scholarly journals Diabetes induces myeloid bias in bone marrow progenitors associated with enhanced wound macrophage accumulation and impaired healing

2019 ◽  
Vol 249 (4) ◽  
pp. 435-446 ◽  
Author(s):  
Pijus K Barman ◽  
Norifumi Urao ◽  
Timothy J Koh
Keyword(s):  
Bone Marrow ◽  
Impaired Healing ◽  
Macrophage Accumulation

scholarly journals Cellular source of hypothalamic macrophage accumulation in diet-induced obesity

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Chan Hee Lee ◽  
Sung Hoon Shin ◽  
Gil Myoung Kang ◽  
Seongjun Kim ◽  
Jiye Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Vascular Permeability ◽  
Marrow Transplantation ◽  
Myeloid Cells ◽  
Postnatal Life ◽  
Obese Mice ◽  
Diet Induced Obesity ◽  
Transplantation Experiments ◽  
Macrophage Accumulation

Abstract Background Obese mice on a high-fat diet (HFD) display signs of inflammation in the hypothalamic arcuate nucleus (ARC), a critical area for controlling systemic energy metabolism. This has been suggested as a key mechanism of obesity-associated hypothalamic dysfunction. We reported earlier that bone marrow-derived macrophages accumulate in the ARC to sustain hypothalamic inflammation upon chronic exposure to an HFD. However, the mechanism underlying hypothalamic macrophage accumulation has remained unclear. Methods We investigated whether circulating monocytes or myeloid precursors contribute to hypothalamic macrophage expansion during chronic HFD feeding. To trace circulating myeloid cells, we generated mice that express green fluorescent protein (GFP) in their lysozyme M-expressing myeloid cells (LysMGFP mice). We conducted parabiosis and bone marrow transplantation experiments using these animals. Mice received an HFD for 12 or 30 weeks and were then sacrificed to analyze LysMGFP cells in the hypothalamus. Hypothalamic vascular permeability in the HFD-fed obese mice was also tested by examining the extravascular leakage of Evans blue and fluorescence-labeled albumin. The timing of LysMGFP cell entry to the hypothalamus during development was also evaluated. Results Our parabiosis and bone marrow transplantation experiments revealed a significant infiltration of circulating LysMGFP cells into the liver, skeletal muscle, choroid plexus, and leptomeninges but not in the hypothalamic ARC during chronic HFD feeding, despite increased hypothalamic vascular permeability. These results suggested that the recruitment of circulating monocytes is not a major mechanism for maintaining and expanding the hypothalamic macrophage population in diet-induced obesity. We demonstrated instead that LysMGFP cells infiltrate the hypothalamus during its development. LysMGFP cells appeared in the hypothalamic area from the late embryonic period. This cellular pool suddenly increased immediately after birth, peaked at the postnatal second week, and adopted an adult pattern of distribution after weaning. Conclusions Bone marrow-derived macrophages mostly populate the hypothalamus in early postnatal life and may maintain their pool without significant recruitment of circulating monocytes throughout life, even under conditions of chronic HFD feeding.

scholarly journals Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance

2016 ◽  
Vol 2 (3) ◽  
pp. e1501332 ◽  
Author(s):  
Sachiko Nishimoto ◽  
Daiju Fukuda ◽  
Yasutomi Higashikuni ◽  
Kimie Tanaka ◽  
Yoichiro Hirata ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bone Marrow ◽  
Adipose Tissue ◽  
Visceral Obesity ◽  
Sterile Inflammation ◽  
Model Assessment ◽  
Wild Type ◽  
Exogenous Dna ◽  
Monocyte Chemoattractant Protein 1 ◽  
Macrophage Accumulation

Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography–determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

scholarly journals Discoidin Domain Receptor 1 on Bone Marrow–Derived Cells Promotes Macrophage Accumulation During Atherogenesis

2009 ◽  
Vol 105 (11) ◽  
pp. 1141-1148 ◽  
Author(s):  
Christopher Franco ◽  
Karen Britto ◽  
Eric Wong ◽  
Guangpei Hou ◽  
Su-Ning Zhu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Discoidin Domain Receptor ◽  
Bone Marrow Derived Cells ◽  
Discoidin Domain Receptor 1 ◽  
Macrophage Accumulation

Abstract 3968: Bone Marrow Derived Growth Differentiation Factor-15 (GDF-15) Protects from Macrophage Accumulation and Effects Atherosclerotic Lesion Stabilisation in Low-Density Lipoprotein Receptor-Null Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michael R Preusch ◽  
Jens Strelau ◽  
Matthias Baeuerle ◽  
Erwin Blessing ◽  
Marc Bischof ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Peritoneal Macrophages ◽  
Lesion Size ◽  
Fibrous Cap ◽  
Atherosclerotic Lesions ◽  
Density Lipoprotein Receptor ◽  
Macrophage Accumulation

Atherosclerosis is considered to be a chronic inflammatory disease. Macrophages are the prime sources of a variety of inflammatory cytokines and growth factors, which contribute to the initiation and progression of atherosclerotic lesions. The cytokine growth differentiation factor-15 (GDF-15) is a newly discovered member of the transforming growth factor-beta cytokine. GDF-15 participates in vascular inflammation and is mostly expressed by macrophages within the lesions. In this study the impact of GDF-15 deficiency in bone marrow-derived cells on atherogenesis in a mouse model was examined. Bone marrow from GDF15 −/−or GDF-15 +/+ mice was transplanted into lethally irradiated low-density lipoprotein receptor (LDLR−/−) mice (n=38). Twentyfour weeks after administration of a high-fat/high-cholesterol Western type diet atherosclerotic lesion size within the aortic root as well as macrophage content was quantified and compared. In addition features of lesion destabilisation like size of the necrotic core, thinning of the fibrous cap, intra-plaque hemorrhage and calcification were evaluated. In an in-vitro experiment peritoneal macrophages from transplanted mice were harvested and stimulated with tumor necrosis factor alpha (TNFα). Transplantation of GDF-15 −/− bone marrow cells resulted in an enhanced macrophage accumulation within the atherosclerotic lesions (ratio mac/lesion 0.51 versus 0.31; p<0.05) and a significant thinning of the fibrous cap (30.5 versus 48.5 μm; p<0.05). Cell culture experiments demonstrated that macrophages from GDF-15 −/− mice had a much higher induction of ICAM-1 and MCP-1 after stimulation with TNFα in comparison to wildtype peritoneal macrophages. However no difference in lesion size could be reported. Furthermore, there was no difference in plasma lipid levels and body weight. Our data indicates that bone marrow derived GDF-15 protects from macrophage accumulation within atherosclerotic lesions and promotes lesion stabilisation possibly due to inhibition of adhesion molecules and MCP-1.

Abstract 3693: Early Growth Response Gene-1 Deficiency In Bone-marrow-derived Cells Reduces Macrophage Accumulation And Atherosclerotic Lesion Formation In A Hyperlipidemic Mouse Model

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michael R Preusch ◽  
Claudia Albrecht ◽  
Gotz Hofmann ◽  
Erwin Blessing ◽  
Hugo A Katus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Atherosclerotic Lesion ◽  
Lesion Development ◽  
Early Growth Response ◽  
Atherosclerotic Lesions ◽  
Early Growth Response Gene ◽  
Bone Marrow Derived Cells ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Development ◽  
Macrophage Accumulation

Early growth response gene-1 (Egr-1), a prototype of a family of zinc-finger transcription factors, is a master regulator of many genes which play important roles in cardiovascular diseases. Within atherosclerotic lesions Egr-1 is expressed in several cell types, such as smooth muscle cells, endothelial cells and monocytes/macrophages. Since macrophages play a pivotal role in atherosclerotic lesion development, this study investigated the effects of Egr-1-deficiency within bone-marrow derived cells on the development of atherosclerosis in a hyperlipidemic mouse model. Therefore we transplanted bone-marrow from Egr-1 deficient mice and wild type controls into lethally irradiated low-density lipoprotein receptor deficient mice. After 20 weeks on a western diet atherosclerotic lesions within the aortic sinus and gene expression of inflammatory genes in the aortas of the recipients were evaluated. Mice receiving Egr-1 deficient bone-marrow had less atherosclerotic lesion development compared with mice receiving wild type bone-marrow (318 736 ± 98 910μm 2 vs. 404 539 ± 92 408μm 2 , p<0.05). The size of the necrotic core within the lesions was also reduced. Immunohistochemistry revealed that mice receiving Egr-1 deficient bone-marrow had less macrophages in comparison to controls. Gene expression analysis in the aortas of the mice demonstrated reduced expression of Vascular Cell Adhesion Molecule (VCAM-1), an important adhesion molecule during the development of atherosclerosis. These results were validated with in vitro studies where Egr-1-deficient peritoneal macrophages revealed less VCAM-1 mRNA expression after stimulation with lipopolysaccharide in comparison to wildtype macrophages. This study demonstrates that bone-marrow derived Egr-1 promotes macrophage accumulation and atherosclerotic lesion development possible over an increased expression of VCAM-1.

scholarly journals Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2476-2483 ◽  
Author(s):  
Joshua D. Milner ◽  
Tatyana Orekov ◽  
Jerrold M. Ward ◽  
Lily Cheng ◽  
Fernando Torres-Velez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Extramedullary Hematopoiesis ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Tissue Macrophage ◽  
Clinical Scenarios ◽  
Ifn Γ ◽  
Factor Α ◽  
Macrophage Accumulation

Abstract Erythrophagocytosis and inflammation from activated macrophages occur in distinct clinical scenarios. The presence of CD8+ T cells and interferon-γ (IFN-γ) production is required to induce disease in mouse models of hemophagocytic lymphohistiocytosis. We investigated the roles of a different class of proinflammatory cytokines, interleukin-4 (IL-4) and IL-13, in the induction of inflammatory tissue macrophage accumulation and/or hemophagocytosis. We found that large amounts of IL-4, but not IL-13, delivered via an implanted mini-pump or IL-4/anti–IL-4 complexes, lead to substantial YM1+ tissue macrophage accumulation, erythrophagocytosis within the liver, spleen, and bone marrow, decreased hemoglobin and platelet levels, and acute weight loss. This effect is not dependent on the presence of antibody or T cells, as treatment of Rag2−/− mice leads to similar disease, and IFN-γ neutralization during IL-4 treatment had no effect. IL-4 treatment results in suppression of IL-12, elevation of serum IFN-γ, IL-10, and the murine IL-8 homolog KC, but not IL-6, IL-1β, or tumor necrosis factor-α. Finally, mice transgenic for IL-4 production developed tissue macrophage accumulation, disruption of splenic architecture, bone marrow hypocellularity, and extramedullary hematopoiesis. These data describe a novel pathophysiologic pathway for erythrophagocytosis in the context of tissue macrophage accumulation and inflammation involving elevations in IL-4 and alternative macrophage activation.

Abstract 876: Combined Inhibition Of Ccl2, Cx3cr1 And Ccr5 Abrogates Ly6chi And Ly6clo Monocytosis And Almost Abolishes Atherosclerosis In Hypercholesterolemic Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Stephane Potteaux ◽  
Christophe Combadiere ◽  
Adeline Pezard ◽  
Stephanie Riou ◽  
Tabassome Simon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vessel Wall ◽  
Lesion Size ◽  
Monocyte Subsets ◽  
Lesion Development ◽  
Prevailing Paradigm ◽  
Almost All ◽  
Deficient Mice ◽  
Macrophage Accumulation

Monocytes are critical mediators of atherogenesis. Specialized chemokine/chemokine receptor pathways orchestrate the infiltration of specific monocyte subsets within atherosclerotic arteries. Interruption of individual chemokine pathways including CCL2/CCR2, CCL5/CCR5, CX3CL1/CX3CR1, CXCL8/CXCR2 or CXCL10/CXCR3, leads to significant but only partial inhibition of lesion development, whereas deficiency in other signals such as CXCL16 or CCR1 accelerates atherosclerosis. Evidence that particular chemokine pathways may cooperate to promote monocyte recruitment into atherosclerotic arteries is still lacking. Here, we show that in addition to the current prevailing paradigm accounting for the role of chemokines as modulators of monocyte trafficking between the blood and the vessel wall, chemokine-mediated signals critically determine the frequency of monocytes in the blood and the bone marrow under both non-inflammatory and atherosclerotic conditions. Particularly, CCL2, CX3CR1 and CCR5-dependent signals differentially alter CD11b+ Ly6G- 7/4hi (also known as Ly6Chi) and CD11b + Ly6G- 7/4lo (Ly6Clo) monocytosis. Combined inhibition of these pathways in hypercholesterolemic, atherosclerosis susceptible apolipoprotein E-deficient mice leads to additive reduction in bone marrow and circulating monocytes, associated with a marked and additive 90% reduction in atherosclerosis. Lesion size highly correlates with the number of circulating monocytes. Thus, signals mediated through CCL2, CX3CR1 and CCR5 critically determine the frequency of circulating monocyte subsets and thereby account for almost all macrophage accumulation into atherosclerotic arteries.

scholarly journals IL-34–Dependent Intrarenal and Systemic Mechanisms Promote Lupus Nephritis in MRL-Faslpr Mice

2019 ◽  
Vol 30 (2) ◽  
pp. 244-259 ◽  
Author(s):  
Yukihiro Wada ◽  
Hilda M. Gonzalez-Sanchez ◽  
Julia Weinmann-Menke ◽  
Yasunori Iwata ◽  
Amrendra K. Ajay ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lupus Nephritis ◽  
Mouse Model ◽  
Knockout Mice ◽  
Therapeutic Target ◽  
Tubular Epithelial Cells ◽  
Circulating Autoantibodies ◽  
Macrophage Accumulation ◽  
Novel Therapeutic

BackgroundIn people with SLE and in the MRL-Faslpr lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ.MethodsTo investigate whether IL-34–dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL-Faslpr mice expressing IL-34 and IL-34 knockout (KO) MRL-Faslpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis.ResultsIntrarenal IL-34 and its two receptors increase during lupus nephritis in MRL-Faslpr mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation via monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and via intrarenal macrophage proliferation. This accumulation leads to macrophage-mediated TEC apoptosis. We also found suppression of circulating autoantibodies and glomerular antibody deposits in the knockout mice. This is consistent with fewer activated and proliferating intrarenal and splenic B cells in mice lacking IL-34, and with our novel discovery that PTPRZ is expressed by macrophages, B and T cells. These findings appear translatable to human patients with lupus nephritis, whose expression of IL-34, cFMS, and PTPRZ is similar to that seen in the MRL-Faslpr lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity.ConclusionsIL-34 is a promising novel therapeutic target for patients with lupus nephritis.

Glycogen in guinea pig neutrophils: Ultrastructural study of neutrophils at the intradermal site of BCG injection

1983 ◽  
Vol 41 ◽  
pp. 726-727
Author(s):  
Corazon D. Bucana
Keyword(s):  
Bone Marrow ◽  
Guinea Pig ◽  
Electron Density ◽  
Peritoneal Cavity ◽  
Ultrastructural Study ◽  
Guinea Pigs ◽  
Random Distribution ◽  
Glycogen Content ◽  
Polymorphonuclear Neutrophils ◽  
Ultrastructural Studies

In the circulating blood of man and guinea pigs, glycogen occurs primarily in polymorphonuclear neutrophils and platelets. The amount of glycogen in neutrophils increases with time after the cells leave the bone marrow, and the distribution of glycogen in neutrophils changes from an apparently random distribution to large clumps when these cells move out of the circulation to the site of inflammation in the peritoneal cavity. The objective of this study was to further investigate changes in glycogen content and distribution in neutrophils. I chose an intradermal site because it allows study of neutrophils at various stages of extravasation.Initially, osmium ferrocyanide and osmium ferricyanide were used to fix glycogen in the neutrophils for ultrastructural studies. My findings confirmed previous reports that showed that glycogen is well preserved by both these fixatives and that osmium ferricyanide protects glycogen from solubilization by uranyl acetate.I found that osmium ferrocyanide similarly protected glycogen. My studies showed, however, that the electron density of mitochondria and other cytoplasmic organelles was lower in samples fixed with osmium ferrocyanide than in samples fixed with osmium ferricyanide.

Mammalian Bone Marrow Acetylcholinesterase

1982 ◽  
Vol 40 ◽  
pp. 44-45
Author(s):  
Ezzatollah Keyhani
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Common Property ◽  
Extracellular Medium ◽  
The Central Nervous System ◽  
The Common ◽  
Mammalian Bone

Acetylcholinesterase (EC 3.1.1.7) (ACHE) has been localized at cholinergic junctions both in the central nervous system and at the periphery and it functions in neurotransmission. ACHE was also found in other tissues without involvement in neurotransmission, but exhibiting the common property of transporting water and ions. This communication describes intracellular ACHE in mammalian bone marrow and its secretion into the extracellular medium.

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