Journal of Molecular Medicine

, Volume 86, Issue 4, pp 391–400

Diabetes-induced alteration of F4/80+ macrophages: a study in mice with streptozotocin-induced diabetes for a long term

  • Haixia Ma
  • Guangwei Liu
  • Wenjun Ding
  • You Wu
  • Lu Cai
  • Yong Zhao
Original Article

Abstract

Macrophages as an early stage of immune responses form a bridge between innate and acquired immunity and shape the adaptive immune response. The immunoregulatory functions of macrophages in hosts with a prolonged exposure to a diabetic milieu remain to be determined. The levels, phenotype, and immunity including antigen-presenting ability, phagocytosis and immunogenicity of F4/80+ splenic macrophages (SPMs), and peritoneal exudates macrophages (PEMs) were detected in age-matched control mice and mice with streptozotocin (STZ)-induced diabetes for 16 weeks. The numbers of F4/80+ SPMs and PEMs significantly decreased in STZ-induced diabetic mice, compared with age-matched non-diabetic mice (control) at 16 weeks after diabetes induction. Functional analysis showed that F4/80+ SPMs and PEMs in STZ-induced diabetic mice exhibit significantly lower immunogenicity and nonopsonic phagocytosis to allogeneic T cells than those of control mice both in vitro and in vivo. Coincidently, the antigen-presenting capacity of F4/80+ PEMs, but not F4/80+ SPMs, in mice with STZ-induced diabetes for 16 or more weeks is also significantly lower than that of control mice. Our results showed that total cell number and immune function of F4/80+ macrophages were significantly defective in mice with a prolonged exposure to a diabetic milieu, which may be a mechanism responsible for the increased macrophage-related complications in diabetic patients such as the high prevalence of infection and cardiovascular mortality.

Keywords

Monocytes/macrophages Diabetes Autoimmune Immunodeficiency Diabetic complications 

Abbreviations

APCs

antigen-presenting cells

DCs

dendritic cells

DTH

delayed-type hypersensitivity

FCM

flow cytometry

IFN-γ

interferon-γ

IL-2

interleukin-2

MFI

median fluorescence intensity

MLR

mixed leukocyte reactions

PEMs

peritoneal exudate macrophages

SPMs

splenic macrophages

References

  1. 1.
    Lee LF, Xu B, Michie SA, Beilhack GF, Warganich T, Turley S, McDevitt HO (2005) The role of TNF-alpha in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: analysis of dendritic cell maturation. Proc Natl Acad Sci USA 102:15995–16000PubMedCrossRefGoogle Scholar
  2. 2.
    Jeffcoate W, Kong MF (2000) Diabete des femmes a barbe: a classic paper reread. Lancet 356:1183–1185PubMedCrossRefGoogle Scholar
  3. 3.
    Calderon B, Suri A, Unanue ER (2006) In CD4 T-cell-induced diabetes, macrophages are the final effector cells that mediate islet beta-cell killing: studies from an acute model. Am J Pathol 169:2137–2147PubMedCrossRefGoogle Scholar
  4. 4.
    Lee KU, Amano K, Yoon JW (1988) Evidence for initial involvement of macrophage in development of insulitis in NOD mice. Diabetes 37:989–991PubMedCrossRefGoogle Scholar
  5. 5.
    Nikolic T, Bouma G, Drexhage HA, Leenen PJ (2005) Diabetes-prone NOD mice show an expanded subpopulation of mature circulating monocytes, which preferentially develop into macrophage-like cells in vitro. J Leukoc Biol 78:70–79PubMedCrossRefGoogle Scholar
  6. 6.
    Hawkins TA, Gala RR, Dunbar JC (1996) The lymphocyte and macrophage profile in the pancreas and spleen of NOD mice: percentage of interleukin-2 and prolactin receptors on immunocompetent cell subsets. J Reprod Immunol 32:55–71PubMedCrossRefGoogle Scholar
  7. 7.
    Bouma G, Nikolic T, Coppens JM, van Helden-Meeuwsen CG, Leenen PJ, Drexhage HA, Sozzani S, Versnel MA (2005) NOD mice have a severely impaired ability to recruit leukocytes into sites of inflammation. Eur J Immunol 35:225–235PubMedCrossRefGoogle Scholar
  8. 8.
    Shah BR, Hux JE (2003) Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care 26:510–513PubMedCrossRefGoogle Scholar
  9. 9.
    Doxey DL, Nares S, Park B, Trieu C, Cutler CW, Iacopino AM (1998) Diabetes-induced impairment of macrophage cytokine release in a rat model: potential role of serum lipids. Life Sci 63:1127–1136PubMedCrossRefGoogle Scholar
  10. 10.
    Lo CJ (2005) Upregulation of cyclooxygenase-II gene and PGE2 production of peritoneal macrophages in diabetic rats. J Surg Res 125:121–127PubMedCrossRefGoogle Scholar
  11. 11.
    Wen Y, Gu J, Li SL, Reddy MA, Natarajan R, Nadler JL (2006) Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages. Endocrinology 147:2518–2525PubMedCrossRefGoogle Scholar
  12. 12.
    Yoshida K, Kikutani H (2000) Genetic and immunological basis of autoimmune diabetes in the NOD mouse. Rev Immunogenet 2:140–146PubMedGoogle Scholar
  13. 13.
    Bernard NF, Ertug F, Margolese H (1992) High incidence of thyroiditis and anti-thyroid autoantibodies in NOD mice. Diabetes 41:40–46PubMedCrossRefGoogle Scholar
  14. 14.
    Hanukoglu A, Mizrachi A, Dalal I, Admoni O, Rakover Y, Bistritzer Z, Levine A, Somekh E, Lehmann D, Tuval M, Boaz M, Golander A (2003) Extrapancreatic autoimmune manifestations in type 1 diabetes patients and their first-degree relatives: a multicenter study. Diabetes Care 26:1235–1240PubMedCrossRefGoogle Scholar
  15. 15.
    Reddy S, Yip S, Karanam M, Poole CA, Ross JM (1999) An immunohistochemical study of macrophage influx and the co-localization of inducible nitric oxide synthase in the pancreas of non-obese diabetic (NOD) mice during disease acceleration with cyclophosphamide. Histochem J 31:303–314PubMedCrossRefGoogle Scholar
  16. 16.
    Serreze DV, Gaedeke JW, Leiter EH (1993) Hematopoietic stem-cell defects underlying abnormal macrophage development and maturation in NOD/Lt mice: defective regulation of cytokine receptors and protein kinase C. Proc Natl Acad Sci USA 90:9625–9629PubMedCrossRefGoogle Scholar
  17. 17.
    Krakowski M, Abdelmalik R, Mocnik L, Krahl T, Sarvetnick N (2002) Granulocyte macrophage-colony stimulating factor (GM-CSF) recruits immune cells to the pancreas and delays STZ-induced diabetes. J Pathol 196:103–112PubMedCrossRefGoogle Scholar
  18. 18.
    Stiles BL, Kuralwalla-Martinez C, Guo W, Gregorian C, Wang Y, Tian J, Magnuson MA, Wu H (2006) Selective deletion of Pten in pancreatic beta cells leads to increased islet mass and resistance to STZ-induced diabetes. Mol Cell Biol 26:2772–2781PubMedCrossRefGoogle Scholar
  19. 19.
    Wang Z, Dohle C, Friemann J, Green BS, Gleichmann H (1993) Prevention of high- and low-dose STZ-induced diabetes with d-glucose and 5-thio-d-glucose. Diabetes 42:420–428PubMedCrossRefGoogle Scholar
  20. 20.
    Robertson JM, Jensen PE, Evavold BD (2000) DO11.10 and OT-II T cells recognize a C-terminal ovalbumin 323-339 epitope. J Immunol 164:4706–4712PubMedGoogle Scholar
  21. 21.
    Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ (2002) Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51:1938–1948PubMedCrossRefGoogle Scholar
  22. 22.
    Cai L, Wang J, Li Y, Sun X, Wang L, Zhou Z, Kang YJ (2005) Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy. Diabetes 54:1829–1837PubMedCrossRefGoogle Scholar
  23. 23.
    Liu G, Xia XP, Gong SL, Zhao Y (2006) The macrophage heterogeneity: difference between mouse peritoneal exudate and splenic F4/80+ macrophages. J Cell Physiol 209:341–352PubMedCrossRefGoogle Scholar
  24. 24.
    Sun Y, Ge BS, Kasai M, Diffendaffer C, Parks N, Li H, Peng J, Langnas AN, Zhao Y (2006) Induction of regulatory T cells from mature T cells by allogeneic thymic epithelial cells in vitro. Transpl Int 19:404–414PubMedCrossRefGoogle Scholar
  25. 25.
    Wang H, Zhao L, Sun Z, Sun L, Zhang B, Zhao Y (2006) A potential side effect of cyclosporin A: inhibition of CD4()CD25() regulatory T cells in mice. Transplantation 82:1484–1492PubMedCrossRefGoogle Scholar
  26. 26.
    Liu GW, Ma HX, Wu Y, Zhao Y (2006) The nonopsonic allogeneic cell phagocytosis of macrophages detected by flow cytometry and two photon fluorescence microscope. Transpl Immunol 16:220–226PubMedCrossRefGoogle Scholar
  27. 27.
    Kim S, Chung EY, Ma X (2005) Immunological consequences of macrophage-mediated clearance of apoptotic cells. Cell Cycle (Georgetown, Tex) 4:231–234Google Scholar
  28. 28.
    Grosse J, Chitu V, Marquardt A, Hanke P, Schmittwolf C, Zeitlmann L, Schropp P, Barth B, Yu P, Paffenholz R, Stumm G, Nehls M, Stanley ER (2006) Mutation of mouse Mayp/Pstpip2 causes a macrophage autoinflammatory disease. Blood 107:3350–3358PubMedCrossRefGoogle Scholar
  29. 29.
    Lambrecht BN (2006) Alveolar macrophage in the driver's seat. Immunity 24:366–368PubMedCrossRefGoogle Scholar
  30. 30.
    Rydstrom J (2006) Mitochondrial transhydrogenase—a key enzyme in insulin secretion and, potentially, diabetes. Trends Biochem Sci 31:355–358PubMedCrossRefGoogle Scholar
  31. 31.
    Nikolic T, Bunk M, Drexhage HA, Leenen PJ (2004) Bone marrow precursors of nonobese diabetic mice develop into defective macrophage-like dendritic cells in vitro. J Immunol 173:4342–4351PubMedGoogle Scholar
  32. 32.
    Kuki S, Imanishi T, Kobayashi K, Matsuo Y, Obana M, Akasaka T (2006) Hyperglycemia accelerated endothelial progenitor cell senescence via the activation of p38 mitogen-activated protein kinase. Circ J 70:1076–1081PubMedCrossRefGoogle Scholar
  33. 33.
    Rota M, LeCapitaine N, Hosoda T, Boni A, De Angelis A, Padin-Iruegas ME, Esposito G, Vitale S, Urbanek K, Casarsa C, Giorgio M, Luscher TF, Pelicci PG, Anversa P, Leri A, Kajstura J (2006) Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ Res 99:42–52PubMedCrossRefGoogle Scholar
  34. 34.
    Fu J, Tay SS, Ling EA, Dheen ST (2006) High glucose alters the expression of genes involved in proliferation and cell-fate specification of embryonic neural stem cells. Diabetologia 49:1027–1038PubMedCrossRefGoogle Scholar
  35. 35.
    Fujiwara N, Kobayashi K (2005) Macrophages in inflammation. Curr Drug Targets 4:281–286CrossRefGoogle Scholar
  36. 36.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964PubMedCrossRefGoogle Scholar
  37. 37.
    Park JB (2003) Phagocytosis induces superoxide formation and apoptosis in macrophages. Exp Mol Med 35:325–335PubMedGoogle Scholar
  38. 38.
    Skoberne M, Beignon AS, Larsson M, Bhardwaj N (2005) Apoptotic cells at the crossroads of tolerance and immunity. Curr Top Microbiol Immunol 289:259–292PubMedCrossRefGoogle Scholar
  39. 39.
    Liu G, Wu C, Wu Y, Zhao Y (2006) Phagocytosis of apoptotic cells and immune regulation. Scand J Immunol 64:1–9PubMedCrossRefGoogle Scholar
  40. 40.
    Jelachich ML, Reddi HV, Trottier MD, Schlitt BP, Lipton HL (2004) Susceptibility of peritoneal macrophages to infection by Theiler’s virus. Virus Res 104:123–127PubMedCrossRefGoogle Scholar
  41. 41.
    Murphy EA, Davis JM, Brown AS, Carmichael MD, Van Rooijen N, Ghaffar A, Mayer EP (2004) Role of lung macrophages on susceptibility to respiratory infection following short-term moderate exercise training. Am J Physiol Regul Integr Comp Physiol 287:R1354–1358PubMedGoogle Scholar
  42. 42.
    Zamboni DS, Rabinovitch M (2004) Phagocytosis of apoptotic cells increases the susceptibility of macrophages to infection with Coxiella burnetii phase II through down-modulation of nitric oxide production. Infect Immun 72:2075–2080PubMedCrossRefGoogle Scholar
  43. 43.
    Song Y, Song Z, Zhang L, McClain CJ, Kang YJ, Cai L (2003) Diabetes enhances lipopolysaccharide-induced cardiac toxicity in the mouse model. Cardiovasc Toxicol 3:363–372PubMedCrossRefGoogle Scholar
  44. 44.
    Mas A, Montane J, Anguela XM, Munoz S, Douar AM, Riu E, Otaegui P, Bosch F (2006) Reversal of type 1 diabetes by engineering a glucose sensor in skeletal muscle. Diabetes 55:1546–1553PubMedCrossRefGoogle Scholar
  45. 45.
    Minto AW, Erwig LP, Rees AJ (2003) Heterogeneity of macrophage activation in anti-Thy-1.1 nephritis. Am J Pathol 163:2033–2041PubMedGoogle Scholar
  46. 46.
    Chakraborty D, Banerjee S, Sen A, Banerjee KK, Das P, Roy S (2005) Leishmania donovani affects antigen presentation of macrophage by disrupting lipid rafts. J Immunol 175:3214–3224PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Haixia Ma
    • 1
    • 2
    • 3
  • Guangwei Liu
    • 1
    • 3
  • Wenjun Ding
    • 2
  • You Wu
    • 1
  • Lu Cai
    • 4
    • 5
  • Yong Zhao
    • 1
    • 3
  1. 1.Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane BiotechnologyInstitute of Zoology, Chinese Academy of SciencesBeijingChina
  2. 2.Graduate SchoolChinese Academy of SciencesBeijingChina
  3. 3.China–U.S. Jointed Research Center for Life SciencesChinese Academy of SciencesBeijingChina
  4. 4.Department Radiation OncologyThe University of LouisvilleLouisvilleUSA
  5. 5.Department of MedicineThe University of LouisvilleLouisvilleUSA

Personalised recommendations