Host antibacterial defense of 6-10 Gy γ-irradiated mice subjected to lentiviral vector-based Gas5 gene therapy.

Gut bacteria-associated sepsis is a serious concern in patients with gastrointestinal acute radiation syndrome (GIARS). In our previous studies, all mice exposed to 8 Gy of whole body γ-irradiation (8 Gy GIARS-mice) died by sepsis stemming from bacterial translocation. M1Mϕ located in the bacterial translocation site (i.

Glycyrrhizin Protects γ-Irradiated Mice from Gut Bacteria-Associated Infectious Complications by Improving -Associated RNA Reduction in Macrophages of the Bacterial Translocation Site.

Gut bacteria-associated sepsis is a serious concern in patients with gastrointestinal acute radiation syndrome (GIARS). In our previous studies, gut bacteria-associated sepsis caused high mortality rates in mice exposed to 6-9 Gy of γ-rays. IL-12CD38 iNOS Mϕ (M1Mϕ) located in the bacterial translocation site (mesenteric lymph nodes [MLNs]) of unirradiated mice were characterized as host defense antibacterial effector cells.

Survival of Mice with Gastrointestinal Acute Radiation Syndrome through Control of Bacterial Translocation.

Macrophages (Mϕ) with the M2b phenotype (Pheno2b-Mϕ) in bacterial translocation sites have been described as cells responsible for the increased susceptibility of mice with gastrointestinal acute radiation syndrome to sepsis caused by gut bacteria. In this study, we tried to reduce the mortality of mice exposed to 7-10 Gy of gamma rays by controlling Pheno2b-Mϕ polarization in bacterial translocation sites. MicroRNA-222 was induced in association with gamma irradiation.

Lamina propria group 2 innate lymphoid cells impair the antibacterial defense of burned mice to enterococcal translocation.

Gut microbiota that invades to the defective mucosal barrier is one of the major sources of infectious complications in severely burned hosts. In this study, a role of group 2 innate lymphoid cells (ILC2) and effects of -{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-2-thiophenesulfonamide (SR3335) on the host antibacterial resistance against infectious complications caused by oral infection were investigated in burned mice. Retinoic acid receptor-related orphan receptor α (RORα) is a transcription factor required for the development of ILC2, and SR3335 is an RORα-selective inverse agonist.

M2b macrophage polarization accompanied with reduction of long noncoding RNA GAS5.

Macrophages (Mϕ) are highly plastic and change their functional phenotypes depending on microenvironmental signals. Recent studies have shown that microRNAs are involved in the polarization of Mϕ. In this study, we demonstrated that the phenotype of M2bMϕ [CCL1(+) IL-10(+) LIGHT(+)] switches to other phenotypes with interchangeability attained through the increased expression of growth arrest-specific 5 RNA (GAS5 RNA), a long noncoding RNA.

Short-Term Alcohol Abstinence Improves Antibacterial Defenses of Chronic Alcohol-Consuming Mice against Gut Bacteria-Associated Sepsis Caused by Enterococcus faecalis Oral Infection.

The effects of short-term alcohol abstinence on host antibacterial resistance against Enterococcus faecalis oral infection was investigated in chronic alcohol-consuming mice [mice with 0.1 g/day of 20% ethanol consumption for 12 or 16 weeks (CAC-mice)]. These mice were highly susceptible to the infection; however, after 7 days of alcohol abstinence (aaCAC-mice), their antibacterial resistances were completely restored to the normal mouse level.

Host antitumor resistance improved by the macrophage polarization in a chimera model of patients with HCC.

Despite major advances in curative and palliative approaches, hepatocellular carcinoma (HCC) is still the third leading cause of cancer-related death worldwide. M1 macrophages (Mϕ) play a key role in host antitumor defenses in HCC. In our study, CD14 cells were isolated from the peripheral blood of four groups of HCC patients (group-1, patients with stage 0 HCC; group-2, patients with stage A HCC; group-3, patients with stage B HCC; and group-4, patients with stage C HCC) and characterized phenotypically.

Macrophage polarization and MRSA infection in burned mice.

Mortality associated with Staphylococcus aureus infection remains high during the sub-acute phase of burn injury. In this study, we aimed to improve antibacterial resistance of sub-acutely burned mice through macrophage polarization. Sepsis did not develop in mice at the sub-acute phase of 5% total body surface area (TBSA) burn after being infected with methicillin-resistant S.

The Polarization of M2b Monocytes in Cultures of Burn Patient Peripheral CD14 Cells Treated with a Selected Human CCL1 Antisense Oligodeoxynucleotide.

M2b macrophages (Mφ) play a major role in the increased susceptibility of subacutely burned patients, to sepsis stemming from enterococcal translocation. Certain opportunistic infections in severely burned mice have been controlled by murine CCL1 antisense oligodeoxynucleotide (ODN), a specific polarizer of mouse M2bMφ. In the present study, we have screened CCL1 antisense ODN, which is active against human M2bMφ.

M2b Monocytes Provoke Bacterial Pneumonia and Gut Bacteria-Associated Sepsis in Alcoholics.

Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections. γ-irradiated NOD-SCID IL-2Rγ(null) mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteria-associated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M1 monocytes (IL-12(+)IL-10(-)CD163(-)CD14(+) cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1(+)CD163(+)CD14(+) cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag-stimulated monocyte conversion from quiescent monocytes to M1 monocytes.

Orosomucoid 1 drives opportunistic infections through the polarization of monocytes to the M2b phenotype.

Orosomucoid (ORM, composed of two isoforms, ORM1 and ORM2) has been described as an inducer of M2 macrophages, which are cells that decrease host antibacterial innate immunities. However, it is unknown which phenotypes of M2 macrophages are induced by ORM. In this study, healthy donor monocytes stimulated with ORM (ORM-monocytes) were characterized phenotypically and biologically.

M2b macrophage elimination and improved resistance of mice with chronic alcohol consumption to opportunistic infections.

Alcohol abuse was found to predispose persons to opportunistic infections. In this study, we tried to improve the host antibacterial resistance of chronic alcohol-consuming (CAC) mice to opportunistic infections. Bactericidal macrophages with functions to produce IL-12 and to express mRNAs for CXCL9 and inducible nitric oxide synthase (M1 macrophages) were characterized as the main effector cells in host antibacterial innate immunities against infections with opportunistic pathogens.

Depressed production of beta-defensins from mouse splenic dendritic cells following thermal injury and its influence on susceptibility to infection.

Purpose: Beta-defensins (BDs) and dendritic cells (DC) have been described as major effectors on host antimicrobial innate immunities. In the present study, the ability of DC to produce BDs was explored using DC from normal mice and full-thickness (FT)-burned mice.

Methods: DCs were isolated from spleens of mice, and 1 × 10(6) cells/ml of them were cultured with LPS or SAC.

Lineage -CD34+CD31+ cells that appear in association with severe burn injury are inhibitory on the production of antimicrobial peptides by epidermal keratinocytes.

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.

Effect of glycyrrhizin on pseudomonal skin infections in human-mouse chimeras.

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.

CCL1 released from M2b macrophages is essentially required for the maintenance of their properties.

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).

Role of M2b macrophages in the acceleration of bacterial translocation and subsequent sepsis in mice exposed to whole body [137Cs] γ-irradiation.

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.

Impaired ability of burn patient neutrophils to stimulate β-defensin production by keratinocytes.

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.

Effect of IL-10 antisense gene therapy in severely burned mice intradermally infected with MRSA.

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.

Effect of CCL2 antisense oligodeoxynucleotides on bacterial translocation and subsequent sepsis in severely burned mice orally infected with Enterococcus faecalis.

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.

Lack of Th17 cell generation in patients with severe burn injuries.

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.

Propranolol as a modulator of M2b monocytes in severely burned patients.

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.

M2b monocytes predominated in peripheral blood of severely burned patients.

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.

Pathogenic role of macrophages in intradermal infection of methicillin-resistant Staphylococcus aureus in thermally injured mice.

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.

Role of natural killer dendritic cells in host resistance against Pseudomonas aeruginosa infection after thermal injury in mice.

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.