2 antisense ODNs. Bacterial growth in MLNs was shown in burned mice orally infected with a lethal dose of E. faecalis. However, after the same infection, sepsis did not develop in burned mice treated with CCL2 antisense ODNs. These results indicate that bacterial translocation and subsequent sepsis are controlled in burned mice orally infected with a lethal dose of E. faecalis by gene therapy utilizing CCL2 antisense ODNs.
European Journal of Immunology 01/2012; 42(1):158-64. · 4.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: The effect of IL-10 antisense oligodeoxynucleotides (ODN) on the susceptibility of burned mice to intradermal (i.d.) infection of methicillin-resistant Staphylococcus aureus (MRSA) was studied. Abscesses formed and sepsis did not develop in normal mice infected i.d. with 10(8)CFU/mouse of MRSA. Similarly, sepsis caused by MRSA i.d. infection did not develop and abscesses formed in burned mice treated with IL-10 antisense ODN. However, all of the burned mice treated with scrambled ODN (control group) died by infectious complications stemming from MRSA i.d. infection, and an MRSA-abscess did not form in these mice. Macrophages (Mϕ) isolated from the infection site tissue of burned mice that were treated with IL-10 antisense ODN were identified as M1Mϕ, while Mϕ isolated from burned mice that were treated with scrambled ODN were shown to be M2Mϕ. MRSA-abscesses formed in burned mice inoculated with M1Mϕ, and these mice resisted a lethal dose of MRSA i.d. infection. However, an abscess did not form, and sepsis caused by MRSA i.d. infection developed in burned mice that were inoculated with M2Mϕ. These results indicate that severely burned mice treated with IL-10 antisense ODN are resistant against i.d. infection with MRSA. M1Mϕ appeared in the infection site tissues of severely burned mice that were treated with IL-10 antisense ODN may play a role on the abscess formation and inhibiting sepsis caused by MRSA i.d. infection.
[show abstract][hide abstract] ABSTRACT: Immunodeficient patients with severe burn injuries are extremely susceptible to infection with Candida albicans. In addition to Th1 cells, IL-17-producing CD4(+) T cells (Th17 cells) have recently been described as an important effector cell in host anti-Candida resistance. In this study, therefore, we tried to induce Th17 cells in cultures of severely burned patient PBMC by stimulation with the C. albicans Ag (CAg). In the results, the biomarkers for Th17 cells (IL-17 production and intracellular expression of IL-17 and retinoic acid receptor-related orphan receptor γt) were not displayed by burn patient PBMC stimulated with CAg, whereas these biomarkers of Th17 cells were detected in cultures of healthy donor PBMC stimulated with CAg. Burn patient sera were shown to be inhibitory on CAg-stimulated Th17 cell generation in healthy donor PBMC cultures; however, Th17 cells were induced by CAg in healthy donor PBMC cultures supplemented with burn patient sera that were previously treated with anti-IL-10 mAb. Also, the biomarkers of Th17 cells were not induced by CAg in healthy donor PBMC cultures supplemented with rIL-10. IL-10 was detected in serum specimens derived from severely burned patients. These results indicate that Th17 cells are not generated in burn patient PBMC cultures supplemented with CAg. IL-10, produced in response to burn injuries, is shown to be inhibitory on Th17 cell generation. The high susceptibility of severely burned patients to C. albicans infection might be influenced if burn-associated IL-10 production is intervened.
The Journal of Immunology 09/2011; 187(5):2155-61. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: A role of immunosuppressive M2 monocytes (IL-12(-)IL-10(+)) on the increased susceptibility of severely burned patients to various opportunistic pathogens has been described. Among M2 monocyte subpopulations, M2b monocytes (IL-17(-)CCL1(+)CXCL13(-)) are predominantly present in the peripheral blood of severely burned patients. In the present study, the rise and fall of M2b monocytes were examined in severely burned patients treated with propranolol. Catecholamine is known as an inducer of M2 monocytes, and propranolol is a competitive blocker of catecholamine binding to β-adrenergic receptors. Twenty-two children with 30% or more TBSA burn were enrolled in the study. Propranolol at a dose of 4 mg/kg/day was administered to these patients by feeding-tube or mouth. Burn patient monocytes exhibited weak bactericidal activity. IL-12 was produced by propranolol-treated patient monocytes after stimulation with Staphylococcus aureus antigen, and the production of IL-10, CCL1, CCL17, or CXCL13 by these monocytes was not demonstrated. These results indicate that a predominance of M2b monocytes in severely burned patients is intervened by the propranolol treatment. The increased susceptibility, to be associated with the appearance of M2b monocytes, of severely burned patients to opportunistic pathogens might be controlled by propranolol.
Journal of leukocyte biology 02/2011; 89(5):797-803. · 4.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Severely burned patients were shown to be carriers of M2 monocytes, and all of the monocytes isolated from peripheral blood of severely burned patients (19 of 19 patients) were demonstrated as M2b monocytes (IL-12(-)IL-10(+)CCL1(+) monocytes). Low levels of M2a (IL-12(-)IL-10(+)CCL17(+) monocytes) and M2c monocytes (IL-12(-)IL-10(+)CXCL13(+) monocytes) were demonstrated in peripheral blood of severely burned patients (M2a, 2 of 19 patients; M2c, 5 of 19 patients). M2b, M2a, and M2c monocytes were not detected in peripheral blood of healthy donors. However, M2b monocytes appeared when healthy donor monocytes were cultured in media supplemented with burn patient serum (15%). CCL2 was detected in sera of all burn patients, and M2b monocytes were not generated from healthy donor monocytes cultured with media containing 15% burn patient sera that were previously treated with anti-CCL2 mAb. In addition, M2b monocytes were generated from healthy donor monocytes in cultures supplemented with rCCL2. These results indicate that M2b monocytes are predominant in peripheral blood of severely burned patients who are carriers of CCL2 that functions to stimulate monocyte conversion from resident monocytes to M2b monocytes.
The Journal of Immunology 11/2010; 185(12):7174-9. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Intradermal infection of methicillin-resistant Staphylococcus aureus (MRSA) in burned mice was pathogenically analyzed. An abscess was formed in normal mice intradermally infected with 10(8) CFU/mouse of MRSA, and all of these mice survived after the infection; however, abscess formation was not demonstrated to occur in burned mice similarly exposed to the pathogen, and all of these mice died within 5 days of infection. In burned mice, MRSA infected at the burn site intradermal tissues spread quickly throughout the whole body, while in normal mice, the pathogen remained localized at the infection site. Macrophages (Mφ) isolated from the infection site tissues of normal mice produced interleukin-12 (IL-12) but not IL-10 and were characterized as M1Mφ. These M1Mφ were not isolated from the infection site tissues of burned mice. When normal-mouse infection site tissue Mφ were adoptively transferred to burned mice at the MRSA infection site, an abscess formed, and the infection did not develop into sepsis. In contrast, an abscess did not form and sepsis developed in normal mice that were inoculated with burned-mouse infection site tissue Mφ. These Mφ produced IL-10 but not IL-12 and were characterized as M2Mφ. These results indicate that abscess formation is a major mechanism of host resistance against intradermal MRSA infection. M1Mφ in the tissues surrounding the infection site play a pivotal role in abscess formation; however, the abscess is not formed in burned mice where M2Mφ predominate. M2Mφ have been described as inhibitor cells for Mφ conversion from resident Mφ to M1Mφ.
Infection and immunity 10/2010; 78(10):4311-9. · 4.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: The contributions of dendritic cells (DCs) and natural killer dendritic cells (NKDCs) on host antibacterial innate immunities have been described. We have previously reported that mice with partial-thickness burn injuries (PT-burn mice) are resistant to burn wound infections, whereas mice with full-thickness burn injuries (FT-burn mice) are susceptible. In this study, the effect of burn stress on the appearance and properties of DCs and NKDCs was investigated in two different murine models of thermal injury. Dendritic cells isolated from PT-burn mice produced CCL3 and IL-12, whereas these soluble factors were not produced by DCs from FT-burn mice. As compared with unburned mouse controls, a large number of NKDCs were isolated from the DC preparations from PT-burn mice, whereas fewer NKDCs were detected in the DC preparations from FT-burn mice. Nonobese diabetic severe combined immunodeficiency mice inoculated with NKDCs were shown to be resistant against a lethal s.c. Pseudomonas aeruginosa infection. These results strongly suggest that NKDCs influenced by partial-thickness burn injury play a role on the resistance of PT-burn mice to P. aeruginosa s.c. infection.
[show abstract][hide abstract] ABSTRACT: The decreased production of antimicrobial peptides in tissues surrounding the burn sites has been described in patients with severe burn injury. Small numbers of Pseudomonas aeruginosa spread easily to the whole body of burn mice when infected at burn site tissues. Gr-1(+)CD11b(+) cells, demonstrated in tissues surrounding the burn site, are inhibitory on the production of antimicrobial peptides by EK. In this paper, the decreased production of antimicrobial peptides by EK influenced by Gr-1(+)CD11b(+) cells was shown to be restored by glycyrrhizin. CCL2 and IL-10 were determined to be effector soluble factors for the suppressor activities of Gr-1(+)CD11b(+) cells on antimicrobial peptide production by EK. However, Gr-1(+)CD11b(+) cells, which were treated previously with glycyrrhizin, did not produce these soluble factors. Also, sepsis stemming from P. aeruginosa burn-site infection was not demonstrated in burn mice treated with glycyrrhizin. These results suggest that through the improved production of antimicrobial peptides in tissues surrounding the burn area, sepsis stemming from P. aeruginosa wound infection is controllable by glycyrrhizin in severely burned mice.
Journal of leukocyte biology 10/2009; 87(1):35-41. · 4.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Here, we investigated a role of CCL2 on the increased susceptibility of severely burned mice to Enterococcus faecalis translocation. After inoculation of Mphi from MLMphi of normal mice, 80% of the SCIDbgMN mice orally infected with the lethal dose of E. faecalis survived, and all mice inoculated with MLMphi from thermally injured mice died. At this time, SCIDbgMN mice inoculated with MLMphi from thermally injured CCL2(-/-) mice were shown to be resistant (90% survival). M1Mphi were not induced by E. faecalis antigen in cultures of MLMphi from thermally injured wild-type mice, and MLMphi from thermally injured CCL2(-/-) mice converted to M1Mphi after the antigen stimulation. MLMphi from wild-type mice 2 days postburn injury possessed M2a- and M2cMphi properties, and those from mice 7-21 days postburn injury carried M2bMphi properties. However, MLMphi from thermally injured CCL2(-/-) mice did not show any typical properties for M2a- or M2cMphi. CCL17 and CXCL13 (biomarkers for M2a- and M2cMphi), but not CCL1 (a biomarker of M2bMphi), were produced by MLMphi from thermally injured CCL2(-/-) mice treated with rCCL2. These results indicate that CCL2 converts resident MLMphi to M2a- and M2cMphi, detected early after burn injury, and decreases host antibacterial innate immunity against sepsis stemming from oral E. faecalis infection.
Journal of leukocyte biology 08/2009; 86(4):999-1005. · 4.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: It has been described that polymorphonuclear neutrophils (PMNs) enhance the replication of CC-chemokine receptor 5/macrophage-tropic (R5) HIV in cultures of monocyte-derived macrophages (MDMs). In this study, the inhibitory effect of glycyrrhizin (GL) on R5 HIV replication influenced by PMNs was investigated in MDM cultures. The replication of R5 HIV in MDMs was greatly enhanced when cells were co-cultured with freshly isolated PMNs (syngeneic to MDMs). When GL was added to this culture, however, the viral replication enhanced by PMNs was completely inhibited. CCL2 and interleukin 10 (IL-10) were produced in cultures of PMNs exposed to R5 HIV, and the replication of R5 HIV was greatly enhanced in MDM cultures supplemented with a mixture of recombinant CCL2 and IL-10. However, CCL2 and IL-10 were not produced by PMNs exposed to R5 HIV, when GL was added to the cultures. In the presence of GL, these soluble factors were not detected in co-cultures of MDMs and PMNs exposed to R5 HIV. In addition, the replication of R5 HIV in MDMs stimulated with CCL2 and IL-10 was not directly influenced by GL. These results indicated that GL suppresses the PMN-dependent increase of R5 HIV replication in MDMs through inhibiting CCL2/IL-10 production by PMNs stimulated with R5 HIV.
Immunology and Cell Biology 07/2009; 87(7):554-8. · 3.93 Impact Factor
[show abstract][hide abstract] ABSTRACT: Severe experimental infections with Cryptosporidium parvum have been reported in immunocompromised animals such as SCID mice (mice without functional T cells and B cells). In a C. parvum infection with 1 x 10(6) oocysts/mouse in SCID beige (SCIDbg) mice (SCID mice lacking functional NK cells), oocyst shedding was first demonstrated 18 days after infection. However, shedding was shown as early as 3 days after the same infection in SCIDbgMN mice. All of the SCIDbgMN mice died within 16 days of C. parvum infection, while 100% of the SCIDbg mice exposed to the parasite survived. SCIDbgMN mice are SCIDbg mice depleted of functional macrophages (Mphi) and neutrophils (PMN), suggesting that the severity early after C. parvum infection is strongly influenced by the functions of Mphi and PMN. All SCIDbgMN mice orally infected with a lethal dose of C. parvum survived after they were inoculated with Mphi from SCIDbg mice exposed to C. parvum (CP-Mphi) or resident Mphi previously cultured with PMN from C. parvum-infected SCIDbg mice (CP-PMN). However, all SCIDbgMN mice inoculated with CP-PMN alone or resident Mphi alone died after C. parvum infection. CP-Mphi were identified as classically activated Mphi (M1Mphi), and CP-PMN were characterized as PMN-I. In in vitro studies, resident Mphi converted to M1Mphi after transwell cultivation with CP-PMN. These results indicate that the resistance of SCIDbg mice early after C. parvum infection is displayed through the function of M1Mphi which are converted from resident Mphi influenced by CP-PMN (PMN-I).
Infection and immunity 08/2008; 76(8):3657-63. · 4.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: Using a mouse model of thermal injury, we studied why antimicrobial peptides are not produced at the burn-site tissues and how this defect contributes to the increased susceptibility to Pseudomonas aeruginosa burn-wound infection. Logarithmic growth of P. aeruginosa was demonstrated locally (at the burn site) and systemically (in circulation) in thermally injured mice exposed to 10(2) CFU/mouse of the pathogen beneath the burn wound. However, neither systemic nor local growth of the pathogen was observed in sham burn mice when they were infected intradermally with 10(6) CFU/mouse P. aeruginosa. Murine beta-defensins (MBDs) were detected in the skin homogenates of sham burn mice. However, the amounts of MBDs were reduced greatly in the same tissue homogenates from thermally injured mice. Gr-1(+)CD11b(+) cells, with an ability to suppress antimicrobial peptide production by skin keratinocytes, were isolated from tissues surrounding the burn areas, and these cells were not obtained from skin tissues of sham burn mice. After intradermal inoculation of Gr-1(+)CD11b(+) cells, which were isolated from burn-site tissues, the production of antimicrobial peptides around the cell-inoculation site of sham burn mice decreased. Also, like thermally injured mice, these mice were shown to be susceptible to P. aeruginosa intradermal infection. These results indicate that sepsis stemming from P. aeruginosa burn-wound infection is accelerated by burn-induced Gr-1(+)CD11b(+) cells with abilities to suppress antimicrobial peptide production by epidermal keratinocytes.
Journal of Leukocyte Biology 07/2008; 83(6):1354-62. · 4.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: The susceptibility of mice to infectious complications is dramatically increased in an accompaniment with systemic inflammatory response syndrome (SIRS). Polymorphonuclear neutrophils with immunosuppressive ability (PMN-II) that appear in response to SIRS have been classified as one of the cells responsible for the increased susceptibility of mice with SIRS (SIRS mice) to sepsis induced by cecal-ligation and puncture (CLP). Since a high level of norepinephrine (NE) is demonstrated in the plasma of SIRS mice, in the present study, the role of NE on the appearance of PMN-II in SIRS mice was studied. Similar to SIRS mice, normal mice became susceptible to CLP-induced infectious complications after inoculation with NE-treated PMN. CCL2 and IL-10 (biomarkers for PMN-II) were equally produced by PMN-II prepared from SIRS mice and NE-treated PMN. However, CCL3 and IL-12 (biomarkers for immunostimulatory PMN, PMN-I) were not detected in culture fluids from either PMN preparation. These results indicate that NE mass-produced in association with SIRS development plays a role on the generation of PMN-II and the appearing PMN-II are responsible, in part, for increased susceptibility of SIRS mice to CLP-induced infectious complications.
[show abstract][hide abstract] ABSTRACT: Thermally injured mice are susceptible to Enterococcus faecalis translocation. In this study, the role of polymorphonuclear neutrophils (PMN) on the development of sepsis stemming from E. faecalis translocation was studied in SCID-beige (SCIDbg) mice depleted of PMN (SCIDbgN mice) or macrophages (Mphi) and PMN (SCIDbgMN mice). Sepsis was not developed in SCIDbgN mice orally infected with E. faecalis, while the orally infected pathogen spread systemically in the same mice inoculated with PMN from thermally injured mice (TI-PMN). SCIDbgMN mice were shown to be greatly susceptible to sepsis caused by E. faecalis translocation, while orally infected E. faecalis did not spread into sepsis in the same mice that were previously inoculated with Mphi from unburned SCIDbg mice (resident Mphi). In contrast, orally infected E. faecalis spread systemically in SCIDbgMN mice inoculated with resident Mphi and TI-PMN, while all SCIDbgMN mice inoculated in combination with resident Mphi and PMN from unburned SCIDbg mice survived after the infection. After cultivation with TI-PMN in a dual-chamber transwell, resident Mphi converted to alternatively activated Mphi, which are inhibitory on the generation of classically activated Mphi (typical effector cells in host antibacterial innate immunities). TI-PMN were characterized as immunosuppressive PMN (PMN-II) with abilities to produce cc-chemokine ligand-2 and IL-10. These results indicate that PMN-II appearing in response to burn injury impair host antibacterial resistance against sepsis stemming from E. faecalis translocation through the conversion of resident Mphi to alternatively activated Mphi.
The Journal of Immunology 04/2008; 180(6):4133-8. · 5.52 Impact Factor