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
[1]   Vascular Endothelial Growth Factor-Mediated Islet Hypervascularization and Inflammation Contribute to Progressive Reduction of β-Cell Mass [J].
Agudo, Judith ;
Ayuso, Eduard ;
Jimenez, Veronica ;
Casellas, Alba ;
Mallol, Cristina ;
Salavert, Ariana ;
Tafuro, Sabrina ;
Obach, Merce ;
Ruzo, Albert ;
Moya, Marta ;
Pujol, Anna ;
Bosch, Fatima .
DIABETES, 2012, 61 (11) :2851-2861
[2]   IL-1 produced and released endogenously within human islets inhibits β cell function [J].
Arnush, M ;
Heitmeier, MR ;
Scarim, AL ;
Marino, MH ;
Manning, PT ;
Corbett, JA .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 102 (03) :516-526
[3]   Differential role of CD80 and CD86 on alveolar macrophages in the presentation of allergen to T lymphocytes in asthma [J].
Balbo, P ;
Silvestri, M ;
Rossi, GA ;
Crimi, E ;
Burastero, SE .
CLINICAL AND EXPERIMENTAL ALLERGY, 2001, 31 (04) :625-636
[4]   CYTOTOXICITY OF HUMAN PI-7 INTERLEUKIN-1 FOR PANCREATIC-ISLETS OF LANGERHANS [J].
BENDTZEN, K ;
MANDRUPPOULSEN, T ;
NERUP, J ;
NIELSEN, JH ;
DINARELLO, CA ;
SVENSON, M .
SCIENCE, 1986, 232 (4757) :1545-1547
[5]   Macrophage polarization in bacterial infections [J].
Benoit, Marie ;
Desnues, Benoit ;
Mege, Jean-Louis .
JOURNAL OF IMMUNOLOGY, 2008, 181 (06) :3733-3739
[6]   Free Fatty Acids Induce a Proinflammatory Response in Islets via the Abundantly Expressed Interleukin-1 Receptor I [J].
Boeni-Schnetzler, Marianne ;
Boller, Simone ;
Debray, Sarah ;
Bouzakri, Karim ;
Meier, Daniel T. ;
Prazak, Richard ;
Kerr-Conte, Julie ;
Pattou, Francois ;
Ehses, Jan A. ;
Schuit, Frans C. ;
Donath, Marc Y. .
ENDOCRINOLOGY, 2009, 150 (12) :5218-5229
[7]   Distinct Phenotype and Function of NK Cells in the Pancreas of Nonobese Diabetic Mice [J].
Brauner, Hanna ;
Elemans, Marjet ;
Lemos, Sara ;
Broberger, Christian ;
Holmberg, Dan ;
Flodstrom-Tullberg, Malin ;
Karre, Klas ;
Hoglund, Petter .
JOURNAL OF IMMUNOLOGY, 2010, 184 (05) :2272-2280
[8]   β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes [J].
Butler, AE ;
Janson, J ;
Bonner-Weir, S ;
Ritzel, R ;
Rizza, RA ;
Butler, PC .
DIABETES, 2003, 52 (01) :102-110
[9]   Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes [J].
Cameron, MJ ;
Arreaza, GA ;
Grattan, M ;
Meagher, C ;
Sharif, S ;
Burdick, MD ;
Strieter, RM ;
Cook, DN ;
Delovitch, TL .
JOURNAL OF IMMUNOLOGY, 2000, 165 (02) :1102-1110
[10]   The worldwide epidemiology of type 2 diabetes mellitus-present and future perspectives [J].
Chen, Lei ;
Magliano, Dianna J. ;
Zimmet, Paul Z. .
NATURE REVIEWS ENDOCRINOLOGY, 2012, 8 (04) :228-236