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Oliveira GS, Rivera J, Rodrigues TC, Carneiro GB, Ribeiro OG, Miyaji EN, Pirofski L, Oliveira MLS. Serotype 3 Streptococcus pneumoniae Escapes the Immune Responses Induced by PCV13 in Mice With High Susceptibility to Infection. Immun Inflamm Dis 2024; 12:e70062. [PMID: 39641265 PMCID: PMC11621863 DOI: 10.1002/iid3.70062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Streptococcus pneumoniae (pneumococcus) is a common cause of respiratory and invasive infections in humans. PCV13, a pneumococcal conjugate vaccine used globally, is highly effective against diseases caused by pneumococcal serotypes included in its formulation. However, one of them, the serotype 3 (ST3) is still being relatively commonly isolated from patients, suggesting an escape from vaccine-induced immunity. The thick capsule produced by ST3 facilitates bacterial evasion from the immune system. Additionally, host immune responses may influence the outcome of ST3 infection. Here we evaluated the influence of inflammation in the adaptive immune responses and protection induced by PCV13 against ST3, using two outbred mice lines that were phenotypically selected for high (AIRmax) and low (AIRmin) inflammatory responses. METHODS AIRmin and AIRmax mice were immunized with PCV13. Inbred BALB/c mice were used as reference for vaccine efficacy. Induction of IgG against polysaccharides (PS) from pneumococcal serotype 1 (ST1) and ST3 were evaluated by ELISA. Protection was tested against invasive infections with ST1 and ST3 pneumococcal strains. Sera were compared by IgG binding to pneumococcal surface, induction of pneumococcal agglutination and opsonophagocytosis. The phagocytic capacity of mice-derived neutrophils was also evaluated. RESULTS Immunization of AIRmin, AIRmax and BALB/c mice with PCV13 induced IgG against PS from ST1 and ST3 pneumococci. Despite vaccination, AIRmin mice were not protected against fatal infection with ST3. Sera from AIRmin mice immunized with PCV13 presented lower levels of anti-PS3 IgG, with reduced capacity to bind to pneumococcal surface. Reduced capacity to induce opsonophagocytosis of ST3 pneumococci in vitro was also observed. Conversely, PCV13 protected AIRmin mice against fatal infection with ST1 and this correlated with the capacity of the sera to induce ST1 opsonophagocytosis. CONCLUSIONS Our results show that both host and bacterial features can influence the outcome of protection induced by PCV13 against ST3 pneumococcal infection.
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Affiliation(s)
| | - Johanna Rivera
- Division of Infectious Diseases, Department of MedicineAlbert Einstein College of Medicine and Montefiore Medical CenterNew YorkBronxUSA
| | | | | | | | | | - Liise‐anne Pirofski
- Division of Infectious Diseases, Department of MedicineAlbert Einstein College of Medicine and Montefiore Medical CenterNew YorkBronxUSA
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Colavite PM, Azevedo MDCS, Francisconi CF, Fonseca AC, Tabanez AP, Melchiades JL, Passadori DC, Borrego A, De Franco M, Trombone APF, Garlet GP. Intermediate and Transitory Inflammation Mediate Proper Alveolar Bone Healing Outcome in Contrast to Extreme Low/High Responses: Evidence from Mice Strains Selected for Distinct Inflammatory Phenotypes. BIOLOGY 2024; 13:972. [PMID: 39765639 PMCID: PMC11673754 DOI: 10.3390/biology13120972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/14/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025]
Abstract
Alveolar bone healing is influenced by various local and systemic factors, including the local inflammatory response. This study aimed to evaluate the role of inflammatory responsiveness in alveolar bone healing using 8-week-old male and female mice (N = 5/time/group) strains selected for maximum (AIRmax) or minimum (AIRmin) acute inflammatory response carrying distinct homozygous RR/SS Slc11a1 genotypes, namely AIRminRR, AIRminSS, AIRmaxRR, and AIRmaxSS mice. After upper right incisor extraction, bone healing was analyzed at 0, 3, 7, and 14 days using micro-computed tomography, histomorphometry, birefringence, immunohistochemistry, and PCRArray analysis. AIRmaxSS and AIRminRR presented the highest and lowest inflammatory readouts, respectively, associated with lowest repair levels in both strains, while intermediate inflammatory phenotypes observed in AIRminSS and AIRmaxRR were associated with higher repair levels in such strains. The better healing outcomes are associated with intermediate inflammatory cell counts, a balanced expression of pro- and anti-inflammatory cytokines and chemokines, increased expression of growth and osteogenic factors and MSCs markers. Our results demonstrate that extreme high and low inflammatory responses are not ideal for a proper bone repair outcome, while an intermediate and transitory inflammation is associated with a proper alveolar bone healing outcome.
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Affiliation(s)
- Priscila Maria Colavite
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Octávio Pinheiro Brisola, 9-75, Bauru CEP 17012-901, SP, Brazil; (P.M.C.); (M.d.C.S.A.); (A.C.F.); (D.C.P.)
| | - Michelle de Campos Soriani Azevedo
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Octávio Pinheiro Brisola, 9-75, Bauru CEP 17012-901, SP, Brazil; (P.M.C.); (M.d.C.S.A.); (A.C.F.); (D.C.P.)
| | - Carolina Fávaro Francisconi
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Octávio Pinheiro Brisola, 9-75, Bauru CEP 17012-901, SP, Brazil; (P.M.C.); (M.d.C.S.A.); (A.C.F.); (D.C.P.)
| | - Angélica Cristina Fonseca
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Octávio Pinheiro Brisola, 9-75, Bauru CEP 17012-901, SP, Brazil; (P.M.C.); (M.d.C.S.A.); (A.C.F.); (D.C.P.)
| | - André Petenucci Tabanez
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Octávio Pinheiro Brisola, 9-75, Bauru CEP 17012-901, SP, Brazil; (P.M.C.); (M.d.C.S.A.); (A.C.F.); (D.C.P.)
| | - Jéssica Lima Melchiades
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Octávio Pinheiro Brisola, 9-75, Bauru CEP 17012-901, SP, Brazil; (P.M.C.); (M.d.C.S.A.); (A.C.F.); (D.C.P.)
| | - Daniela Carignatto Passadori
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Octávio Pinheiro Brisola, 9-75, Bauru CEP 17012-901, SP, Brazil; (P.M.C.); (M.d.C.S.A.); (A.C.F.); (D.C.P.)
| | - Andrea Borrego
- Laboratory of Immunogenetics, Butantan Institute, Secretary of Health, Government of the State of São Paulo, Sao Paulo CEP 05503-900, SP, Brazil; (A.B.); (M.D.F.)
| | - Marcelo De Franco
- Laboratory of Immunogenetics, Butantan Institute, Secretary of Health, Government of the State of São Paulo, Sao Paulo CEP 05503-900, SP, Brazil; (A.B.); (M.D.F.)
- Pasteur Institute, Diagnostic Section, Sao Paulo CEP 01311-000, SP, Brazil
| | | | - Gustavo Pompermaier Garlet
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Octávio Pinheiro Brisola, 9-75, Bauru CEP 17012-901, SP, Brazil; (P.M.C.); (M.d.C.S.A.); (A.C.F.); (D.C.P.)
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Cytotoxic Activity and Lymphocyte Subtypes in Mice Selected for Maximal and Minimal Inflammatory Response after Transplantation of B16F10 and S91 Melanoma Cells. Int J Inflam 2022; 2022:3298542. [PMID: 35265317 PMCID: PMC8901355 DOI: 10.1155/2022/3298542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/12/2022] [Indexed: 11/17/2022] Open
Abstract
AIRmax and AIRmin mice strains were selected according to the intensity of their acute inflammatory responsiveness. Previous studies have shown that AIR mice differ in their resistance to chemically induced skin tumors and in the development of melanoma metastases, in addition to differences in neutrophil and NK cells activity. In the present work, we aimed to evaluate whether the difference of susceptibility to murine melanoma is associated with NK cytotoxic activity against Yac.1 cells and lymphocyte subsets. Mice were subcutaneously inoculated with B16F10 or S91 melanoma cells. After 7, 14, or 30 days, the animals were euthanized to analyze the number of lymphocyte subsets, cytotoxic activity, and number of cytokine-producing spleen cells. AIRmax mice presented a higher number of CD4+/CD25+ cells than that of AIRmin mice following inoculation of B16F10 cells, whereas inoculation of S91 cells reduced CD4+/CD25+ and increased TCD8+ cell subsets in the AIRmax mice. AIRmax mice had a higher number of interleukin (IL)-10- and IL-12-producing cells and a lower number of interferon-γ–producing cells than those of AIRmin mice at 30 days. The cytotoxic activity of nonadherent spleen cells was similar in both the AIR strains. These results suggest that melanoma cells can induce different responses in AIR mice, possibly owing to alterations in regulatory mechanisms, such as the action of CD4+/CD25+ regulatory T cells and IL-10, in AIRmax mice.
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Kondo FV, Cabrera WHK, Ribeiro OG, De Franco M, Jensen JR, Picolo G, Sant’Anna MB, Spadafora-Ferreira M, Borrego A, Ibañez OM, Starobinas N. Pain and Cellular Migration Induced by Bothrops jararaca Venom in Mice Selected for an Acute Inflammatory Response: Involvement of Mast Cells. Front Immunol 2022; 12:779473. [PMID: 35185861 PMCID: PMC8854176 DOI: 10.3389/fimmu.2021.779473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
Bothrops jararaca venom (BjV) can induce mast cell degranulation. In order to investigate the role of mast cells and the interference of the host genetic background in the inflammation induced by BjV, we have used mouse strains selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory response (AIR). Mice were pretreated with an inhibitor of mast cell degranulation, cromolyn (CROM), and injected in footpads or intraperitoneally (i.p.) with BjV. Pain was measured with von Frey hairs, cell migration in the peritoneum by flow cytometry, and reactive oxygen species (ROS) production by chemiluminescence assays. The nociceptive response to BjV was higher in AIRmax than AIRmin mice; however, this difference was abolished by pretreatment with CROM. BjV induced peritoneal neutrophil (CD11b+ GR-1+) infiltration and ROS secretion in AIRmax mice only, which were partially inhibited by CROM. Our findings evidence a role for mast cells in pain, neutrophil migration, and ROS production triggered by BjV in AIRmax mice that are more susceptible to the action of BjV.
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Affiliation(s)
| | | | | | | | | | - Gisele Picolo
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, Brazil
| | | | | | - Andrea Borrego
- Laboratory Immunogenetics, Butantan Institute, São Paulo, Brazil
| | - Olga M. Ibañez
- Laboratory Immunogenetics, Butantan Institute, São Paulo, Brazil
| | - Nancy Starobinas
- Laboratory Immunogenetics, Butantan Institute, São Paulo, Brazil
- *Correspondence: Nancy Starobinas,
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Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response. J Immunol Res 2019; 2019:5298792. [PMID: 31049358 PMCID: PMC6462334 DOI: 10.1155/2019/5298792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/24/2019] [Indexed: 11/18/2022] Open
Abstract
AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-α, IL-1β, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control.
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Colavite PM, Vieira AE, Palanch Repeke CE, de Araujo Linhari RP, De Andrade RGCS, Borrego A, De Franco M, Trombone APF, Garlet GP. Alveolar bone healing in mice genetically selected in the maximum (AIRmax) or minimum (AIRmin) inflammatory reaction. Cytokine 2018; 114:47-60. [PMID: 30584949 DOI: 10.1016/j.cyto.2018.11.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/09/2018] [Accepted: 11/27/2018] [Indexed: 01/15/2023]
Abstract
The exact role of inflammatory immune response in bone healing process is still unclear, but the success of the alveolar bone healing process seems to be associated with a moderate and transitory inflammatory response, while insufficient or exacerbated responses seems to have a detrimental influence in the healing outcome. In this context, we performed a comparative analysis of mice strains genetically selected for maximum (AIRmax) or minimum (AIRmin) acute inflammatory response to address the influence of inflammation genes in alveolar bone healing outcome. Experimental groups comprised 8-week-old male or female AIRmax and AIRmin submitted to extraction of upper right incisor, and evaluated at 0, 3, 7, 14 and 21 days after upper incision extraction by micro-computed tomography (μCT), histomorphometry, birefringence, immunohistochemistry and molecular (PCRArray) analysis. Overall, the results demonstrate a similar successful bone healing outcome at the endpoint was evidenced in both AIRmin and AIRmax strains. The histormophometric analysis reveal a slight but significant decrease in blood clot and inflammatory cells density, as well a delay in the bone formation in AIRmax strain in the early times, associated with a decreased expression of BMP2, BMP4, BMP7, TGFb1, RUNX2, and ALP. The evaluation of inflammatory cells nature reveals increased GR1+ cells counts in AIRmax strain at 3d, associated with increased levels of neutrophil chemoattractants such as CXCL1 and CXCL2, and its receptor CXCR1, while F4/80+ cell prevails in AIRmin strain at 7d. Also, our results demonstrate a relative predominance of M2 macrophages in AIRmin strain, associated with an increased expression of ARG1, IL10, TGFb, while M1 macrophages prevail in AIRmax, which parallel with increased IL-1B, IL-6 and TNF expression. At late repair stage, AIRmax presents evidences of increased bone remodeling, characterized by increased density of blood vessels and osteoclasts in parallel with decreased bone matrix density, as well increased levels of MMPs, osteoclastogenic and osteocyte markers. In the view of contrasting inflammatory and healing phenotypes of AIRmin and AIRmax strains in other models, the unpredicted phenotype observed suggests the existence of specific QTLs (Quantitative trait loci) responsible for the regulation 'sterile' inflammation and bone healing events. Despite the similar endpoint healing, AIRmax strain delayed repair was associated with increased presence of neutrophils and M1 macrophages, supporting the association of M2 cells with faster bone healing. Further studies are required to clarify the elements responsible for the regulation of inflammatory events at bone healing sites, as well the determinants of bone healing outcome.
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Affiliation(s)
- Priscila Maria Colavite
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil
| | - Andreia Espindola Vieira
- Histology and Embryology Laboratory, Institute of Biological and Health Sciences (ICBS), Federal University of Alagoas (UFAL), Maceió, AL, Brazil
| | | | | | | | - Andrea Borrego
- Laboratory of Immunogenetics, Butantan Institute, Secretary of Health, Government of the State of São Paulo, SP, Brazil
| | - Marcelo De Franco
- Diagnostic Section, Pasteur Institute, Secretary of Health, Government of the State of São Paulo, SP, Brazil
| | | | - Gustavo Pompermaier Garlet
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.
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miRNA Expression and Interaction with Genes Involved in Susceptibility to Pristane-Induced Arthritis. J Immunol Res 2018; 2018:1928405. [PMID: 30648118 PMCID: PMC6311868 DOI: 10.1155/2018/1928405] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 10/10/2018] [Indexed: 11/24/2022] Open
Abstract
Pristane-induced arthritis (PIA) in mice is an experimental model that resembles human rheumatoid arthritis, a chronic autoimmune disease that affects joints and is characterized by synovial inflammation and articular cartilage and bone destruction. AIRmax and AIRmin mouse lines differ in their susceptibility to PIA, and linkage analysis in this model mapped arthritis severity QTLs in chromosomes 5 and 8. miRNAs are a class of small RNA molecules that have been extensively studied in the development of arthritis. We analyzed miRNA and gene expression profiles in peritoneal cells of AIRmax and AIRmin lines, in order to evaluate the genetic architecture in this model. Susceptible AIRmax mice showed higher gene (2025 vs 1043) and miRNA (240 vs 59) modulation than resistant AIRmin mice at the onset of disease symptoms. miR-132-3p/212-3p, miR-106-5p, miR-27b-3p, and miR-25-3p were among the miRNAs with the highest expression in susceptible animals, showing a negative correlation with the expression of predicted target genes (Il10, Cd69, and Sp1r1). Our study showed that global gene and miRNA expression profiles in peritoneal cells of susceptible AIRmax and resistant AIRmin lines during pristane-induced arthritis are distinct, evidencing interesting targets for further validation.
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Mancuso RI, Miyaji EN, Silva CCF, Portaro FV, Soares-Schanoski A, Ribeiro OG, Oliveira MLS. Impaired expression of CXCL5 and matrix metalloproteinases in the lungs of mice with high susceptibility to Streptococcus pneumoniae infection. IMMUNITY INFLAMMATION AND DISEASE 2017; 6:128-142. [PMID: 29119707 PMCID: PMC5818448 DOI: 10.1002/iid3.205] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/13/2017] [Accepted: 10/11/2017] [Indexed: 12/31/2022]
Abstract
Introduction Streptococcus pneumoniae colonizes the nasopharynx of healthy individuals establishing a commensal relationship with the host. In some conditions, bacteria invade the lower respiratory tract and innate immune responses are crucial to avoid diseases such as pneumonia, sepsis, or meningitis. Methods Here, we compared the susceptibility to pneumococcal respiratory infection of two outbred mouse lines, AIRmin and AIRmax, selected for low or high acute inflammatory responses, respectively. Results AIRmin mice showed increased susceptibility to infection with different pneumococcal serotypes, when compared to AIRmax. Significant higher numbers of alveolar macrophages expressing the CD206 mannose receptor were observed in AIRmin mice when compared to AIRmax mice. Despite this difference, secretion of several cytokines and chemokines in the respiratory tract of AIRmin and AIRmax mice, after infection, was similar. The only exception was CXCL5, which was highly induced after pneumococcal infection in AIRmax mice but not in AIRmin mice. Reduced expression of the matrix metalloproteinases (MMP) 2, 3, 8, and 9, as well as reduced activities of MMPs were also observed in the lungs of AIRmin mice, after infection. Such impaired responses may have contributed to the low influx of neutrophils observed in the airways of these mice. Finally, high percentages of macrophages and neutrophils in apoptosis or necrosis, at the site of infection, were also observed in AIRmin mice, suggesting that leukocyte functionality is also compromised. Conclusions Our results indicate that CXCL5 and MMPs contribute to the resistance to pneumococcal infection in mice.
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Affiliation(s)
- Rubia I Mancuso
- Laboratório de Bacteriologia, Instituto Butantan, São Paulo-SP, Brazil
| | - Eliane N Miyaji
- Laboratório de Bacteriologia, Instituto Butantan, São Paulo-SP, Brazil
| | | | | | | | - Orlando G Ribeiro
- Laboratório de Imunogenética, Instituto Butantan, São Paulo-SP, Brazil
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Yosaee S, Akbari Fakhrabadi M, Shidfar F. Positive evidence for vitamin A role in prevention of type 1 diabetes. World J Diabetes 2016; 7:177-188. [PMID: 27162582 PMCID: PMC4856890 DOI: 10.4239/wjd.v7.i9.177] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 03/23/2016] [Accepted: 04/07/2016] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) as one of the most well-known autoimmune disease, results from the destruction of β-cells in pancreas by autoimmune process. T1DM is fatal without insulin treatment. The expansion of alternative treatment to insulin is a dream to be fulfilled. Currently autoimmunity is considered as main factor in development of T1DM. So manipulation of the immune system can be considered as alternative treatment to insulin. For the past decades, vitamin A has been implicated as an essential dietary micronutrient in regulator of immune function. Despite major advantage in the knowledge of vitamin A biology, patients who present T1DM are at risk for deficiency in vitamin A and carotenoids. Applying such evidences, vitamin A treatment may be the key approach in preventing T1DM.
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Fernandes JG, Canhamero T, Borrego A, Jensen JR, Cabrera WH, Correa MA, Starobinas N, Ribeiro OG, Ibañez OM, De Franco M. Distinct gene expression profiles provoked by polyacrylamide beads (Biogel) during chronic and acute inflammation in mice selected for maximal and minimal inflammatory responses. Inflamm Res 2016; 65:313-23. [DOI: 10.1007/s00011-016-0918-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 01/11/2016] [Accepted: 01/12/2016] [Indexed: 11/30/2022] Open
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7,12-Dimethylbenz(a)anthracene-induced genotoxicity on bone marrow cells from mice phenotypically selected for low acute inflammatory response. DNA Repair (Amst) 2016; 37:43-52. [DOI: 10.1016/j.dnarep.2015.11.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/24/2015] [Accepted: 11/24/2015] [Indexed: 01/25/2023]
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Canhamero T, Garcia LV, De Franco M. Acute Inflammation Loci Are Involved in Wound Healing in the Mouse Ear Punch Model. Adv Wound Care (New Rochelle) 2014; 3:582-591. [PMID: 25207201 PMCID: PMC4152789 DOI: 10.1089/wound.2013.0494] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Accepted: 11/18/2013] [Indexed: 11/12/2022] Open
Abstract
Significance: Molecular biology techniques are being used to aid in determining the mechanisms responsible for tissue repair without scar formation. Wound healing is genetically determined, but there have been few studies that examine the genes responsible for tissue regeneration in mammals. Research using genetic mapping is extremely important for understanding the molecular mechanisms involved in the different phases of tissue regeneration. This process is complex, but an early inflammatory phase appears to influence lesion closure, and the present study demonstrates that acute inflammation loci influence tissue regeneration in mice in a positive manner. Recent Advances: Mapping studies of quantitative trait loci (QTL) have been undertaken in recent years to examine candidate genes that participate in the regeneration phenotype. Our laboratory has identified inflammation modifier QTL for wound healing. Mouse lines selected for the maximum (AIRmax) or minimum (AIRmin) acute inflammatory reactivity (AIR) have been used to study not only the tissue repair but also the impact of the genetic control of inflammation on susceptibility to autoimmune, neoplasic, and infectious diseases. Murphy Roths Large and AIRmax mice are exclusive in their complete epimorphic regeneration, although middle-aged inbred mice may also be capable of healing. Critical Issues: Inflammatory reactions have traditionally been described in the literature as negative factors in the process of skin injury closure. Inflammation is exacerbated due to the early release of mediators or the intense release of factors that cause cell proliferation after injury. The initial release of these factors as well as the clean-up of the lesion microenvironment are both crucial for following events. In addition, the activation and repression of some genes related to the regeneration phenotype may modulate lesion closure, demonstrating the significance of genetic studies to better understand the mechanisms involved in the initiation of wound repair processes. Future Directions: The pleiotropic effects of the QTL are important in the identification of the genes responsible for tissue repair processes, especially when combined with global gene expression research. Microarray analysis complements the biological information obtained in QTL mapping, making this tool essential for gene identification. This approach will allow the investigation of future targets for therapeutic wound healing treatments.
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Affiliation(s)
- Tatiane Canhamero
- Laboratory of Immunogenetics, Butantan Institute, Secretary of Health, Government of the State of São Paulo, São Paulo, Brazil
| | - Ludmila Valino Garcia
- Laboratory of Immunogenetics, Butantan Institute, Secretary of Health, Government of the State of São Paulo, São Paulo, Brazil
| | - Marcelo De Franco
- Laboratory of Immunogenetics, Butantan Institute, Secretary of Health, Government of the State of São Paulo, São Paulo, Brazil
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Katz ISS, Albuquerque LL, Suppa AP, de Siqueira DM, Rossato C, da Silva GB, Jensen JR, Starobinas N, Cabrera WHK, De Franco M, Borelli P, Ibañez OM, Ribeiro OG. 7,12-Dimethylbenz(a)anthracene-induced myelotoxicity differs in mice selected for high or low acute inflammatory response: relationship with aryl hydrocarbon receptor polymorphism. Int J Toxicol 2014; 33:130-42. [PMID: 24563413 DOI: 10.1177/1091581814522837] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Polycyclic aromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), are environmental pollutants that exert multiple toxic and carcinogenic effects. Studies showed that these effects are mediated by activation of the aryl hydrocarbon receptor (AhR) and modulated by allelic variants of Ahr gene. Here, we investigated the effects of DMBA treatment in the inflammatory response and bone marrow (BM) hematopoietic function of maximal acute inflammatory response (AIRmax) and minimal acute inflammatory response (AIRmin) heterogeneous mouse lines selected for high and low acute inflammatory responsiveness, respectively. The phenotypic selection resulted in the segregation of the Ahr(d) and Ahr(b1) alleles that confer low and high receptor ligand-binding affinity, respectively, in AIRmax and AIRmin mice. We observed a reduction in BM mature granulocyte population in AIRmin mice 24 hours after DMBA treatment while both blast and immature myeloid cells were increased. Proliferation and differentiation of BM myeloid cells in response to in vitro granulocyte-macrophage colony-stimulating factor stimulus were impaired in AIRmin-treated mice. These DMBA effects on myeloid BM cells (BMCs) affected the in vivo leukocyte migration to an inflammatory site induced by polyacrylamide beads (Biogel P-100, Bio-Rad, France) injection in AIRmin mice. On the other hand, these alterations were not observed in DMBA-treated AIRmax mice. These data indicate that DMBA affects myeloid cell differentiation and inflammatory response and Ahr(b1) allele in the genetic background of AIRmin mice contributes to this effect.
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Affiliation(s)
- Iana Suly Santos Katz
- Laboratório de Imunogenética, Instituto Butantan, Av Dr Vital Brazil, 1500, CEP 05503-900, São Paulo, SP, Brazil.
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De Franco M, Peters LC, Correa MA, Galvan A, Canhamero T, Borrego A, Jensen JR, Gonçalves J, Cabrera WHK, Starobinas N, Ribeiro OG, Dragani T, Ibañez OM. Pristane-induced arthritis loci interact with the Slc11a1 gene to determine susceptibility in mice selected for high inflammation. PLoS One 2014; 9:e88302. [PMID: 24505471 PMCID: PMC3914970 DOI: 10.1371/journal.pone.0088302] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 01/06/2014] [Indexed: 02/05/2023] Open
Abstract
AIRmax (maximal inflammation) and AIRmin (minimal inflammation) mice show distinct susceptibilities to pristane-induced arthritis (PIA). The Slc11a1 gene, which regulates macrophage and neutrophil activity, is involved in this infirmity. AIRmaxSS mice homozygous for the non-functional Slc11a1 S (gly169asp) allele obtained by genotype-assisted crosses from AIRmax and AIRmin mice are more susceptible than mice homozygous for the Slc11a1 resistant (R) allele. The present work sought to identify the quantitative trait loci (QTL) regulating PIA and to examine the interactions of these QTL with Slc11a1 alleles in modulating PIA. Mice were given two ip injections of 0.5 mL pristane at 60 day intervals, and the incidence and severity of PIA was scored up to 160 days. Genome-wide linkage studies were performed to search for arthritis QTL in an F2 (AIRmax × AIRmin, n = 290) population. Significant arthritis QTL (LODscore>4) were detected on chromosomes 5 and 8, and suggestive QTL on chromosomes 7, 17 and 19. Global gene expression analyses performed on Affymetrix mouse 1.0 ST bioarrays (27k genes) using RNA from arthritic or control mice paws showed 419 differentially expressed genes between AIRmax and AIRmin mice and demonstrated significantly (P<0.001) over-represented genes related to inflammatory responses and chemotaxis. Up-regulation of the chemokine genes Cxcl1, Cxcl9, Cxcl5, Cxcl13 on chromosome 5 was higher in AIRmaxSS than in the other lines. Macrophage scavenger receptor 1 and hemeoxigenase (decycling) 1 genes on chromosome 8 were also expressed at higher levels in AIRmaxSS mice. Our results show that the gene expression profiles of the two arthritis QTL (on chromosomes 5 and 8) correlate with Slc11a1 alleles, resulting in enhanced AIRmaxSS mice susceptibility to PIA.
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Affiliation(s)
- Marcelo De Franco
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil
- * E-mail:
| | | | - Mara A. Correa
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil
| | - Antonella Galvan
- Department of Experimental Oncology, Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Andrea Borrego
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil
| | - José R. Jensen
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil
| | | | | | - Nancy Starobinas
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil
| | | | - Tommaso Dragani
- Department of Experimental Oncology, Istituto Nazionale dei Tumori, Milan, Italy
| | - Olga M. Ibañez
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil
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Genetic control of renal tumorigenesis by the mouse Rtm1 locus. BMC Genomics 2013; 14:724. [PMID: 24148528 PMCID: PMC4046818 DOI: 10.1186/1471-2164-14-724] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Accepted: 10/11/2013] [Indexed: 01/04/2023] Open
Abstract
Background The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, using SNP arrays, in an (AIRmax x AIRmin)F2 intercross population treated with a single urethane dose at 1 week of age and phenotyped for renal tumors at 35 weeks of age. Results AIRmax mice did not develop renal tumors spontaneously nor in response to urethane, whereas in AIRmin mice renal tumors formed spontaneously (in 52% of animals) and after urethane induction (89%). The tumors had a papillary morphology and were positive for alpha-methylacyl-CoA racemase and negative for CD10. By analysis of 879 informative SNPs in 662 mice, we mapped a single quantitative trait locus modulating the incidence of renal tumors in the (AIRmax x AIRmin)F2 intercross population. This locus, which we named Renal tumor modifier QTL 1 (Rtm1), mapped to chromosome 17 at 23.4 Mb (LOD score = 15.8), with SNPs rs3696835 and rs3719497 flanking the LOD score peak. The A allele of rs3719497 from AIRmin mice was associated with a 2.5-fold increased odds ratio for renal tumor development. The LOD score peak included the Tuberous sclerosis 2 (Tsc2) gene which has already been implicated in kidney disease: loss of function by germline retroviral insertion is associated with spontaneous renal tumorigenesis in the Eker rat, and heterozygous-null Tsc2(+/-) mice develop renal cystadenomas. Conclusions We mapped Rtm1 as a single major locus modulating renal tumorigenesis in a murine intercross population. Thus, the AIR mouse lines can be considered a new genetic model for studying the role of germline and somatic molecular alterations in kidney neoplastic disease.
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Genetic linkage analysis identifies Pas1 as the common locus modulating lung tumorigenesis and acute inflammatory response in mice. Genes Immun 2013; 14:512-7. [PMID: 24067788 DOI: 10.1038/gene.2013.49] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 08/21/2013] [Accepted: 08/23/2013] [Indexed: 12/28/2022]
Abstract
Selective breeding for the acute inflammatory response (AIR) generated two mouse lines characterized by maximum (AIRmax) and minimum (AIRmin) responses, explained by the additive effect of alleles differentially fixed in quantitative trait loci (QTLs). These mice also differ in their susceptibility to lung tumorigenesis, raising the possibility that the same loci are involved in the control of both phenotypes. To map the QTLs responsible for the different phenotypes, we carried out a genome-wide linkage analysis using single-nucleotide polymorphism arrays in a pedigree consisting of 802 mice, including 693 (AIRmax × AIRmin)F2 intercross mice treated with urethane and phenotyped for AIR and lung tumor multiplicity. We mapped five loci on chromosomes 4, 6, 7, 11 and 13 linked to AIR (logarithm of odds (LOD)=3.56, 3.52, 15.74, 7.74 and 3.34, respectively) and two loci linked to lung tumor multiplicity, on chromosomes 6 and 18 (LOD=12.18 and 4.69, respectively). The known pulmonary adenoma susceptibility 1 (Pas1) locus on chromosome 6 was the only locus linked to both phenotypes, suggesting that alleles of this locus were differentially fixed during breeding and selection of AIR mice. These results represent a step toward understanding the link between inflammation and cancer.
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17
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Role of m2 muscarinic receptor in the airway response to methacholine of mice selected for minimal or maximal acute inflammatory response. BIOMED RESEARCH INTERNATIONAL 2013; 2013:805627. [PMID: 23691511 PMCID: PMC3652127 DOI: 10.1155/2013/805627] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 02/16/2013] [Accepted: 02/18/2013] [Indexed: 01/24/2023]
Abstract
Airway smooth muscle constriction induced by cholinergic agonists such as methacholine (MCh), which is typically increased in asthmatic patients, is regulated mainly by muscle muscarinic M3 receptors and negatively by vagal muscarinic M2 receptors. Here we evaluated basal (intrinsic) and allergen-induced (extrinsic) airway responses to MCh. We used two mouse lines selected to respond maximally (AIRmax) or minimally (AIRmin) to innate inflammatory stimuli. We found that in basal condition AIRmin mice responded more vigorously to MCh than AIRmax. Treatment with a specific M2 antagonist increased airway response of AIRmax but not of AIRmin mice. The expression of M2 receptors in the lung was significantly lower in AIRmin compared to AIRmax animals. AIRmax mice developed a more intense allergic inflammation than AIRmin, and both allergic mouse lines increased airway responses to MCh. However, gallamine treatment of allergic groups did not affect the responses to MCh. Our results confirm that low or dysfunctional M2 receptor activity is associated with increased airway responsiveness to MCh and that this trait was inherited during the selective breeding of AIRmin mice and was acquired by AIRmax mice during allergic lung inflammation.
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18
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Canhamero T, Reines B, Peters LC, Borrego A, Carneiro PS, Albuquerque LL, Cabrera WH, Ribeiro OG, Jensen JR, Starobinas N, Ibañez OM, De Franco M. Distinct early inflammatory events during ear tissue regeneration in mice selected for high inflammation bearing Slc11a1 R and S alleles. Inflammation 2012; 34:303-13. [PMID: 20665098 DOI: 10.1007/s10753-010-9235-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
High inflammatory AIRmax mice homozygous for Slc11a1 R and S alleles were produced. AIRmax(SS) mice showed faster ear tissue regeneration than AIRmax(RR) mice, suggesting that the S allele favored tissue restoration. Here, we investigated the gene expression profiles and the inflammatory reactions of AIRmax(RR) and AIRmax(SS) mice during the initial phase of ear tissue regeneration. We observed superior levels of analysis of wound myeloperoxidase and edema in AIRmax(SS) mice, although similar cell influx was verified in both lines. Of the genes, 794 were up- and 674 down-regulated in AIRmax(RR), while 735 genes were found to be up- and 1616 down-regulated in AIRmax(SS) mice 48 h after punch. Both mouse lines showed significant over-represented genes related to cell proliferation; however AIRmax(SS) displayed up-regulation of inflammatory response genes. Quantitative PCR experiments showed higher expressions of Tgfb1, Dap12 and Trem1 genes in AIRmax(SS) mice. These results indicate that Slc11a1 gene modulated the early inflammatory events of ear tissue regeneration.
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Affiliation(s)
- Tatiane Canhamero
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, SP, Brasil
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Souto JC, Vila L, Brú A. Polymorphonuclear neutrophils and cancer: intense and sustained neutrophilia as a treatment against solid tumors. Med Res Rev 2011; 31:311-63. [PMID: 19967776 DOI: 10.1002/med.20185] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Polymorphonuclear neutrophils (PMN) are the most abundant circulating immune cells and represent the first line of immune defense against infection. This review of the biomedical literature of the last 40 years shows that they also have a powerful antitumoral effect under certain circumstances. Typically, the microenvironment surrounding a solid tumor possesses many of the characteristics of chronic inflammation, a condition considered very favorable for tumor growth and spread. However, there are many circumstances that shift the chronic inflammatory state toward an acute inflammatory response around a tumor. This shift seems to convert PMN into very efficient anticancer effector cells. Clinical reports of unexpected antitumoral effects linked to the prolonged use of granulocyte colony-stimulating factor, which stimulates an intense and sustained neutrophilia, suggest that an easy way to fight solid tumors would be to encourage the development of intense peritumoral PMN infiltrates. Specifically designed clinical trials are urgently needed to evaluate the safety and efficacy of such drug-induced neutrophilia in patients with solid tumors. This antitumoral role of neutrophils may provide new avenues for the clinical treatment of cancer.
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Affiliation(s)
- Juan Carlos Souto
- Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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20
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Toufeer M, Bonnefont CMD, Foulon E, Caubet C, Tasca C, Aurel MR, Robert-Granié C, Rupp R, Foucras G. Gene expression profiling of dendritic cells reveals important mechanisms associated with predisposition to Staphylococcus infections. PLoS One 2011; 6:e22147. [PMID: 21857913 PMCID: PMC3155527 DOI: 10.1371/journal.pone.0022147] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 06/19/2011] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Staphylococcus aureus is a major pathogen of humans and animals and emerging antibiotic-resistant strains have further increased the concern of this health issue. Host genetics influence susceptibility to S. aureus infections, and the genes determining the outcome of infections should be identified to find alternative therapies to treatment with antibiotics. Here, we used outbred animals from a divergent selection based on susceptibility towards Staphylococcus infection to explore host immunogenetics. METHODOLOGY/PRINCIPAL FINDINGS We investigated how dendritic cells respond to heat-inactivated S. aureus and whether dendritic cells from animals showing different degrees of susceptibility had distinct gene expression profiles. We measured gene expression levels of in vitro S. aureus-stimulated bone marrow-derived dendritic cells at three different time points (0, 3 and 8 hrs) by using 15 k ovine Agilent microarrays. Furthermore, differential expression of a selected number of genes was confirmed by RT-qPCR. Gene signatures of stimulated DCs were obtained and showed that genes involved in the inflammatory process and T helper cell polarization were highly up-regulated upon stimulation. Moreover, a set of 204 genes were statistically differentially expressed between susceptible and resistant animals, and grouped them according to their predisposition to staphylococcal infection. Interestingly, over-expression of the C1q and Ido1 genes was observed in the resistant line and suggested a role of classical pathway of complement and early regulation of inflammation pathways, respectively. On the contrary, over expression of genes involved in the IL1R pathway was observed in susceptible animals. Furthermore, the leucocyte extravasation pathway was also found to be dominant in the susceptible line. CONCLUSION/SIGNIFICANCE We successfully obtained Staphylococcus aureus associated gene expression of ovine BM-DC in an 8-hour kinetics experiment. The distinct transcriptional profiles of dendritic cells obtained from resistant and susceptible animals may explain susceptibility towards S. aureus infections in a broader context.
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Affiliation(s)
- Mehdi Toufeer
- Université de Toulouse, INP, ENVT; UMR 1225, IHAP, Toulouse, France
- INRA, UMR1225, IHAP, Toulouse, France
| | - Cécile M. D. Bonnefont
- Université de Toulouse, INP, ENVT; UMR 1225, IHAP, Toulouse, France
- INRA, UMR1225, IHAP, Toulouse, France
- INRA, UR631, SAGA, Castanet-Tolosan, France
| | - Eliane Foulon
- Université de Toulouse, INP, ENVT; UMR 1225, IHAP, Toulouse, France
- INRA, UMR1225, IHAP, Toulouse, France
| | - Cécile Caubet
- Université de Toulouse, INP, ENVT; UMR 1225, IHAP, Toulouse, France
- INRA, UMR1225, IHAP, Toulouse, France
| | - Christian Tasca
- Université de Toulouse, INP, ENVT; UMR 1225, IHAP, Toulouse, France
- INRA, UMR1225, IHAP, Toulouse, France
| | | | | | | | - Gilles Foucras
- Université de Toulouse, INP, ENVT; UMR 1225, IHAP, Toulouse, France
- INRA, UMR1225, IHAP, Toulouse, France
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21
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Vorraro F, Galvan A, Cabrera WHK, Carneiro PS, Ribeiro OG, De Franco M, Starobinas N, Jensen JR, Seman M, Dragani TA, Ibañez OCM. Genetic control of IL-1 beta production and inflammatory response by the mouse Irm1 locus. THE JOURNAL OF IMMUNOLOGY 2010; 185:1616-21. [PMID: 20610646 DOI: 10.4049/jimmunol.1000358] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Genome-wide linkage analysis using single nucleotide polymorphism arrays was carried out in pedigrees of mice differing in the extent of acute inflammatory response (AIRmax or AIRmin). The AIR phenotype was determined by quantifying the number of infiltrating cells in the 24-h exudate induced by Biogel P-100 s.c. injection and by ex vivo IL-1beta production by leukocytes stimulated with LPS and ATP. We mapped the major inflammatory response modulator 1 locus on chromosome 7, at the 1-logarithm of odds (LOD) confidence interval from 116.75 to 139.75 Mb, linked to the number of infiltrating cells (LOD = 3.61) through the production of IL-1beta (LOD = 9.35). Of several interesting candidate genes mapping to the inflammatory response modulator 1 locus, 28 of these were differentially expressed in the bone marrow of AIRmax and AIRmin mice. These findings represent a step toward the identification of the genes underlying this complex phenotype.
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Tumour cell lines HT-29 and FaDu produce proinflammatory cytokines and activate neutrophils in vitro: possible applications for neutrophil-based antitumour treatment. Mediators Inflamm 2010; 2009:817498. [PMID: 20169105 PMCID: PMC2821782 DOI: 10.1155/2009/817498] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Accepted: 11/01/2009] [Indexed: 01/13/2023] Open
Abstract
There is evidence that polymorphonuclear neutrophils (PMNs) can exert severe antineoplastic effects. Cross-talk between tumour cells and endothelial cells (ECs) is necessary for the accumulation of PMN around a tumour. This work reports the ability of two PMN-sensitive, human, permanent cell lines—colorectal adenocarcinoma (HT-29) and pharyngeal squamous-cell carcinoma (FaDu) cells—to act as inflammatory foci. PMNs were cytotoxic to both lines, the adhesion of the PMNs to the tumour cells being important in this effect. The tumour cells released appreciable amounts of IL-8 and GROα, and induced the transmigration of PMN through human microvascular-EC monolayers. Conditioning media associated with both lines induced the adhesion of PMN and the surface expression of ICAM-1 in microvascular-EC. In addition, FaDu-conditioning-medium strongly induced the production of proinflammatory cytokines by microvascular-EC. These results support the idea that tumour cells might normally induce a potent acute inflammatory response, leading to their own
destruction.
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De Souza VRC, Cabrera WK, Galvan A, Ribeiro OG, De Franco M, Vorraro F, Starobinas N, Massa S, Dragani TA, Ibañez OM. Aryl hydrocarbon receptor polymorphism modulates DMBA-induced inflammation and carcinogenesis in phenotypically selected mice. Int J Cancer 2009; 124:1478-82. [PMID: 19065662 DOI: 10.1002/ijc.24066] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We tested the role of aryl hydrocarbon receptor (Ahr) gene polymorphism in the inflammatory response and in skin and lung tumorigenesis in 2 lines of mice phenotypically selected for maximum or minimum acute inflammatory reaction (AIRmax and AIRmin, respectively). Following 7,12-dimethylbenz[a]anthracene (DMBA) treatment, AIRmin but not AIRmax mice showed early skin reactions and eventually developed malignant skin tumors and lung adenocarcinomas. In skin tissue, transcript levels of IL1beta, Tnf, Il6, Tgfbeta1 and Cyp1b1 genes were upregulated in AIRmin but not AIRmax mice, consistent with the inflammatory responses to the carcinogen. These findings appeared to be related to the homozygosity status of the Ahr functional A375V polymorphism, which influences the binding capability of the receptor for DMBA: the 375A allele, encoding the high-affinity ligand-binding receptor (Ahr(b1)), segregated in AIRmin mice, whereas AIRmax mice carried the 375V, corresponding to the low-affinity binding receptor (Ahr(d)), to DMBA. The differential segregation of Ahr functional Ahr(d)versus Ahr(b1) alleles in AIRmax and AIRmin suggests a role for the Ahr gene in the control of inflammatory responsiveness and tumor development of these mouse lines.
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Carneiro PDS, Peters LC, Vorraro F, Borrego A, Ribeiro OG, Starobinas N, Jensen JR, Cabrera WHK, Ibañez OM, De Franco M. Gene expression profiles of bone marrow cells from mice phenotype-selected for maximal or minimal acute inflammations: searching for genes in acute inflammation modifier loci. Immunology 2008; 128:e562-71. [PMID: 19740317 DOI: 10.1111/j.1365-2567.2008.03032.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Two mouse lines were phenotype-selected for maximum (AIRmax) or minimum (AIRmin) acute inflammation responses to polyacrylamide bead (Biogel) injection. These lines differ in terms of bone marrow granulopoiesis, neutrophil resistance to apoptosis, and inflammatory cytokine production during acute inflammation responses. We compared gene expression profiles in bone marrow cells (BMC) of AIRmax and AIRmin mice during acute inflammatory reactions. The BMC from femurs were recovered 24 hr after subcutaneous injections of Biogel. Global gene expression analysis was performed on CodeLink Bioarrays (36K genes) using RNA pools of BMC from both control and treated AIRmax and AIRmin mice. Differentially expressed genes were statistically established and the over-represented gene ontology biological process categories were identified. Upregulations of about 136 and 198 genes were observed in the BMC of Biogel-treated AIRmax and AIRmin mice, respectively, but 740 genes were found to be downregulated in AIRmin mice compared with 94 genes in AIRmax mice. The over-represented biological themes of the differently expressed genes among AIRmax and AIRmin mice represent inflammatory response, signal transduction, cell proliferation and immune cell chemotaxis. We were able to demonstrate a broad downmodulation of gene transcripts in BMC from AIRmin mice during acute inflammation, and significant differentially expressed genes colocalized with previously mapped regions for inflammation-related phenotypes in chromosomes 1, 3, 6 and 11.
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25
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Lasisi AO. The role of retinol in the etiology and outcome of suppurative otitis media. Eur Arch Otorhinolaryngol 2008; 266:647-52. [PMID: 18704470 DOI: 10.1007/s00405-008-0794-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2008] [Accepted: 07/30/2008] [Indexed: 10/21/2022]
Abstract
Vitamin A deficiency is still a serious public health problem affecting an estimated 127 million preschool children. The resulting immunological dysfunctions lead to increased risks of respiratory tract infections, diarrhoeal diseases and blindness, among others. The aim of this study is to determine the significance of the role of serum retinol in the etiology of acute suppurative otitis media (ASOM) and its chronicity (CSOM). In a prospective follow-up of patients with ASOM for 6-9 months, serum retinol determination was done using the high performance liquid chromatography. Participants comprised 358 ASOM and 52 control subjects. Six-month follow-up was achieved in 264 subjects (74%); of these, there was persistence of otorrhoea (CSOM) in 116, while 148 had resolved ASOM. Of the 264 subjects, 146 were males and 118 were females, between the ages of 6 months and 9 years and a mean of 7 years (SD = 2.32), whereas the control subjects comprised 29 males and 22 females, between the ages of 6 months and 11 years and a mean of 7.8 years (SD = 3.6). The range of serum retinol in the ASOM subjects was 1.63-2.64 microg/L, mean of 1.53 microg/L, median value of 2.61 microg/L and (SD = 0.16). Among control subjects, the range was 2.5-2.8 microg/L, mean of 2.58 microg/L and median value of 2.61 microg/L (SD = 0.14) (Table 1). The range of serum retinol in the resolved ASOM subjects was 1.61-2.63 microg/L, mean of 2.07 microg/L and median value of 2.09 microg/L (SD = 0.16) while the CSOM subjects ranged between 0.8-2.86 microg/L, mean of 1.58 microg/L and median value of 1.28 microg/L, (SD = 0.48) (Table 2). Univariate analysis using unpaired t test to compare the mean serum retinol revealed significant difference between ASOM and control (P = 0.0000) and between resolved ASOM and CSOM (P = 0.0000). In conclusion, hyporetinolaemia was a significant etiological factor in the etiology ASOM and CSOM, suggesting retinol supplementation as one strategy in control of SOM.
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Affiliation(s)
- Akeem O Lasisi
- Department of Otorhinolaryngology, Faculty of Clinical Sciences, College of Medicine, University of Ibadan, Ibadan, Nigeria.
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Carneiro AS, Ribeiro OG, Cabrera WHK, Vorraro F, De Franco M, Ibañez OM, Starobinas N. Bothrops jararaca venom (BjV) induces differential leukocyte accumulation in mice genetically selected for acute inflammatory reaction: the role of host genetic background on expression of adhesion molecules and release of endogenous mediators. Toxicon 2008; 52:619-27. [PMID: 18723041 DOI: 10.1016/j.toxicon.2008.07.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2008] [Revised: 07/24/2008] [Accepted: 07/25/2008] [Indexed: 10/21/2022]
Abstract
The dynamics of the local inflammatory events induced by Bothrops jararaca venom (BjV) inoculation in footpad of mice genetically selected for maximal (AIRmax) and minimal (AIRmin) acute inflammatory reactivity (AIR) was investigated. The BjV injection induced a marked inflammatory cell infiltrate with predominance of neutrophils, with increased blood cell numbers before its accumulation, suggesting a stimulatory action of BjV on mechanisms of cell mobilization from bone marrow. The process of cell migration is regulated by different cell-adhesion molecules (CAM). Our results showed that neutrophil cells from both lines had the same pattern of response concerning CAMs expression, presenting the involvement of l-selectin, Mac-1 and PECAM-1 adhesion molecules in BjV-induced neutrophil accumulation. The effect of BjV on the release of pro-inflammatory cytokines and chemokines related with cellular migration was also studied and IL-1beta, IL-6, TNF-alpha and MIP-2 levels could be detected after venom injection. The AIRmax mice were shown to be more responsive than AIRmin with respect to leukocyte influx, expression of MIP-2 and release of IL-1beta and IL-6. These results demonstrate the importance of host genetic background in the local response and the involvement of alleles accumulated in AIRmax mice in the inflammatory events induced by BjV.
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Affiliation(s)
- Adriana S Carneiro
- Laboratório de Imunogenética, Instituto Butantan, Av. Vital Brasil 1500 - cep 05503-900, São Paulo, SP, Brazil
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Adriouch S, Hubert S, Pechberty S, Koch-Nolte F, Haag F, Seman M. NAD+ released during inflammation participates in T cell homeostasis by inducing ART2-mediated death of naive T cells in vivo. THE JOURNAL OF IMMUNOLOGY 2007; 179:186-94. [PMID: 17579037 DOI: 10.4049/jimmunol.179.1.186] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Mono ADP-ribosyltransferase 2 (ART2) is an ectoenzyme expressed on mouse T lymphocytes, which catalyze the transfer of ADP-ribose groups from NAD(+) onto several target proteins. In vitro, ADP-ribosylation by ART2 activates the P2X7 ATP receptor and is responsible for NAD(+)-induced T cell death (NICD). Yet, the origin of extracellular NAD(+) and the role of NICD in vivo remain elusive. In a model of acute inflammation induced by polyacrylamide beads, we demonstrate release of NAD(+) into exudates during the early phase of the inflammatory response. This leads to T cell depletion in the draining lymph nodes from wild-type and, more severely, from mice lacking the CD38 NAD(+) glycohydrolase, whereas no effect is observed in ART2-deficient animals. Intravenous injection of NAD(+) used to exacerbate NICD in vivo results in fast and dramatic ART2- and P2X7-dependent depletion of CD4+ and CD8+ T lymphocytes, which can affect up to 80% of peripheral T cells in CD38(-/-) mice. This affects mainly naive T cells as most cells surviving in vivo NAD+ treatment exhibit the phenotype of recently activated/memory cells. Consistently, treatment with NAD(+) abolishes primary Ab response to a T-dependent Ag in NICD-susceptible CD38(-/-) mice but has no effect on the secondary response when given several days after priming. Unexpectedly NAD+ treatment improves the response in their wild-type BALB/c counterparts. We propose that NAD(+) released during early inflammation facilitates the expansion of primed T cells, through ART2-driven death of resting cells, thus contributing to the dynamic regulation of T cell homeostasis.
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De Franco M, Carneiro PDS, Peters LC, Vorraro F, Borrego A, Ribeiro OG, Starobinas N, Cabrera WK, Ibañez OM. Slc11a1 (Nramp1) alleles interact with acute inflammation loci to modulate wound-healing traits in mice. Mamm Genome 2007; 18:263-9. [PMID: 17486412 DOI: 10.1007/s00335-007-9012-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2006] [Accepted: 03/02/2007] [Indexed: 11/30/2022]
Abstract
Lines of mice were obtained by selective breeding for maximum (AIRmax) or minimum (AIRmin) acute inflammation. They present distinct neutrophil influx and show frequency disequilibrium of the solute carrier family 11a member 1 (Slc11a1) alleles. This gene is involved in ion transport at the endosomes within macrophages and neutrophils, interfering in their activation. Homozygous AIRmax and AIRmin sublines for the Slc11a1 gene were produced to examine the interaction of this gene with the acute inflammatory loci. The present work investigated wound-healing traits in AIRmax and AIRmin mice, in F(1) and F(2) intercrosses, and in Slc11a1 sublines. Two-millimeter ear punches were made in the mice and hole closure was measured during 40 days. AIRmax mice demonstrated significant tissue repair while AIRmin mice did not. Significant differences between the responses of male and female mice were also observed. Wound-healing traits demonstrated a correlation with neutrophil influx in F(2) populations. AIRmax( SS )showed higher ear-wound closure than AIRmax( RR ) mice, suggesting that the Slc11a1 S allele favored ear tissue repair. QTL analysis has detected two inflammatory loci modulating ear wound healing on chromosomes 1 and 14. These results suggest the involvement of the acute inflammation modifier QTL in the wound-healing phenotype.
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Affiliation(s)
- Marcelo De Franco
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.
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Laragione T, Yarlett NC, Brenner M, Mello A, Sherry B, Miller EJ, Metz CN, Gulko PS. The arthritis severity quantitative trait loci Cia4 and Cia6 regulate neutrophil migration into inflammatory sites and levels of TNF-alpha and nitric oxide. THE JOURNAL OF IMMUNOLOGY 2007; 178:2344-51. [PMID: 17277140 DOI: 10.4049/jimmunol.178.4.2344] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Neutrophils are required for the development of arthritis, and their migration into the synovial tissue coincides with the onset of clinical disease. Synovial neutrophil numbers also correlate with rheumatoid arthritis disease activity and severity. We hypothesized that certain arthritis severity genes regulate disease via the regulation of neutrophil migration into the joint. This hypothesis was tested in the synovial-like air pouch model injected with carrageenan using arthritis-susceptible DA and arthritis-resistant F344 rats. DA had nearly 3-fold higher numbers of exudate neutrophils compared with F344 (p < 0.001). Five DA.F344(QTL) strains congenic for severity loci and protected from autoimmune arthritis were studied. Only DA.F344(Cia4) (chromosome 7) and DA.F344(Cia6) (chromosome 8) congenics had significantly lower exudate neutrophil counts compared with DA. TNF-alpha levels were 2.5-fold higher in DA exudates as compared with F344 exudates, and that difference was accounted for by the Cia4 locus. Exudate levels of NO, a known inhibitor of neutrophil chemotaxis, were higher in F344, compared with DA, and that difference was accounted for by Cia6. This is the first time that non-MHC autoimmune arthritis loci are found to regulate three central components of the innate immune response implicated in disease pathogenesis, namely neutrophil migration into an inflammatory site, as well as exudate levels of TNF-alpha and NO. These observations underscore the importance of identifying the Cia4 and Cia6 genes, and suggest that they should generate useful novel targets for development of new therapies.
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Affiliation(s)
- Teresina Laragione
- Laboratory of Experimental Rheumatology, Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, NY, USA
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Castoldi L, Golim MA, Filho OGR, Romagnoli GG, Ibañez OCM, Kaneno R. Enhanced natural killer activity and production of pro-inflammatory cytokines in mice selected for high acute inflammatory response (AIRmax). Immunology 2007; 120:372-9. [PMID: 17163963 PMCID: PMC2265892 DOI: 10.1111/j.1365-2567.2006.02513.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2006] [Revised: 10/13/2006] [Accepted: 10/13/2006] [Indexed: 01/11/2023] Open
Abstract
Strains of mice with maximal and minimal acute inflammatory responsiveness (AIRmax and AIRmin, respectively) were developed through selective breeding based on their high- or low-acute inflammatory responsiveness. Previous reports have shown that AIRmax mice are more resistant to the development of a variety of tumours than AIRmin mice, including spontaneous metastasis of murine melanoma. Natural killer activity is involved in immunosurveillance against tumour development, so we analysed the number and activity of natural killer cells (CD49b(+)), T-lymphocyte subsets and in vitro cytokine production by spleen cells of normal AIRmax and AIRmin mice. Analysis of lymphocyte subsets by flow cytometry showed that AIRmax mice had a higher relative number of CD49b(+) cells than AIRmin mice, as well as cytolytic activity against Yac.1 target cells. The number of CD3(+) CD8(+) cells was also higher in AIRmax mice. These findings were associated with the ability of spleen cells from AIRmax mice in vitro to produce higher levels of the pro-inflammatory cytokines tumour necrosis factor-alpha, interleukin-12p40 and interferon-gamma but not the anti-inflammatory interleukin-10. Taken together, our data suggest that the selective breeding to achieve the AIRmax and AIRmin strains was able to polarize the genes associated with cytotoxic activity, which can be responsible for the antitumour resistance observed in AIRmax mice.
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Affiliation(s)
- Lindsey Castoldi
- UNESP, Department of Pathology, Faculty of Medicine of Botucatu, Botucatu-SP, Brazil
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Laragione T, Brenner M, Yarlett NC, Mello A, Miller EJ, Metz CN, Sherry B, Gulko PS. The arthritis severity quantitative trait locus Cia7 regulates neutrophil migration into inflammatory sites. Genes Immun 2007; 8:147-53. [PMID: 17268510 DOI: 10.1038/sj.gene.6364371] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Neutrophils are required for the development of arthritis in rodents, and are the predominant cell in the synovial fluid of active rheumatoid arthritis. We hypothesized that neutrophil migration into the inflammed joint is genetically regulated. In addition, this genetic regulation would be accounted for by one of the arthritis loci that we have previously identified in an intercross between arthritis-susceptible DA and arthritis-resistant ACI rats studied for collagen-induced arthritis. We used the synovial-like air pouch model injected with carrageenan, and tested DA, ACI, and four congenic strains. ACI exudates had a significantly lower number of neutrophils compared with DA. Transfer of DA alleles at Cia7 into the ACI background, as in ACI.DA(Cia7) congenics, was enough to increase exudate neutrophil numbers to levels identical to DA, and this locus accounted for the difference between parental strains. None of the other congenic intervals explained the differences in exudate neutrophil counts. In conclusion, we have identified a novel function for Cia7, and determined that it regulates neutrophil migration into a synovial-like inflammatory site. Our data revealed no intrinsic defect in neutrophil responses to chemotactic agents, and suggest that Cia7 regulates an as yet unidentified factor central to neutrophil recruitment into inflammed tissues.
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Affiliation(s)
- T Laragione
- 1Laboratory of Experimental Rheumatology, The Robert S Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
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Ha T, Hua F, Grant D, Xia Y, Ma J, Gao X, Kelley J, Williams DL, Kalbfleisch J, Browder IW, Kao RL, Li C. Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice. Am J Physiol Heart Circ Physiol 2006; 291:H1910-8. [PMID: 16766637 DOI: 10.1152/ajpheart.01264.2005] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice. GP was administered to ICR/HSD mice 1 h before induction of CLP. Sham surgically operated mice served as control. Cardiac function was significantly decreased 6 h after CLP-induced sepsis compared with sham control. In contrast, GP administration prevented CLP-induced cardiac dysfunction. Macrophage migration inhibitory factor (MIF) has been implicated as a major factor in cardiomyocyte apoptosis and cardiac dysfunction during septic shock. CLP increased myocardial MIF expression by 88.3% ( P < 0.05) and cardiomyocyte apoptosis by 7.8-fold ( P < 0.05) compared with sham control. GP administration, however, prevented CLP-increased MIF expression and decreased cardiomyocyte apoptosis by 51.2% ( P < 0.05) compared with untreated CLP mice. GP also prevented sepsis-caused decreases in phospho-Akt, phospho-GSK-3β, and Bcl-2 levels in the myocardium of septic mice. These data suggest that GP treatment attenuates cardiovascular dysfunction in fulminating sepsis. GP administration also activates the phosphoinositide 3-kinase/Akt pathway, decreases myocardial MIF expression, and reduces cardiomyocyte apoptosis.
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Affiliation(s)
- Tuanzhu Ha
- Dept. of Surgery, East Tennessee State Univ., Campus Box 70575, Johnson City, TN 37614-0575, USA
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Borrego A, Peters LC, Jensen JR, Ribeiro OG, Koury Cabrera WH, Starobinas N, Seman M, Ibañez OM, De Franco M. Genetic determinants of acute inflammation regulate Salmonella infection and modulate Slc11a1 gene (formerly Nramp1) effects in selected mouse lines. Microbes Infect 2006; 8:2766-71. [PMID: 17035062 DOI: 10.1016/j.micinf.2006.08.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2006] [Revised: 07/26/2006] [Accepted: 08/14/2006] [Indexed: 11/17/2022]
Abstract
Two lines of mice selected to produce maximal (AIRmax) or minimal (AIRmin) acute inflammatory reactions (AIR) differ in their susceptibility to infection by Salmonella enterica serotype Typhimurium (S. Typhimurium). The LD(50) for AIRmax mice is 1000 times higher than that observed for AIRmin mice, and higher frequencies of Slc11a1 alleles (known to confer either resistance (R) or high susceptibility (S) to S. Typhimurium) were consistently found in AIRmax and AIRmin mouse lines, respectively. In order to evaluate the effect of the quantitative trait loci (QTL) segregated in AIRmax and AIRmin mice on Slc11a1 dependent susceptibility to S. Typhimurium, the R and S alleles were fixed in homozygosity in AIRmax and AIRmin backgrounds by genotype assisted breedings. These new lines were named AIRmax(RR), AIRmax(SS), AIRmin(RR), and AIRmin(SS). Acute inflammation of Slc11a1(RR) animals was more severe in comparison to their Slc11a1(SS) counterparts, implicating Slc11a1 (or other linked genes) in AIR regulation. The LD(50) of S. Typhimurium was 800-times higher for AIRmax(SS) than for AIRmin(SS), demonstrating that AIR QTL can act as modifiers of the Slc11a1(SS) susceptibility gene. Four microsatellite markers for S. Typhimurium susceptibility QTL described in other mouse lines showed specific allele fixation in AIRmax or AIRmin mice, suggesting that these chromosomal regions also segregate with inflammatory phenotypes.
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Affiliation(s)
- Andrea Borrego
- Laboratório de Imunogenética - Instituto Butantan, Av. Vital Brasil, 1500, São Paulo, SP 05503900, Brazil
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Palić D, Andreasen CB, Herolt DM, Menzel BW, Roth JA. Immunomodulatory effects of beta-glucan on neutrophil function in fathead minnows (Pimephales promelas Rafinesque, 1820). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2006; 30:817-30. [PMID: 16423394 DOI: 10.1016/j.dci.2005.11.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2005] [Revised: 11/01/2005] [Accepted: 11/22/2005] [Indexed: 05/06/2023]
Abstract
Stimulatory effects of yeast beta-1,3-1,6-glucans on neutrophils have long been recognized, but effects of glucans on degranulation of primary granules in fish neutrophils have not been previously reported. Neutrophil function was monitored during in vitro and in vivo application of glucans to non- (NS), acute- (AS) and chronically stressed (CS) fish. beta-Glucan proved to be a strong and quick (80%, 2 min) stimulant of degranulation. Dietary glucan increased degranulation in NS fish, and prevented a decrease in AS fish. Degranulation in CS fish returned to NS levels 3 days after the glucan diet was fed. Fathead minnows appear to be a useful model to investigate neutrophil degranulation in fish exposed to different environmental conditions and immunomodulators. Use of beta-glucans in fish diets prior to AS and during chronic stress can enhance neutrophil function, potentially increasing disease resistance and survival rates after transportation or exposure to poor water quality.
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Affiliation(s)
- Dusan Palić
- Department of Natural Resource, Ecology and Management, College of Agriculture, Iowa State University, 339 Science 2, Ames, IA 50011, USA.
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Villamor E, Fawzi WW. Effects of vitamin a supplementation on immune responses and correlation with clinical outcomes. Clin Microbiol Rev 2005; 18:446-64. [PMID: 16020684 PMCID: PMC1195969 DOI: 10.1128/cmr.18.3.446-464.2005] [Citation(s) in RCA: 237] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Vitamin A supplementation to preschool children is known to decrease the risks of mortality and morbidity from some forms of diarrhea, measles, human immunodeficiency virus (HIV) infection, and malaria. These effects are likely to be the result of the actions of vitamin A on immunity. Some of the immunomodulatory mechanisms of vitamin A have been described in clinical trials and can be correlated with clinical outcomes of supplementation. The effects on morbidity from measles are related to enhanced antibody production and lymphocyte proliferation. Benefits for severe diarrhea could be attributable to the functions of vitamin A in sustaining the integrity of mucosal epithelia in the gut, whereas positive effects among HIV-infected children could also be related to increased T-cell lymphopoiesis. There is no conclusive evidence for a direct effect of vitamin A supplementation on cytokine production or lymphocyte activation. Under certain circumstances, vitamin A supplementation to infants has the potential to improve the antibody response to some vaccines, including tetanus and diphtheria toxoids and measles. There is limited research on the effects of vitamin A supplementation to adults and the elderly on their immune function; currently available data provide no consistent evidence for beneficial effects. Additional studies with these age groups are needed.
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Affiliation(s)
- Eduardo Villamor
- Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA.
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Ribeiro OG, Cabrera WH, Maria DA, De Franco M, Massa S, Di Pace RF, de Souza VRC, Starobinas N, Semen M, Ibañez OM. Genetic selection for high acute inflammatory response confers resistance to lung carcinogenesis in the mouse. Exp Lung Res 2005; 31:105-16. [PMID: 15765921 DOI: 10.1080/01902140490495237] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Mice selected for a high acute inflammatory response (AIRmax) are resistant to chemically induced lung tumorigenesis, whereas the low responders (AIRmin) are susceptible. In urethane-treated mice, anti-inflammatory drugs increased the tumor incidence in AIRmax but not AIRmin mice, and an inverse correlation (P<.001) between the degree of acute inflammatory response (AIR) and lung tumorigenesis was found in an F2 (AIRmax x AIRmin) intercross population. The results provide evidence for the involvement of lung tumor modifier loci in AIR regulation and implicate AIR quantitative trait loci in the inherited predisposition to lung cancer.
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