Accumulation of M1-like macrophages in type 2 diabetic islets is followed by a systemic shift in macrophage polarization

被引:108
作者
Cucak, Helena [1 ]
Grunnet, Lars Groth [2 ]
Rosendahl, Alexander [1 ]
机构
[1] Novo Nordisk AS, Dept Diabet Complicat Biol, DK-2760 Malov, Denmark
[2] Novo Nordisk AS, Islet Biol, Hagedorn Res Inst, DK-2760 Malov, Denmark
关键词
inflammation; cytokines; insulin; ADIPOSE-TISSUE; NOD MICE; PANCREATIC-ISLETS; DB/DB MICE; INFLAMMATION; OBESITY; ACTIVATION; GALECTIN-3; RECEPTOR; DYSFUNCTION;
D O I
10.1189/jlb.0213075
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Two distinct subsets of pro-inflammatory M1-like macrophages invade type 2 diabetic islets at a time-point when -cells undergo apoptosis, and blood glucose control is lost. Human T2D is characterized by a low-grade systemic inflammation, loss of -cells, and diminished insulin production. Local islet immunity is still poorly understood, and hence, we evaluated macrophage subpopulations in pancreatic islets in the well-established murine model of T2D, the db/db mouse. Already at 8 weeks of disease, on average, 12 macrophages were observed in the diabetic islets, whereas only two were recorded in the nondiabetic littermates. On a detailed level, the islet resident macrophages increased fourfold compared with nondiabetic littermates, whereas a pronounced recruitment (eightfold) of a novel subset of macrophages (CD68(+)F4/80(-)) was observed. The majority of the CD68(+)F4/80(+) but only 40% of the CD68(+)F4/80(-) islet macrophages expressed CD11b. Both islet-derived macrophage subsets expressed moderate MHC-II, high galectin-3, and low CD80/CD86 levels, suggesting the cells to be macrophages rather than DCs. On a functional level, the vast majority of the macrophages in the diabetic islets was of the proinflammatory, M1-like phenotype. The systemic immunity in diabetic animals was characterized by a low-grade inflammation with elevated cytokine levels and increase of splenic cytokine, producing CD68(+)F4/80(-) macrophages. In late-stage diabetes, the cytokine signature changed toward a TGF--dominated profile, coinciding with a significant increase of galectin-3-positive macrophages in the spleen. In summary, our results show that proinflammatory M1-like galectin-3(+) CD80/CD86(low) macrophages invade diabetic islets. Moreover, the innate immunity matures in a diabetes-dependent manner from an initial proinflammatory toward a profibrotic phenotype, supporting the concept that T2D is an inflammatory disease.
引用
收藏
页码:149 / 160
页数:12
相关论文
共 48 条
[31]   Advanced Age Impairs Macrophage Polarization [J].
Mahbub, Shegufta ;
Deburghgraeve, Cory R. ;
Kovacs, Elizabeth J. .
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 2012, 32 (01) :18-26
[32]   The chemokine system in diverse forms of macrophage activation and polarization [J].
Mantovani, A ;
Sica, A ;
Sozzani, S ;
Allavena, P ;
Vecchi, A ;
Locati, M .
TRENDS IN IMMUNOLOGY, 2004, 25 (12) :677-686
[33]   Inflamed fat: what starts the fire? [J].
Neels, JG ;
Olefsky, JM .
JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (01) :33-35
[34]   Galectin-1 and galectin-3 expression profiles in classically and alternatively activated human macrophages [J].
Novak, Ruder ;
Dabelic, Sanja ;
Dumic, Jerka .
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 2012, 1820 (09) :1383-1390
[35]   QUANTITATIVE-ANALYSIS OF PANCREATIC PROINSULIN MESSENGER-RNA IN GENETICALLY DIABETIC (DB/DB) MICE [J].
ORLAND, MJ ;
PERMUTT, MA .
DIABETES, 1987, 36 (03) :341-347
[36]   Inducible transgenes under the control of the hCD68 promoter identifies mouse macrophages with a distribution that differs from the F4/80-and CSF-1R-expressing populations [J].
Pillai, Manoj M. ;
Hayes, Brian ;
Torok-Storb, Beverly .
EXPERIMENTAL HEMATOLOGY, 2009, 37 (12) :1387-1392
[37]   The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes [J].
Richardson, S. J. ;
Willcox, A. ;
Bone, A. J. ;
Foulis, A. K. ;
Morgan, N. G. .
DIABETOLOGIA, 2009, 52 (06) :1143-1151
[38]   Obesity, inflammation, and atherosclerosis [J].
Rocha, Viviane Z. ;
Libby, Peter .
NATURE REVIEWS CARDIOLOGY, 2009, 6 (06) :399-409
[39]   Galectin-3 deficiency protects pancreatic islet cells from cytokine-triggered apoptosis in vitro [J].
Saksida, Tamara ;
Nikolic, Ivana ;
Vujicic, Milica ;
Nilsson, Ulf J. ;
Leffler, Hakon ;
Lukic, Miodrag L. ;
Stojanovic, Ivana ;
Stosic-Grujicic, Stanislava .
JOURNAL OF CELLULAR PHYSIOLOGY, 2013, 228 (07) :1568-1576
[40]   Deletion of the murine scavenger receptor CD68 [J].
Song, Li ;
Lee, Carolyn ;
Schindler, Christian .
JOURNAL OF LIPID RESEARCH, 2011, 52 (08) :1542-1550