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Distinct Early Inflammatory Events during Ear Tissue Regeneration in Mice Selected for High Inflammation Bearing Slc11a1 R and S Alleles

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Abstract

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 S allele 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 in AIRmaxSS 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.

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References

  1. Clark, L.D., R.K. Clark, and E. Heber-Katz. 1998. A new murine model for mammalian wound repair and regeneration. Clinical Immunology and Immunopathology 88: 35–45.

    Article  PubMed  CAS  Google Scholar 

  2. Blankenhorn, E.P., S. Troutman, L.D. Clark, X.M. Zhang, P. Chen, and E. Heber-Katz. 2003. Sexually dimorphic genes regulate healing and regeneration in MRL mice. Mammalian Genome 14: 250–260.

    Article  PubMed  Google Scholar 

  3. Heber-Katz, E., P. Chen, L. Clark, X.M. Zhang, S. Troutman, and E.P. Blankenhorn. 2004. Regeneration in MRL mice: further genetic loci controlling the ear hole closure trait using MRL and M.m. Castaneus mice. Wound Repair and Regeneration 12: 384–392.

    Article  PubMed  Google Scholar 

  4. Masinde, G.L., X. Li, W. Gu, H. Davidson, S. Mohan, and D.J. Baylink. 2001. Identification of wound healing/regeneration quantitative trait loci (QTL) at multiple time points that explain seventy percent of variance in (MRL/MpJ and SJL/J) mice F2 population. Genome Research 11: 2027–2033.

    Article  PubMed  CAS  Google Scholar 

  5. McBrearty, B.A., L.D. Clark, X.M. Zhang, E.P. Blankenhorn, and E. Heber-Katz. 1998. Genetic analysis of a mammalian wound-healing trait. Proceedings of the National Academy of Sciences of the United States of America 95: 11792–11797.

    Article  PubMed  CAS  Google Scholar 

  6. Masinde, G.L., R. Li, B. Nguyen, H. Yu, A.K. Srivastava, B. Edderkaoui, J.E. Wergedal, D.J. Baylink, and S. Mohan. 2006. New quantitative trait loci that regulate wound healing in an intercross progeny from DBA/1J and 129 x 1/SvJ inbred strains of mice. Functional & Integrative Genomics 6: 157–163.

    Article  CAS  Google Scholar 

  7. Singer, A.J., and R.A. Clark. 1999. Cutaneous wound healing. The New England Journal of Medicine 341: 738–746.

    Article  PubMed  CAS  Google Scholar 

  8. Martin, P. 1997. Wound healing–aiming for perfect skin regeneration. Science 276: 75–81.

    Article  PubMed  CAS  Google Scholar 

  9. Stocum, D.L. 2004. Tissue restoration through regenerative biology and medicine. Advances in Anatomy, Embryology and Cell Biology 176: III–101. back.

    CAS  Google Scholar 

  10. Heber-Katz, E., and D. Gourevitch. 2009. The relationship between inflammation and regeneration in the MRL mouse: potential relevance for putative human regenerative (scarless wound healing) capacities? Annals of the New York Academy of Sciences 1172: 110–114.

    Article  PubMed  Google Scholar 

  11. De Franco, M., P.S. Carneiro, L.C. Peters, F. Vorraro, A. Borrego, O.G. Ribeiro, N. Starobinas, W.K. Cabrera, and O.M. Ibanez. 2007. Slc11a1 (Nramp1) alleles interact with acute inflammation loci to modulate wound-healing traits in mice. Mammalian Genome 18: 263–269.

    Article  PubMed  Google Scholar 

  12. Vigar, N.D., W.H. Cabrera, L.M. Araujo, O.G. Ribeiro, T.R. Ogata, M. Siqueira, O.M. Ibanez, and M. De Franco. 2000. Pristane-induced arthritis in mice selected for maximal or minimal acute inflammatory reaction. European Journal of Immunology 30: 431–437.

    Article  PubMed  CAS  Google Scholar 

  13. Biozzi, G., O.G. Ribeiro, A. Saran, M.L. Araujo, D.A. Maria, M. De Franco, W.K. Cabrera, O.A. Sant'Anna, S. Massa, V. Covelli, D. Mouton, T. Neveu, M. Siqueira, and O.M. Ibanez. 1998. Effect of genetic modification of acute inflammatory responsiveness on tumorigenesis in the mouse. Carcinogenesis 19: 337–346.

    Article  PubMed  CAS  Google Scholar 

  14. Araujo, L.M., O.G. Ribeiro, M. Siqueira, M. De Franco, N. Starobinas, S. Massa, W.H. Cabrera, D. Mouton, M. Seman, and O.M. Ibanez. 1998. Innate resistance to infection by intracellular bacterial pathogens differs in mice selected for maximal or minimal acute inflammatory response. European Journal of Immunology 28: 2913–2920.

    Article  PubMed  CAS  Google Scholar 

  15. Ibanez, O.M., C. Stiffel, O.G. Ribeiro, W.K. Cabrera, S. Massa, M. De Franco, O.A. Sant'Anna, C. Decreusefond, D. Mouton, and M. Siqueira. 1992. Genetics of nonspecific immunity: I. Bidirectional selective breeding of lines of mice endowed with maximal or minimal inflammatory responsiveness. European Journal of Immunology 22: 2555–2563.

    Article  PubMed  CAS  Google Scholar 

  16. Peters, L.C., J.R. Jensen, A. Borrego, W.H. Cabrera, N. Baker, N. Starobinas, O.G. Ribeiro, O.M. Ibanez, and M. De Franco. 2007. Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice. Genes and Immunity 8: 51–56.

    Article  PubMed  CAS  Google Scholar 

  17. Borrego, A., L.C. Peters, J.R. Jensen, O.G. Ribeiro, W.H. Koury Cabrera, N. Starobinas, M. Seman, O.M. Ibanez, and M. De Franco. 2006. Genetic determinants of acute inflammation regulate Salmonella infection and modulate Slc11a1 gene (formerly Nramp1) effects in selected mouse lines. Microbes and Infection 8: 2766–2771.

    Article  PubMed  CAS  Google Scholar 

  18. Ribeiro, O.G., D.A. Maria, S. Adriouch, S. Pechberty, W.H. Cabrera, J. Morisset, O.M. Ibanez, and M. Seman. 2003. Convergent alteration of granulopoiesis, chemotactic activity, and neutrophil apoptosis during mouse selection for high acute inflammatory response. Journal of Leukocyte Biology 74: 497–506.

    Article  PubMed  CAS  Google Scholar 

  19. Reines, B., L.I. Cheng, and P. Matzinger. 2009. Unexpected regeneration in middle-aged mice. Rejuvenation Research 12: 45–52.

    Article  PubMed  Google Scholar 

  20. Belkaid, Y., H. Jouin, and G. Milon. 1996. A method to recover, enumerate and identify lymphomyeloid cells present in an inflammatory dermal site: a study in laboratory mice. Journal of Immunological Methods 199: 5–25.

    Article  PubMed  CAS  Google Scholar 

  21. Cavriani, G., R.M. Oliveira-Filho, A.G. Trezena, Z.L. da Silva, H.V. Domingos, M.J. de Arruda, S. Jancar, and L.W. Tavares de. 2004. Lung microvascular permeability and neutrophil recruitment are differently regulated by nitric oxide in a rat model of intestinal ischemia-reperfusion. European Journal of Pharmacology 494: 241–249.

    Article  PubMed  CAS  Google Scholar 

  22. Otuki, M.F., F. Vieira-Lima, A. Malheiros, R.A. Yunes, and J.B. Calixto. 2005. Topical antiinflammatory effects of the ether extract from Protium kleinii and alpha-amyrin pentacyclic triterpene. European Journal of Pharmacology 507: 253–259.

    Article  PubMed  CAS  Google Scholar 

  23. Carneiro, P.D., L.C. Peters, F. Vorraro, A. Borrego, O.G. Ribeiro, N. Starobinas, J.R. Jensen, W.H.K. Cabrera, O.M. Ibanez, and M. De Franco. 2009. 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 128: e562–e571.

    Article  Google Scholar 

  24. Livak, K.J., and T.D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408.

    Article  PubMed  CAS  Google Scholar 

  25. Tusher, V.G., R. Tibshirani, and G. Chu. 2001. Significance analysis of microarrays applied to the ionizing radiation response. Proceedings of the National Academy of Sciences of the United States of America 98: 5116–5121.

    Article  PubMed  CAS  Google Scholar 

  26. Hosack, D.A., G. Dennis Jr., B.T. Sherman, H.C. Lane, and R.A. Lempicki. 2003. Identifying biological themes within lists of genes with EASE. Genome Biology 4: R70.

    Article  PubMed  Google Scholar 

  27. Tsirogianni, A.K., N.M. Moutsopoulos, and H.M. Moutsopoulos. 2006. Wound healing: immunological aspects. Injury 37(Suppl 1): S5–S12.

    Article  PubMed  Google Scholar 

  28. Heber-Katz, E., J. Leferovich, K. Bedelbaeva, D. Gourevitch, and L. Clark. 2004. The scarless heart and the MRL mouse. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 359: 785–793.

    Article  PubMed  CAS  Google Scholar 

  29. Heber-Katz, E., J. Leferovich, K. Bedelbaeva, D. Gourevitch, and L. Clark. 2006. Conjecture: can continuous regeneration lead to immortality? Studies in the MRL mouse. Rejuvenation Research 9: 3–9.

    Article  PubMed  Google Scholar 

  30. Barton, C.H., S.H. Whitehead, and J.M. Blackwell. 1995. Nramp transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways. Molecular Medicine 1: 267–279.

    PubMed  CAS  Google Scholar 

  31. Kita, E., M. Emoto, D. Oku, F. Nishikawa, A. Hamuro, N. Kamikaidou, and S. Kashiba. 1992. Contribution of interferon gamma and membrane-associated interleukin 1 to the resistance to murine typhoid of Ityr mice. Journal of Leukocyte Biology 51: 244–250.

    PubMed  CAS  Google Scholar 

  32. Wojciechowski, W., J. DeSanctis, E. Skamene, and D. Radzioch. 1999. Attenuation of MHC class II expression in macrophages infected with Mycobacterium bovis bacillus Calmette–Guerin involves class II transactivator and depends on the Nramp1 gene. Journal of Immunology 163: 2688–2696.

    CAS  Google Scholar 

  33. Li, X., S. Mohan, W. Gu, and D.J. Baylink. 2001. Analysis of gene expression in the wound repair/regeneration process. Mammalian Genome 12: 52–59.

    Article  PubMed  CAS  Google Scholar 

  34. Nowak, D., A. Popow-Wozniak, L. Raznikiewicz, and M. Malicka-Blaszkiewicz. 2009. Actin in the wound healing process. Postepy Biochemii 55: 138–144.

    PubMed  CAS  Google Scholar 

  35. Monaco, J.L., and W.T. Lawrence. 2003. Acute wound healing an overview. Clinics in Plastic Surgery 30: 1–12.

    Article  PubMed  Google Scholar 

  36. Tredget, E.B., J. Demare, G. Chandran, E.E. Tredget, L. Yang, and A. Ghahary. 2005. Transforming growth factor-beta and its effect on reepithelialization of partial-thickness ear wounds in transgenic mice. Wound Repair and Regeneration 13: 61–67.

    Article  PubMed  Google Scholar 

  37. Klesney-Tait, J., I.R. Turnbull, and M. Colonna. 2006. The TREM receptor family and signal integration. Nature Immunology 7: 1266–1273.

    Article  PubMed  CAS  Google Scholar 

  38. Werner, S., and R. Grose. 2003. Regulation of wound healing by growth factors and cytokines. Physiological Reviews 83: 835–870.

    PubMed  CAS  Google Scholar 

  39. Peranteau, W.H., L. Zhang, N. Muvarak, A.T. Badillo, A. Radu, P.W. Zoltick, and K.W. Liechty. 2008. IL-10 overexpression decreases inflammatory mediators and promotes regenerative healing in an adult model of scar formation. The Journal of Investigative Dermatology 128: 1852–1860.

    Article  PubMed  CAS  Google Scholar 

  40. Abbott, R.E., C.J. Corral, D.M. MacIvor, X. Lin, T.J. Ley, and T.A. Mustoe. 1998. Augmented inflammatory responses and altered wound healing in cathepsin G-deficient mice. Archives of Surgery 133: 1002–1006.

    Article  PubMed  CAS  Google Scholar 

  41. Gourevitch, D., L. Clark, P. Chen, A. Seitz, S.J. Samulewicz, and E. Heber-Katz. 2003. Matrix metalloproteinase activity correlates with blastema formation in the regenerating MRL mouse ear hole model. Developmental Dynamics 226: 377–387.

    Article  PubMed  CAS  Google Scholar 

  42. Dovi, J.V., A.M. Szpaderska, and L.A. DiPietro. 2004. Neutrophil function in the healing wound: adding insult to injury? Thromb Haemostasis 92: 275–280.

    CAS  Google Scholar 

  43. Dovi, J.V., L.K. He, and L.A. DiPietro. 2003. Accelerated wound closure in neutrophil-depleted mice. Journal of Leukocyte Biology 73: 448–455.

    Article  PubMed  CAS  Google Scholar 

  44. Trombone, A.P., S.B. Ferreira, Jr., F.M. Raimundo, K.C.de Moura, M.J.vila-Campos, J.S. Silva, A.P. Campanelli, M. De Franco, and G.P. Garlet. 2009. Experimental periodontitis in mice selected for maximal or minimal inflammatory reactions: increased inflammatory immune responsiveness drives increased alveolar bone loss without enhancing the control of periodontal infection. Journal of Periodontal Research 44: 443–451.

    Article  Google Scholar 

  45. Carneiro, A.S., O.G. Ribeiro, M. De Franco, W.H. Cabrera, F. Vorraro, M. Siqueira, O.M. Ibanez, and N. Starobinas. 2002. Local inflammatory reaction induced by Bothrops jararaca venom differs in mice selected for acute inflammatory response. Toxicon 40: 1571–1579.

    Article  PubMed  CAS  Google Scholar 

  46. Carneiro, A.S., O.G. Ribeiro, W.H. Cabrera, F. Vorraro, M. De Franco, O.M. Ibanez, and N. Starobinas. 2008. 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 52: 619–627.

    Article  PubMed  CAS  Google Scholar 

  47. Di Pace, R.F., S. Massa, O.G. Ribeiro, W.H. Cabrera, M. De Franco, N. Starobinas, M. Seman, and O.C. Ibanez. 2006. Inverse genetic predisposition to colon versus lung carcinogenesis in mouse lines selected based on acute inflammatory responsiveness. Carcinogenesis 27: 1517–1525.

    Article  PubMed  Google Scholar 

  48. Maria, D.A., G. Manenti, F. Galbiati, O.G. Ribeiro, W.H. Cabrera, R.G. Barrera, A. Pettinicchio, M. De Franco, N. Starobinas, M. Siqueira, T.A. Dragani, and O.M. Ibanez. 2003. Pulmonary adenoma susceptibility 1 (Pas1) locus affects inflammatory response. Oncogene 22: 426–432.

    Article  PubMed  CAS  Google Scholar 

  49. de Souza, V., W.K. Cabrera, A. Galvan, O.G. Ribeiro, M. De Franco, F. Vorraro, N. Starobinas, S. Massa, T.A. Dragani, and O.M. Ibanez. 2009. Aryl hydrocarbon receptor polymorphism modulates DMBA-induced inflammation and carcinogenesis in phenotypically selected mice. International Journal of Cancer 124: 1478–1482.

    Article  Google Scholar 

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Acknowledgments

This work was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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Canhamero, T., Reines, B., Peters, L.C. et al. Distinct Early Inflammatory Events during Ear Tissue Regeneration in Mice Selected for High Inflammation Bearing Slc11a1 R and S Alleles. Inflammation 34, 303–313 (2011). https://doi.org/10.1007/s10753-010-9235-y

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