RESUMO
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.
Assuntos
Bothrops , Venenos de Crotalídeos , Animais , Movimento Celular , Venenos de Crotalídeos/efeitos adversos , Inflamação/induzido quimicamente , Mastócitos , Camundongos , Dor , Espécies Reativas de OxigênioRESUMO
Mouse lines selected for maximal (AIRmax) or minimal acute inflammatory reaction (AIRmin) were used to characterize the immune response and the influence of genetic background during pristane-induced arthritis (PIA). Susceptible AIRmax mice demonstrated exacerbated cellular profiles during PIA, with intense infiltration of lymphocytes, as well as monocytes/macrophages and neutrophils, producing higher levels of IL-1ß, IFN-γ, TNF-α, IL-10, total IgG3, and chemokines. Resistant AIRmin mice controlled cell activation more efficiently than the AIRmax during arthritis progression. The weight alterations of the spleen and thymus in the course of PIA were observed. Our data suggest that selected AIRmax cellular and genetic immune mechanisms contribute to cartilage damage and arthritis severity, evidencing many targets for therapeutic actions.
Assuntos
Artrite Experimental/imunologia , Citocinas/imunologia , Imunoglobulina G/imunologia , Terpenos/efeitos adversos , Doença Aguda , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/genética , Artrite Experimental/patologia , Citocinas/genética , Imunoglobulina G/genética , Inflamação , Camundongos , Baço/imunologia , Baço/patologia , Terpenos/farmacologia , Timo/imunologia , Timo/patologiaRESUMO
OBJECTIVE AND DESIGN: Pristane-induced arthritis (PIA) in AIRmax mice homozygous for Slc11a1 R and S alleles was used to characterize the influence of Slc11a1 gene polymorphism on immune responses during disease manifestation. Previous reports demonstrated that the presence of the Slc11a1 S allele increased the incidence and severity of PIA in AIRmax SS , suggesting that this gene could interact with inflammatory loci to modulate PIA. We investigated the effects of Slc11a1 alleles on the activation of phagocytes during PIA. TREATMENT: Mice were injected intraperitoneally with two doses of 0.5 mL of mineral oil pristane at 60-day intervals. Arthritis development was accompanied for 180 days. RESULTS: AIRmax SS mice showed differential peritoneal macrophage gene expression profiles during PIA, with higher expression and production of H2O2, NO, IL-1ß, IL-6, TNF-α, and several chemokines. The presence of the Slc11a1 R allele, on the other hand, diminished the intensity of macrophage activation, restricting arthritis development. CONCLUSION: Our data demonstrated the fine-tuning roles of Slc11a1 alleles modulating macrophage activation, and consequent PIA susceptibility, in those mouse lines. (AU)
Assuntos
Animais , Artrite Reumatoide/genética , Inflamação/genética , Polimorfismo Genético , Artrite Experimental , Expressão Gênica , Citocinas , Macrófagos , CamundongosRESUMO
OBJECTIVE AND DESIGN: Pristane-induced arthritis (PIA) in AIRmax mice homozygous for Slc11a1 R and S alleles was used to characterize the influence of Slc11a1 gene polymorphism on immune responses during disease manifestation. Previous reports demonstrated that the presence of the Slc11a1 S allele increased the incidence and severity of PIA in AIRmax SS , suggesting that this gene could interact with inflammatory loci to modulate PIA. We investigated the effects of Slc11a1 alleles on the activation of phagocytes during PIA. TREATMENT: Mice were injected intraperitoneally with two doses of 0.5 mL of mineral oil pristane at 60-day intervals. Arthritis development was accompanied for 180 days. RESULTS: AIRmax SS mice showed differential peritoneal macrophage gene expression profiles during PIA, with higher expression and production of H2O2, NO, IL-1ß, IL-6, TNF-α, and several chemokines. The presence of the Slc11a1 R allele, on the other hand, diminished the intensity of macrophage activation, restricting arthritis development. CONCLUSION: Our data demonstrated the fine-tuning roles of Slc11a1 alleles modulating macrophage activation, and consequent PIA susceptibility, in those mouse lines.
Assuntos
Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/imunologia , Macrófagos Peritoneais/imunologia , Animais , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Peróxido de Hidrogênio/imunologia , Articulações/patologia , Masculino , Camundongos , Óxido Nítrico/imunologia , Terpenos , TranscriptomaRESUMO
Trypanosoma cruzi infection was studied in mouse lines selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory reaction and for high (HIII) or low (LIII) antibody (Ab) responses to complex antigens. Resistance was associated with gender (females) and strain-the high responder lines AIRmax and HIII were resistant. The higher resistance of HIII as compared to LIII mice extended to higher infective doses and was correlated with enhanced production of IFN-γ and nitric oxide production by peritoneal and lymph node cells, in HIII males and females. We also analyzed the involvement of previously mapped Ab and T. cruzi response QTL with the survival of Selection III mice to T. cruzi infections in a segregating backcross [F1(HIII×LIII) ×LIII] population. An Ab production QTL marker mapping to mouse chromosome 1 (34.8 cM) significantly cosegregated with survival after acute T. cruzi infections, indicating that this region also harbors genes whose alleles modulate resistance to acute T. cruzi infection.
Assuntos
Doença de Chagas/genética , Doença de Chagas/imunologia , Ligação Genética/genética , Locos de Características Quantitativas/genética , Trypanosoma cruzi/patogenicidade , Animais , Formação de Anticorpos/genética , Formação de Anticorpos/fisiologia , Feminino , Masculino , Camundongos , Trypanosoma cruzi/imunologiaRESUMO
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. AIRmax (SS) 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, nâ=â290) 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 AIRmax(SS) than in the other lines. Macrophage scavenger receptor 1 and hemeoxigenase (decycling) 1 genes on chromosome 8 were also expressed at higher levels in AIRmax(SS) 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 AIRmax(SS) mice susceptibility to PIA.
Assuntos
Artrite/genética , Proteínas de Transporte de Cátions/genética , Locos de Características Quantitativas , Alelos , Animais , Artrite/induzido quimicamente , Suscetibilidade a Doenças , Feminino , Inflamação/induzido quimicamente , Inflamação/genética , Masculino , Camundongos , Terpenos , TranscriptomaRESUMO
High inflammatory AIRmax mice homozygous for Slc11a1 R and S alleles were produced. AIRmaxSS mice showed faster ear tissue regeneration than AIRmaxRR mice, suggesting that the Sallele favored tissue restoration. Here, we investigated the gene expression profiles and the inflammatory reactions of AIRmaxRR and AIRmaxSS mice during the initial phase of ear tissue regeneration. We observed superior levels of analysis of wound myeloperoxidase and edema inAIRmaxSS mice, although similar cell influx was verified in both lines. Of the genes, 794 were up- and 674 down-regulated in AIRmaxRR, while 735 genes were found to be up- and 1616 down-regulated in AIRmaxSS mice 48 h after punch. Both mouse lines showed significant over-represented genes related to cell proliferation; however AIRmaxSS displayed up-regulation of inflammatory response genes. Quantitative PCR experiments showed higher expressions of Tgfb1, Dap12 and Trem1 genes in AIRmaxSS mice. These results indicate that Slc11a1 gene modulated the early inflammatory events of ear tissue regeneration.
Assuntos
Camundongos , Inflamação/genética , Inflamação/imunologia , Regeneração/genética , Regeneração/imunologia , Alelos , Modulação Antigênica/genética , Modulação Antigênica/imunologiaRESUMO
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.
Assuntos
Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/fisiologia , Inflamação/genética , Inflamação/fisiopatologia , Regeneração/genética , Regeneração/fisiologia , Alelos , Animais , Sequência de Bases , Primers do DNA/genética , Orelha Externa/lesões , Orelha Externa/fisiologia , Feminino , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos , Peroxidase/metabolismo , Locos de Características Quantitativas , Reação em Cadeia da Polimerase em Tempo Real , Cicatrização/genética , Cicatrização/fisiologiaRESUMO
AIRmax and AIRmin mouse lines show a differential lung inflammatory response and differential lung tumor susceptibility after urethane treatment. The transcript profile of approximately 24,000 known genes was analyzed in normal lung tissue of untreated and urethane-treated AIRmax and AIRmin mice. In lungs of untreated mice, inflammation-associated genes involved in pathways such as "leukocyte transendothelial migration", "cell adhesion" and "tight junctions" were differentially expressed. Moreover, gene expression levels differed significantly in urethane-treated mice; in AIRmin mice, modulation of expression of genes involved in pathways associated with inflammatory response paralleled the previously observed persistent infiltration of inflammatory cells in the lung of these mice.
Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Pulmonares/genética , Pulmão/fisiologia , Pneumonia/genética , Animais , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pneumonia/induzido quimicamente , Pneumonia/patologia , UretanaRESUMO
AIRmax and AIRmin mouse lines show a differential lung inflammatory response and differential lung tumor susceptibility after urethane treatment. The transcript profile of 24,000 known genes was analyzed in normal lung tissue of untreated and urethane-treatedAIRmax and AIRmin mice. In lungs of untreated mice, inflammation-associated genes involved in pathways such as leukocyte transendothelial migration, cell adhesion and tight junctions were differentially expressed. Moreover, gene expression levels differed significantly in urethane-treated mice; in AIRmin mice, modulation of expression of genes involved in pathways associated with inflammatory response paralleled the previously observed persistent infiltration of inflammatory cells in the lung of these mice.