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.
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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
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 102:15995–16000
Jeffcoate W, Kong MF (2000) Diabete des femmes a barbe: a classic paper reread. Lancet 356:1183–1185
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 169:2137–2147
Lee KU, Amano K, Yoon JW (1988) Evidence for initial involvement of macrophage in development of insulitis in NOD mice. Diabetes 37:989–991
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 78:70–79
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 32:55–71
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 35:225–235
Shah BR, Hux JE (2003) Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care 26:510–513
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 63:1127–1136
Lo CJ (2005) Upregulation of cyclooxygenase-II gene and PGE2 production of peritoneal macrophages in diabetic rats. J Surg Res 125:121–127
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 147:2518–2525
Yoshida K, Kikutani H (2000) Genetic and immunological basis of autoimmune diabetes in the NOD mouse. Rev Immunogenet 2:140–146
Bernard NF, Ertug F, Margolese H (1992) High incidence of thyroiditis and anti-thyroid autoantibodies in NOD mice. Diabetes 41:40–46
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 26:1235–1240
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 31:303–314
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 90:9625–9629
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 196:103–112
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 26:2772–2781
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 42:420–428
Robertson JM, Jensen PE, Evavold BD (2000) DO11.10 and OT-II T cells recognize a C-terminal ovalbumin 323-339 epitope. J Immunol 164:4706–4712
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 51:1938–1948
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 54:1829–1837
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 209:341–352
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 19:404–414
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 82:1484–1492
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 16:220–226
Kim S, Chung EY, Ma X (2005) Immunological consequences of macrophage-mediated clearance of apoptotic cells. Cell Cycle (Georgetown, Tex) 4:231–234
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 107:3350–3358
Lambrecht BN (2006) Alveolar macrophage in the driver's seat. Immunity 24:366–368
Rydstrom J (2006) Mitochondrial transhydrogenase—a key enzyme in insulin secretion and, potentially, diabetes. Trends Biochem Sci 31:355–358
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 173:4342–4351
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 70:1076–1081
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 99:42–52
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 49:1027–1038
Fujiwara N, Kobayashi K (2005) Macrophages in inflammation. Curr Drug Targets 4:281–286
Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964
Park JB (2003) Phagocytosis induces superoxide formation and apoptosis in macrophages. Exp Mol Med 35:325–335
Skoberne M, Beignon AS, Larsson M, Bhardwaj N (2005) Apoptotic cells at the crossroads of tolerance and immunity. Curr Top Microbiol Immunol 289:259–292
Liu G, Wu C, Wu Y, Zhao Y (2006) Phagocytosis of apoptotic cells and immune regulation. Scand J Immunol 64:1–9
Jelachich ML, Reddi HV, Trottier MD, Schlitt BP, Lipton HL (2004) Susceptibility of peritoneal macrophages to infection by Theiler’s virus. Virus Res 104:123–127
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:R1354–1358
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 72:2075–2080
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 3:363–372
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 55:1546–1553
Minto AW, Erwig LP, Rees AJ (2003) Heterogeneity of macrophage activation in anti-Thy-1.1 nephritis. Am J Pathol 163:2033–2041
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 175:3214–3224
Acknowledgments
The authors wish to thank Dr. Hong Shen for her kind review of the manuscript; Ms. Jing Wang, Mr. Yabing Liu, and Ms. Jianxia Peng for their expert technical assistance; Ms. Qinghuan Li for her excellent laboratory management; and Ms. Yuli Liu for her outstanding animal husbandry. This work was supported by grants from the National Natural Science Foundation for Key Programs (C30630060, Y.Z.), the National Natural Science Foundation for Young Scientists (C30600567, G.L.), the National Natural Science Foundation for Distinguished Young Scholars (C03020504, Y.Z.), and the Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry (2005-546, Y.Z.).
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Ma, H., Liu, G., Ding, W. et al. Diabetes-induced alteration of F4/80+ macrophages: a study in mice with streptozotocin-induced diabetes for a long term. J Mol Med 86, 391–400 (2008). https://doi.org/10.1007/s00109-008-0304-8
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DOI: https://doi.org/10.1007/s00109-008-0304-8