Roles of the Innate Immune System in Mammary Gland Remodeling During Involution

Article

Abstract

Mammary gland involution is a period of intensive tissue remodeling. Over the course of a relatively brief period, a large proportion of the mammary gland epithelium undergoes programmed cell death and is removed by phagocytes. In addition, the gland is cleared of residual milk fat globules as well as milk and adipocytes become the predominant cell type. The role of the immune system in this process has not been clearly defined. Professional phagocytes derived from the immune system can participate in the clearance of apoptotic and autophagic cells, the removal of residual milk components, and the prevention of mastitis during mammary gland involution. However, many of these functions can also be performed by non-professional phagocytes (e.g. mammary epithelial cells). This review will discuss the evidence that supports a role for innate immune cells in mammary gland remodeling during involution.

Keywords

Involution Mammary gland Phagocytosis Innate immunity Remodeling 

Abbreviations

MEC

mammary epithelial cells

PCD

programmed cell death

References

  1. 1.
    Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary gland development requires macrophages and eosinophils. Development 2000;127(11):2269–82.PubMedGoogle Scholar
  2. 2.
    Pollard JW, Hennighausen L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc Natl Acad Sci USA 1994;91(20):9312–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Marti A, Feng Z, Altermatt HJ, Jaggi R. Milk accumulation triggers apoptosis of mammary epithelial cells. Eur J Cell Biol 1997;73(2):158–65.PubMedGoogle Scholar
  4. 4.
    Lund LR, Romer J, Thomasset N, Solberg H, Pyke C, Bissell MJ, et al. Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways. Development 1996;122(1):181–93.PubMedGoogle Scholar
  5. 5.
    Quarrie LH, Addey CV, Wilde CJ. Programmed cell death during mammary tissue involution induced by weaning, litter removal, and milk stasis. J Cell Physiol 1996;168(3):559–69.PubMedCrossRefGoogle Scholar
  6. 6.
    Quarrie LH, Addey CV, Wilde CJ. Apoptosis in lactating and involuting mouse mammary tissue demonstrated by nick-end DNA labelling. Cell Tissue Res 1995;281(3):413–9.PubMedGoogle Scholar
  7. 7.
    Atabai K, Fernandez R, Huang X, Ueki I, Kline A, Li Y, et al. Mfge8 is critical for mammary gland remodeling during involution. Mol Biol Cell 2005;16(12):5528–37.PubMedCrossRefGoogle Scholar
  8. 8.
    Monks J, Rosner D, Geske FJ, Lehman L, Hanson L, Neville MC, et al. Epithelial cells as phagocytes: apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release. Cell Death Differ 2005;12(2):107–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Walker NI, Bennett RE, Kerr JF. Cell death by apoptosis during involution of the lactating breast in mice and rats. Am J Anat 1989;185(1):19–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Li M, Liu X, Robinson G, Bar-Peled U, Wagner KU, Young WS, et al. Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci USA 1997;94(7):3425–30.PubMedCrossRefGoogle Scholar
  11. 11.
    Alexander CM, Selvarajan S, Mudgett J, Werb Z. Stromelysin-1 regulates adipogenesis during mammary gland involution. J Cell Biol 2001;152(4):693–703.PubMedCrossRefGoogle Scholar
  12. 12.
    Hanayama R, Nagata S. Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. Proc Natl Acad Sci USA 2005;102(46):16886–91.PubMedCrossRefGoogle Scholar
  13. 13.
    Fadok VA. Clearance: the last and often forgotten stage of apoptosis. J Mammary Gland Biol Neoplasia 1999;4(2):203–11.PubMedCrossRefGoogle Scholar
  14. 14.
    Henson PM, Bratton DL, Fadok VA. Apoptotic cell removal. Curr Biol 2001;11(19):R795–805.PubMedCrossRefGoogle Scholar
  15. 15.
    Geske FJ, Monks J, Lehman L, Fadok VA. The role of the macrophage in apoptosis: hunter, gatherer, and regulator. Int J Hematol 2002;76(1):16–26.PubMedGoogle Scholar
  16. 16.
    Bennett MR, Gibson DF, Schwartz SM, Tait JF. Binding and phagocytosis of apoptotic vascular smooth muscle cells is mediated in part by exposure of phosphatidylserine. Circ Res 1995;77(6):1136–42.PubMedGoogle Scholar
  17. 17.
    Dini L, Lentini A, Diez GD, Rocha M, Falasca L, Serafino L, et al. Phagocytosis of apoptotic bodies by liver endothelial cells. J Cell Sci 1995;108(Pt 3):967–73.PubMedGoogle Scholar
  18. 18.
    Hughes J, Liu Y, Van Damme J, Savill J. Human glomerular mesangial cell phagocytosis of apoptotic neutrophils: mediation by a novel CD36-independent vitronectin receptor/thrombospondin recognition mechanism that is uncoupled from chemokine secretion. J Immunol 1997;158(9):4389–97.PubMedGoogle Scholar
  19. 19.
    Finnemann SC. Role of alphavbeta5 integrin in regulating phagocytosis by the retinal pigment epithelium. Adv Exp Med Biol 2003;533:337–42.PubMedGoogle Scholar
  20. 20.
    Nandrot EF, Kim Y, Brodie SE, Huang X, Sheppard D, Finnemann SC. Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking alphavbeta5 integrin. J Exp Med 2004;200(12):1539–45.PubMedCrossRefGoogle Scholar
  21. 21.
    Sexton DW, Blaylock MG, Walsh GM. Human alveolar epithelial cells engulf apoptotic eosinophils by means of integrin- and phosphatidylserine receptor-dependent mechanisms: a process upregulated by dexamethasone. J Allergy Clin Immunol 2001;108(6):962–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Sexton DW, Al-Rabia M, Blaylock MG, Walsh GM. Phagocytosis of apoptotic eosinophils but not neutrophils by bronchial epithelial cells. Clin Exp Allergy 2004;34(10):1514–24.PubMedCrossRefGoogle Scholar
  23. 23.
    Walsh GM, Sexton DW, Blaylock MG, Convery CM. Resting and cytokine-stimulated human small airway epithelial cells recognize and engulf apoptotic eosinophils. Blood 1999;94(8):2827–35.PubMedGoogle Scholar
  24. 24.
    Parnaik R, Raff MC, Scholes J. Differences between the clearance of apoptotic cells by professional and non-professional phagocytes. Curr Biol 2000;10(14):857–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Boudjellab N, Chan-Tang HS, Li X, Zhao X. Interleukin 8 response by bovine mammary epithelial cells to lipopolysaccharide stimulation. Am J Vet Res 1998;59(12):1563–7.PubMedGoogle Scholar
  26. 26.
    McClenahan DJ, Sotos JP, Czuprynski CJ. Cytokine response of bovine mammary gland epithelial cells to Escherichia coli, coliform culture filtrate, or lipopolysaccharide. Am J Vet Res 2005;66(9):1590–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Savill J, Smith J, Sarraf C, Ren Y, Abbott F, Rees A. Glomerular mesangial cells and inflammatory macrophages ingest neutrophils undergoing apoptosis. Kidney Int 1992;42(4):924–36.PubMedGoogle Scholar
  28. 28.
    Sekhri KK, Pitelka DR, DeOme KB. Studies of mouse mammary glands. I. Cytomorphology of the normal mammary gland. J Natl Cancer Inst 1967;39(3):459–90.PubMedGoogle Scholar
  29. 29.
    Richards RC, Benson GK. Involvement of the macrophage system in the involution of the mammary gland in the albino rat. J Endocrinol 1971;51(1):149–56.PubMedGoogle Scholar
  30. 30.
    Richards RC, Benson GK. Ultrastructural changes accompanying involution of the mammary gland in the albino rat. J Endocrinol 1971;51(1):127–35.PubMedCrossRefGoogle Scholar
  31. 31.
    Devitt A, Parker KG, Ogden CA, Oldreive C, Clay MF, Melville LA, et al. Persistence of apoptotic cells without autoimmune disease or inflammation in CD14-/- mice. J Cell Biol 2004;167(6):1161–70.PubMedCrossRefGoogle Scholar
  32. 32.
    Stein T, Morris JS, Davies CR, Weber-Hall SJ, Duffy MA, Heath VJ, et al. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res 2004;6(2):R75–91.PubMedCrossRefGoogle Scholar
  33. 33.
    Lonnerdal B. Human milk proteins: key components for the biological activity of human milk. Adv Exp Med Biol 2004;554:11–25.PubMedGoogle Scholar
  34. 34.
    Moodley Y, Rigby P, Bundell C, Bunt S, Hayashi H, Misso N, et al. Macrophage recognition and phagocytosis of apoptotic fibroblasts is critically dependent on fibroblast-derived thrombospondin 1 and CD36. Am J Pathol 2003;162(3):771–9.PubMedGoogle Scholar
  35. 35.
    Pechoux C, Clezardin P, Dante R, Serre CM, Clerget M, Bertin N, et al. Localization of thrombospondin, CD36 and CD51 during prenatal development of the human mammary gland. Differentiation 1994;57(2):133–41.PubMedGoogle Scholar
  36. 36.
    Rodriguez-Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci USA 2001;98(22):12485–90.PubMedCrossRefGoogle Scholar
  37. 37.
    Monks J, Geske FJ, Lehman L, Fadok VA. Do inflammatory cells participate in mammary gland involution? J Mammary Gland Biol Neoplasia 2002;7(2):163–76.PubMedCrossRefGoogle Scholar
  38. 38.
    Golpon HA, Fadok VA, Taraseviciene-Stewart L, Scerbavicius R, Sauer C, Welte T, et al. Life after corpse engulfment: phagocytosis of apoptotic cells leads to VEGF secretion and cell growth. FASEB J 2004;18(14):1716–8.PubMedGoogle Scholar
  39. 39.
    Brooker BE. Pseudopod formation and phagocytosis of milk components by epithelial cells of the bovine mammary gland. Cell Tissue Res 1983;229(3):639–50.PubMedCrossRefGoogle Scholar
  40. 40.
    Mayberry HE. Macrophages in post-secretory mammary involution in mice. Anat Rec 1964;149:99–111.PubMedCrossRefGoogle Scholar
  41. 41.
    Tatarczuch L, Philip C, Bischof R, Lee CS. Leucocyte phenotypes in involuting and fully involuted mammary glandular tissues and secretions of sheep. J Anat 2000;196(Pt 3):313–26.PubMedCrossRefGoogle Scholar
  42. 42.
    Tatarczuch L, Bischof RJ, Philip CJ, Lee CS. Phagocytic capacity of leucocytes in sheep mammary secretions following weaning. J Anat 2002;201(5):351–61.PubMedCrossRefGoogle Scholar
  43. 43.
    Nickerson SC. Immunological aspects of mammary involution. J Dairy Sci 1989;72(6):1665–78.PubMedGoogle Scholar
  44. 44.
    Lee CS, McDowell GH, Lascelles AK. The importance of macrophages in the removal of fat from the involuting mammary gland. Res Vet Sci 1969;10(1):34–8.PubMedGoogle Scholar
  45. 45.
    Lee CS, Outteridge PM. Leucocytes of sheep colostrum, milk and involution secretion, with particular reference to ultrastructure and lymphocyte sub-populations. J Dairy Res 1981;48(2):225–37.PubMedCrossRefGoogle Scholar
  46. 46.
    Nickerson SC, Sordillo LM. Role of macrophages and multinucleate giant cells in the resorption of corpora amylacea in the involuting bovine mammary gland. Cell Tissue Res 1985;240(2):397–401.PubMedCrossRefGoogle Scholar
  47. 47.
    Crago SS, Prince SJ, Pretlow TG, McGhee JR, Mestecky J. Human colostral cells. I. Separation and characterization. Clin Exp Immunol 1979;38(3):585–97.PubMedGoogle Scholar
  48. 48.
    Dulin AM, Paape MJ, Nickerson SC. Comparison of phagocytosis and chemiluminescence by blood and mammary gland neutrophils from multiparous and nulliparous cows. Am J Vet Res 1988;49(2):172–7.PubMedGoogle Scholar
  49. 49.
    Fox LK, McDonald JS, Hillers JK, Corbeil LB. Function of phagocytes obtained from lacteal secretions of lactating and nonlactating cows. Am J Vet Res 1988;49(5):678–81.PubMedGoogle Scholar
  50. 50.
    Sordillo LM, Shafer-Weaver K, DeRosa D. Immunobiology of the mammary gland. J Dairy Sci 1997;80(8):1851–65.PubMedCrossRefGoogle Scholar
  51. 51.
    Paape MJ, Shafer-Weaver K, Capuco AV, Van Oostveldt K, Burvenich C. Immune surveillance of mammary tissue by phagocytic cells. Adv Exp Med Biol 2000;480:259–77.PubMedCrossRefGoogle Scholar
  52. 52.
    Clarkson RW, Watson CJ. Microarray analysis of the involution switch. J Mammary Gland Biol Neoplasia 2003;8(3):309–19.PubMedCrossRefGoogle Scholar
  53. 53.
    Clarkson RW, Wayland MT, Lee J, Freeman T, Watson CJ. Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Res 2004;6(2):R92–109.PubMedCrossRefGoogle Scholar
  54. 54.
    Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ 2001;8(6):569–81.PubMedCrossRefGoogle Scholar
  55. 55.
    Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004;15(3):1101–11.PubMedCrossRefGoogle Scholar
  56. 56.
    Helminen HJ, Ericsson JL. Effects of enforced milk stasis on mammary gland epithelium, with special reference to changes in lysosomes and lysosomal enzymes. Exp Cell Res 1971;68(2):411–27.PubMedCrossRefGoogle Scholar
  57. 57.
    Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402(6762):672–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E, et al. A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 2001;61(2):439–44.PubMedGoogle Scholar
  59. 59.
    Gajewska M, Gajkowska B, Motyl T. Apoptosis and autophagy induced by TGF-B1 in bovine mammary epithelial BME-UV1 cells. J Physiol Pharmacol 2005;56 Suppl 3:143–57.PubMedGoogle Scholar
  60. 60.
    Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 1992;148(7):2207–16.PubMedGoogle Scholar
  61. 61.
    Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 2002;109(1):41–50.PubMedCrossRefGoogle Scholar
  62. 62.
    Politis I, Zhao X, McBride BW, Burton JH. Function of bovine mammary macrophages as antigen-presenting cells. Vet Immunol Immunopathol 1992;30(4):399–410.PubMedCrossRefGoogle Scholar
  63. 63.
    Paape M, Mehrzad J, Zhao X, Detilleux J, Burvenich C. Defense of the bovine mammary gland by polymorphonuclear neutrophil leukocytes. J Mammary Gland Biol Neoplasia 2002;7(2):109–21.PubMedCrossRefGoogle Scholar
  64. 64.
    Lund LR, Bjorn SF, Sternlicht MD, Nielsen BS, Solberg H, Usher PA, et al. Lactational competence and involution of the mouse mammary gland require plasminogen. Development 2000;127(20):4481–92.PubMedGoogle Scholar
  65. 65.
    Jakobisiak M, Lasek W, Golab J. Natural mechanisms protecting against cancer. Immunol Lett 2003;90(2–3):103–22.PubMedCrossRefGoogle Scholar
  66. 66.
    Fioretti F, Fradelizi D, Stoppacciaro A, Ramponi S, Ruco L, Minty A, et al. Reduced tumorigenicity and augmented leukocyte infiltration after monocyte chemotactic protein-3 (MCP-3) gene transfer: perivascular accumulation of dendritic cells in peritumoral tissue and neutrophil recruitment within the tumor. J Immunol 1998;161(1):342–6.PubMedGoogle Scholar
  67. 67.
    Zhang L, Yoshimura T, Graves DT. Antibody to Mac-1 or monocyte chemoattractant protein-1 inhibits monocyte recruitment and promotes tumor growth. J Immunol 1997;158(10):4855–61.PubMedGoogle Scholar
  68. 68.
    Bhan AK, DesMarais CL. Immunohistologic characterization of major histocompatibility antigens and inflammatory cellular infiltrate in human breast cancer. J Natl Cancer Inst 1983;71(3):507–16.PubMedGoogle Scholar
  69. 69.
    Hurlimann J, Saraga P. Mononuclear cells infiltrating human mammary carcinomas: immunohistochemical analysis with monoclonal antibodies. Int J Cancer 1985;35(6):753–70.PubMedCrossRefGoogle Scholar
  70. 70.
    Queen MM, Ryan RE, Holzer RG, Keller-Peck CR, Jorcyk CL. Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for tumor progression. Cancer Res 2005;65(19):8896–904.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Lung Biology Center, Cardiovascular Research Institute, Department of MedicineUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of AnatomyUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations