Publications by authors named "Andrea Borrego"

20 Publications

  • Page 1 of 1

The Crotoxin:SBA-15 Complex Down-Regulates the Incidence and Intensity of Experimental Autoimmune Encephalomyelitis Through Peripheral and Central Actions.

Front Immunol 2020 28;11:591563. Epub 2020 Oct 28.

Laboratory of Pain and Signaling, Butantan Institute, Sao Paulo, Brazil.

Crotoxin (CTX), the main neurotoxin from snake venom, has anti-inflammatory, immunomodulatory and antinociceptive activities. However, the CTX-induced toxicity may compromise its use. Under this scenario, the use of nanoparticle such as nanostructured mesoporous silica (SBA-15) as a carrier might become a feasible approach to improve CTX safety. Here, we determined the benefits of SBA-15 on CTX-related neuroinflammatory and immunomodulatory properties during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis that replicates several histopathological and immunological features observed in humans. We showed that a single administration of CTX:SBA-15 (54 μg/kg) was more effective in reducing pain and ameliorated the clinical score (motor impairment) in EAE animals compared to the CTX-treated EAE group; therefore, improving the disease outcome. Of interest, CTX:SBA-15, but not unconjugated CTX, prevented EAE-induced atrophy and loss of muscle function. Further supporting an immune mechanism, CTX:SBA-15 treatment reduced both recruitment and proliferation of peripheral Th17 cells as well as diminished IL-17 expression and glial cells activation in the spinal cord in EAE animals when compared with CTX-treated EAE group. Finally, CTX:SBA-15, but not unconjugated CTX, prevented the EAE-induced cell infiltration in the CNS. These results provide evidence that SBA-15 maximizes the immunomodulatory and anti-inflammatory effects of CTX in an EAE model; therefore, suggesting that SBA-15 has the potential to improve CTX effectiveness in the treatment of MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.591563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655790PMC
October 2020

Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response.

J Immunol Res 2019 31;2019:5298792. Epub 2019 Mar 31.

Laboratory of Immunogenetics, Instituto Butantan, São Paulo, Brazil.

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-, IL-1, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/5298792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462334PMC
August 2019

Early Peritoneal CC Chemokine Production Correlates with Divergent Inflammatory Phenotypes and Susceptibility to Experimental Arthritis in Mice.

J Immunol Res 2019 26;2019:2641098. Epub 2019 Feb 26.

Immunogenetics Laboratory, Butantan Institute, Avenida Vital Brasil, 1500, São Paulo 05503-900, Brazil.

The inflammatory and autoimmune events preceding clinical symptoms in rheumatoid arthritis (RA) and other autoimmune diseases are difficult to study in human patients. Therefore, animal models that share immunologic and clinical features with human RA, such as pristane-induced arthritis (PIA), are valuable tools for assessing the primordial events related to arthritis susceptibility. PIA-resistant HIII and susceptible LIII mice were injected i.p. with pristane, and peritoneal lavage fluid was harvested in the early (7 days) and late (35 days) preclinical phases of PIA. Chemokine and cytokine levels were measured in lavage supernatant with ELISA, peritoneal inflammatory leukocytes were immunophenotyped by flow cytometry, and gene expression was determined by qRT-PCR. Leukocyte recruitment was quantitatively and qualitatively divergent in the peritoneum of HIII and LIII mice, with an early increase of CC chemokines (CCL2/CCL3/CCL5/CCL12/CCL22) in the susceptible LIII strain. Also, cytokines such as IL-12p40, IL-23, and IL-18 were elevated in LIII mice while IL-6 was increased in HIII animals. The results show that an early peritoneal CC chemokine response is an important feature of arthritis susceptibility and defines potential biomarkers in this model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/2641098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413398PMC
July 2019

miRNA Expression and Interaction with Genes Involved in Susceptibility to Pristane-Induced Arthritis.

J Immunol Res 2018 16;2018:1928405. Epub 2018 Dec 16.

Laboratório de Imunogenética, Instituto Butantan, São Paulo 05503000, Brazil.

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 (, , and ). 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/1928405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311868PMC
April 2019

Alveolar bone healing in mice genetically selected in the maximum (AIRmax) or minimum (AIRmin) inflammatory reaction.

Cytokine 2019 02 22;114:47-60. Epub 2018 Dec 22.

Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cyto.2018.11.027DOI Listing
February 2019

Mice Selected for Acute Inflammation Present Altered Immune Response during Pristane-Induced Arthritis Progression.

Biomed Res Int 2018 8;2018:1267038. Epub 2018 Oct 8.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

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-1, IFN-, TNF-, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/1267038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197000PMC
February 2019

Overcoming the Challenges of Experimental Research: Lessons From a Criminal Justice Case Study Involving TASER Exposure.

Eval Rev 2018 06 16;42(3):358-385. Epub 2018 Oct 16.

4 Department of Criminal Justice and Criminology, Metropolitan State University of Denver, Denver, CO, USA.

Objective: To provide guidance to criminologists for conducting experiments in light of two common discouraging factors: the belief that they are overly time-consuming and the belief that they can compromise the ethical principles of human subjects' research.

Method: A case study approach is used, based on a large-scale randomized controlled trial experiment in which we exposed participants to a 5-s TASER shock, to describe how the authors overcame ethical, methodological, and logistical difficulties.

Results: We derive four pieces of advice from our experiences carrying out this experimental trial: (1) know your limitations, (2) employ pilot testing, (3) remain flexible and patient, and (4) "hold the line" to maintain the integrity of the research and the safety of human subjects.

Conclusions: Criminologists have an obligation to provide the best possible evidence regarding the impact and consequences of criminal justice practices and programs. Experiments, considered by many to be the gold standard of empirical research methodologies, should be used whenever possible in order to fulfill this obligation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0193841X18803205DOI Listing
June 2018

Germline control of somatic Kras mutations in mouse lung tumors.

Mol Carcinog 2018 06 25;57(6):745-751. Epub 2018 Mar 25.

Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Somatic KRAS mutations are common in human lung adenocarcinomas and are associated with worse prognosis. In mice, Kras is frequently mutated in both spontaneous and experimentally induced lung tumors, although the pattern of mutation varies among strains, suggesting that such mutations are not random events. We tested if the occurrence of Kras mutations is under genetic control in two mouse intercrosses. Codon 61 mutations were prevalent, but the patterns of nucleotide changes differed between the intercrosses. Whole genome analysis with SNPs in (A/J x C57BL/6)F4 mice revealed a significant linkage between a locus on chromosome 19 and 2 particular codon 61 variants (CTA and CGA). In (AIRmax × AIRmin) F2 mice, there was a significant linkage between SNPs located on distal chromosome 6 (around 135 Mbp) and the frequency of codon 61 mutation. These results reveal the presence of two loci, on chromosomes 6 and 19, that modulate Kras mutation frequency in different mouse intercrosses. These findings indicate that somatic mutation frequency and type are not simple random events, but are under genetic control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mc.22796DOI Listing
June 2018

Complex genetic control of lung tumorigenesis in resistant mice strains.

Cancer Sci 2017 Nov 6;108(11):2281-2286. Epub 2017 Oct 6.

Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.

The SM/J mouse strain is resistant to chemically-induced lung tumorigenesis despite having a haplotype, in the pulmonary adenoma susceptibility locus (Pas1) locus, that confers tumor susceptibility in other strains. To clarify this inconsistent genotype-phenotype correlation, we crossed SM/J mice with another resistant strain and conducted genome-wide linkage analysis in the (C57BL/6J × SM/J)F2 progeny exposed to urethane to induce lung tumors. Overall, >80% of F2 mice of both sexes developed from 1 to 20 lung tumors. Genotyping of 372 F2 mice for 744 informative non-redundant SNPs dispersed over all autosomal chromosomes revealed four quantitative trait loci (QTLs) affecting lung tumor multiplicity, on chromosomes 3 (near rs13477379), 15 (rs6285067), 17 (rs33373629) and 18 (rs3706601), all with logarithm of the odds (LOD) scores >5. Four QTLs modulated total lung tumor volume, on chromosome 3 (rs13477379), 10 (rs13480702), 15 (rs6285067) and 17 (rs3682923), all with LOD scores >4. No QTL modulating lung tumor multiplicity or total volume was detected in Pas1 on chromosome 6. The present study demonstrates that the SM/J strain carries, at the Pas1 locus, the resistance allele: a finding that will facilitate identification of the Pas1 causal element. More generally, it demonstrates that lung tumorigenesis is under complex polygenic control even in a pedigree with low susceptibility to this neoplasia, suggesting that the genetics of lung tumorigenesis is much more complex than evidenced by the pulmonary adenoma susceptibility and resistance loci that have, so far, been mapped in a small number of crosses between a few inbred strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.13349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666032PMC
November 2017

Slc11a1 (Nramp-1) gene modulates immune-inflammation genes in macrophages during pristane-induced arthritis in mice.

Inflamm Res 2017 Nov 1;66(11):969-980. Epub 2017 Jul 1.

Laboratório de Imunogenética, Instituto Butantan, Avenida Vital Brasil 1500, São Paulo, SP, 05503000, Brazil.

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 , 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 mice showed differential peritoneal macrophage gene expression profiles during PIA, with higher expression and production of HO, NO, IL-1β, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00011-017-1077-8DOI Listing
November 2017

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 Apr 28;65(4):313-23. Epub 2016 Jan 28.

Laboratório de Imunogenética, Instituto Butantan, Avenida Vital Brasil 1500, São Paulo, SP, 05503900, Brazil.

Objective And Design: AIRmax and AIRmin mice differ in their local acute inflammatory reactions to polyacrylamide beads (Biogel). These lines were developed to identify genes that affect the intensity of the acute inflammatory response (AIR) and to investigate the cellular and molecular mechanisms of acute inflammation. Although these lines are well established, differences in their responses to chronic inflammatory Biogel exposure have not yet been described. We investigated whether the selective process that modified the acute inflammatory responses in these animals also affected the development of their chronic inflammatory responses.

Results: Inflammatory exudate cell infiltration was more intense in AIRmax than AIRmin mice at both 48 h and 30 days. Genes involved in signal transduction and immune/inflammatory responses were differentially expressed in the treated skin of AIRmax and AIRmin mice, and divergent expression of some acute inflammatory response genes was detected up to 30 days post-Biogel. However, distinct expression of several pro and anti-inflammatory response genes in both periods was observed.

Conclusion: These results indicate that the selective process for acute inflammation affected the development of chronic inflammatory responses to Biogel, suggesting common genetic control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00011-016-0918-1DOI Listing
April 2016

7,12-Dimethylbenz(a)anthracene-induced genotoxicity on bone marrow cells from mice phenotypically selected for low acute inflammatory response.

DNA Repair (Amst) 2016 Jan 2;37:43-52. Epub 2015 Dec 2.

Immunogenetics Laboratory, Butantan Institute, São Paulo, Brazil. Electronic address:

Exposure to polycyclic aromatic hydrocarbon (PAH) environmental contaminants has been associated with the development of mutations and cancer. 7,12-Dimethylbenz(a)anthracene ( DMBA), a genotoxic agent, reacts with DNA directly, inducing p53-dependent cytotoxicity resulting in cell death by apoptosis or giving rise to cancer. DMBA metabolism largely depends on activation of the aryl hydrocarbon receptor (AhR). Mice phenotypically selected for high (AIRmax) or low (AIRmin) acute inflammatory response present a complete segregation of Ahr alleles endowed with low (Ahr(d)) or high (Ahr(b1)) affinity to PAHs, respectively. To evaluate the role of AhR genetic polymorphism on the bone marrow susceptibility to DMBA, AIRmax and AIRmin mice were treated with a single intraperitoneal injection of DMBA (50mg/kg b.w.) in olive oil. Bone marrow cells (BMCs) were phenotyped by both flow cytometry and cytoslide preparations. Despite a significant decrease in total cell count in BM from AIRmin mice, there was an increase of blast cells and immature neutrophils at 1 and 50 days after DMBA treatment, probably due to a cell-cycle blockade at the G1/S transition leading to immature stage cell production. A panel of proteins related to cell cycle regulation was evaluated in immature BM cells (Lin(-)) by Western Blot, and DNA damage and repair were measured using an alkaline version of the Comet assay. In Lin(-) cells isolated from AIRmin mice, high levels were found in both p53 and p21 protein contents in contrast with the low levels of CDK4 and Ciclin D1. Evaluation of DNA repair in DMBA-treated BMCs, indicated long-lasting genotoxicity and cytotoxicity in BMC from AIRmin mice and a blockade of cell cycle progression. On the other hand, AIRmax mice have a high capacity of DNA damage repair and protection. These mechanisms can be associated with the differential susceptibility to the toxic and carcinogenic effects of DMBA observed in these mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dnarep.2015.11.006DOI Listing
January 2016

Mouse pulmonary adenoma susceptibility 1 locus is an expression QTL modulating Kras-4A.

PLoS Genet 2014 Apr 17;10(4):e1004307. Epub 2014 Apr 17.

Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.

Pulmonary adenoma susceptibility 1 (Pas1) is the major locus responsible for lung tumor susceptibility in mice; among the six genes mapping in this locus, Kras is considered the best candidate for Pas1 function although how it determines tumor susceptibility remains unknown. In an (A/J × C57BL/6)F4 intercross population treated with urethane to induce lung tumors, Pas1 not only modulated tumor susceptibility (LOD score = 48, 69% of phenotypic variance explained) but also acted, in lung tumor tissue, as an expression quantitative trait locus (QTL) for Kras-4A, one of two alternatively spliced Kras transcripts, but not Kras-4B. Additionally, Kras-4A showed differential allelic expression in lung tumor tissue of (A/J × C57BL/6)F4 heterozygous mice, with significantly higher expression from the A/J-derived allele; these results suggest that cis-acting elements control Kras-4A expression. In normal lung tissue from untreated mice of the same cross, Kras-4A levels were also highly linked to the Pas1 locus (LOD score = 23.2, 62% of phenotypic variance explained) and preferentially generated from the A/J-derived allele, indicating that Pas1 is an expression QTL in normal lung tissue as well. Overall, the present findings shed new light on the genetic mechanism by which Pas1 modulates the susceptibility to lung tumorigenesis, through the fine control of Kras isoform levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1004307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990522PMC
April 2014

Pristane-induced arthritis loci interact with the Slc11a1 gene to determine susceptibility in mice selected for high inflammation.

PLoS One 2014 5;9(2):e88302. Epub 2014 Feb 5.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

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, 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914970PMC
September 2014

Genetic control of renal tumorigenesis by the mouse Rtm1 locus.

BMC Genomics 2013 Oct 22;14:724. Epub 2013 Oct 22.

Laboratory of Immunogenetics, Instituto Butantan, Avenida Dr, Vital Brazil, 1500, 05503-900 São Paulo, Brazil.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2164-14-724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046818PMC
October 2013

Distinct early inflammatory events during ear tissue regeneration in mice selected for high inflammation bearing Slc11a1 R and S alleles.

Inflammation 2011 Oct;34(5):303-13

Laboratório de Imunogenética, Instituto Butantan, São Paulo, SP, Brasil.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10753-010-9235-yDOI Listing
October 2011

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 2009 Sep 18;128(1 Suppl):e562-71. Epub 2008 Dec 18.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2567.2008.03032.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753958PMC
September 2009

Slc11a1 (Nramp1) alleles interact with acute inflammation loci to modulate wound-healing traits in mice.

Mamm Genome 2007 Apr 8;18(4):263-9. Epub 2007 May 8.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00335-007-9012-xDOI Listing
April 2007

Genetic determinants of acute inflammation regulate Salmonella infection and modulate Slc11a1 gene (formerly Nramp1) effects in selected mouse lines.

Microbes Infect 2006 Oct 7;8(12-13):2766-71. Epub 2006 Sep 7.

Laboratório de Imunogenética - Instituto Butantan, Av. Vital Brasil, 1500, São Paulo, SP 05503900, Brazil.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.micinf.2006.08.005DOI Listing
October 2006

Co-localization of quantitative trait loci regulating resistance to Salmonella typhimurium infection and specific antibody production phenotypes.

Microbes Infect 2002 Nov;4(14):1409-15

Laboratório de Vacinas Anaeróbicas, Instituto Butantan, São Paulo, SP, Brazil.

Salmonella enterica serotype typhimurium is a facultative intracellular bacteria that induces systemic infection in mice. Resistance to this pathogen is under polygenic control in which Nramp1 is the major gene involved. Lines of mice obtained by selective breeding for high (HIII) or low (LIII) antibody response to flagellar antigens of salmonellae showed significant susceptibility differences, although both the lines display Nramp1(R) alleles. The HIII line was extremely susceptible to infection, while the LIII line was resistant. In order to examine the cellular and genetic mechanisms involved in this distinct pattern of resistance, HIII and LIII mice were analyzed for IFNgamma and IL4 production and screened for quantitative trait loci involved in S. typhimurium infection, using several polymorphic microsatellites. In the present work, HIII mice showed an IFNgamma downregulation in the early phase of infection when compared with LIII animals. No interline differences in IL4 production were verified. The loci screening was performed on immunized F2 intercrosses obtained from HIII and LIII mice. Three antibody-controlling chromosomal regions were coincident, and another was mapped near one of the four loci known to affect susceptibility to S. typhimurium. These results indicate a major role of IFNgamma in our model, and suggest the co-localization of quantitative trait loci modulating both infection and antibody production phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s1286-4579(02)00023-0DOI Listing
November 2002