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 F1 and F2 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 F2 populations. AIRmaxSSshowed higher ear-wound closure than AIRmaxRR 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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References
Araujo LM, Ribeiro OG, Siqueira M, De Franco M, Starobinas N, et al. (1998) Innate resistance to infection by intracellular bacterial pathogens differs in mice selected for maximal or minimal acute inflammatory response. Eur J Immunol 28:2913–2920
Barton CH, Whitehead SH, Blackwell JM (1995) Nramp transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways. Mol Med 1:267–279
Biozzi G, Ribeiro OG, Saran A, Araujo ML, Maria DA, et al. (1998) Effect of genetic modification of acute inflammatory responsiveness on tumorigenesis in the mouse. Carcinogenesis 19:337–346
Blankenhorn EP, Troutman S, Clark LD, Zhang XM, Chen P, et al. (2003) Sexually dimorphic genes regulate healing and regeneration in MRL mice. Mamm Genome 14:250–260
Borrego A, Peters LC, Jensen JR, Ribeiro OG, Koury Cabrera WH, et al. (2006) Genetic determinants of acute inflammation regulate Salmonella infection and modulate Slc11a1 gene (formerly Nramp1) effects in selected mouse lines. Microbes Infect 8:2766–2771
Catchpole B, Ward FJ, Hamblin AS, Staines NA (2002) Autoreactivity in collagen-induced arthritis of rats: a potential role for T cell responses to self MHC peptides. J Autoimmun 18:271–280
Cho CH, Sung HK, Kim KT, Cheon HG, Oh GT, et al. (2006) COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model. Proc Natl Acad Sci USA 103:4946–4951
Clark LD, Clark RK, Heber-Katz E (1998) A new murine model for mammalian wound repair and regeneration. Clin Immunol Immunopathol 88:35–45
Cooper L, Johnson C, Burslem F, Martin P (2005) Wound healing and inflammation genes revealed by array analysis of ‘macrophageless’ PU.1 null mice. Genome Biol 6:R5
Darvasi A (1997) The effect of selective genotyping on QTL mapping accuracy. Mamm Genome 8:67–68
Dauer DJ, Ferraro B, Song L, Yu B, Mora L, et al. (2005) Stat3 regulates genes common to both wound healing and cancer. Oncogene 24:3397–3408
Debidda M, Wang L, Zang H, Poli V, Zheng Y (2005) A role of STAT3 in Rho GTPase-regulated cell migration and proliferation. J Biol Chem 280:17275–17285
Di Pace RF, Massa S, Ribeiro OG, Cabrera WH, De Franco M, et al. (2006) Inverse genetic predisposition to colon versus lung carcinogenesis in mouse lines selected based on acute inflammatory responsiveness. Carcinogenesis 27:1517–1525
Dovi JV, He LK, DiPietro LA (2003) Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol 73:448–455
Dovi JV, Szpaderska AM, DiPietro LA (2004) Neutrophil function in the healing wound: adding insult to injury? Thromb Haemost 92:275–280
Gordon AH (1972) Acute-phase proteins in wound healing. Ciba Found Symp 9:73–90
Gourevitch D, Clark L, Chen P, Seitz A, Samulewicz SJ, et al. (2003) Matrix metalloproteinase activity correlates with blastema formation in the regenerating MRL mouse ear hole model. Dev Dyn 226:377–387
Hackam DJ, Rotstein OD, Zhang W, Gruenheid S, Gros P, et al. (1998) Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J Exp Med 188:351–364
Heber-Katz E (1999) The regenerating mouse ear. Semin Cell Dev Biol 10:415–419
Heber-Katz E, Chen P, Clark L, Zhang XM, Troutman S, et al. (2004) Regeneration in MRL mice: further genetic loci controlling the ear hole closure trait using MRL and M.m. castaneus mice. Wound Repair Regen 12:384–392
Ibanez OM, Stiffel C, Ribeiro OG, Cabrera WK, MassaS, et al. (1992) Genetics of nonspecific immunity: I. Bidirectional selective breeding of lines of mice endowed with maximal or minimal inflammatory responsiveness. Eur J Immunol 22:2555–2563
Kita E, Emoto M, Oku D, Nishikawa F, Hamuro A, et al. (1992) Contribution of interferon gamma and membrane-associated interleukin 1 to the resistance to murine typhoid of Ityr mice. J Leukoc Biol 51:244–250
Lefaucheur JP, Gjata B, Lafont H, Sebille A (1996) Angiogenic and inflammatory responses following skeletal muscle injury are altered by immune neutralization of endogenous basic fibroblast growth factor, insulin-like growth factor-1 and transforming growth factor-beta 1. J Neuroimmunol 70:37–44
Li X, Gu W, Masinde G, Hamilton-Ulland M, Xu S, et al. (2001) Genetic control of the rate of wound healing in mice. Heredity 86:668-674
Manly KF, Cudmore RH Jr, Meer JM (2001) Map Manager QTX, cross-platform software for genetic mapping. Mamm Genome 12:930–932
Maria DA, Manenti G, Galbiati F, Ribeiro OG, Cabrera WH, et al. (2003) Pulmonary adenoma susceptibility 1 (Pas1) locus affects inflammatory response. Oncogene 22:426–432
Martin P (1997) Wound healing—aiming for perfect skin regeneration. Science 276:75–81
Masinde GL, Li X, Gu W, Davidson H, Mohan S, et al. (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 Res 11:2027–2033
Masinde GL, Li X, Gu W, Hamilton-Ulland M, Mohan S, et al. (2002) Quantitative trait loci that harbor genes regulating muscle size in (MRL/MPJ x SJL/J) F(2) mice. Funct Integr Genomics 2:120–125
Masinde GL, Li R, Nguyen B, Yu H, Srivastava AK, et al. (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. Funct Integr Genomics 6:157–163
McBrearty BA, Clark LD, Zhang XM, Blankenhorn EP, Heber-Katz E (1998) Genetic analysis of a mammalian wound-healing trait. Proc Natl Acad Sci USA 95:11792–11797
Morgan R, Wu B, Song Z, Wooley PH (2004) Immune reactivity to connective tissue antigens in pristane induced arthritis. J Rheumatol 31:1497–1505
Peters LC, Jensen JR, Borrego A, Cabrera WH, Baker N, et al. (2007) Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice. Genes Immun 8:51–56
Ribeiro OG, Maria DA, Adriouch S, Pechberty S, Cabrera WH, et al. (2003) Convergent alteration of granulopoiesis, chemotactic activity, and neutrophil apoptosis during mouse selection for high acute inflammatory response. J Leukoc Biol 74:497–506
Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341:738–746
Stocum DL (2004) Tissue restoration through regenerative biology and medicine. Adv Anat Embryol Cell Biol 176:III–101, back
Thuraisingam T, Sam H, Moisan J, Zhang Y, Ding A, et al. (2006) Delayed cutaneous wound healing in mice lacking solute carrier 11a1 (formerly Nramp1): correlation with decreased expression of secretory leukocyte protease inhibitor. J Invest Dermatol 126:890–901
Vidal SM, Malo D, Vogan K, Skamene E, Gros P (1993) Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73:469–485
Vigar ND, Cabrera WH, Araujo LM, Ribeiro OG, Ogata TR, et al. (2000) Pristane-induced arthritis in mice selected for maximal or minimal acute inflammatory reaction. Eur J Immunol 30:431–437
Weintraub BC, Eckmann L, Okamoto S, Hense M, Hedrick SM, et al. (1997) Role of alphabeta and gammadelta T cells in the host response to Salmonella infection as demonstrated in T-cell-receptor-deficient mice of defined Ity genotypes. Infect Immun 65:2306–2312
Wojciechowski W, DeSanctis J, Skamene E, Radzioch D (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. J Immunol 163:2688–2696
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). The authors dedicate this article to Dr. Guido Biozzi who passed away on 25 December 2006.
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De Franco, M., Carneiro, P.d.S., Peters, L.C. et al. Slc11a1 (Nramp1) alleles interact with acute inflammation loci to modulate wound-healing traits in mice. Mamm Genome 18, 263–269 (2007). https://doi.org/10.1007/s00335-007-9012-x
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DOI: https://doi.org/10.1007/s00335-007-9012-x