Phosphatidylserine-containing liposomes suppress inflammatory bone loss by ameliorating the cytokine imbalance provoked by infiltrated macrophages.
TL;DR: PSL-induced different influence on the activities of p38 MAPK and ERK is a likely underlying mechanism for phenotypic change of infiltrated macrophages after the phagocytosis of PSLs, resulting in the inhibition of inflammatory bone loss.
About: This article is published in Laboratory Investigation.The article was published on 2011-06-01 and is currently open access. It has received 52 citations till now. The article focuses on the topics: Interleukin 10 & Phagocytosis.
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TL;DR: The restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade, offering a therapeutic strategy to this orphan pathological process.
Abstract: Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl4-induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11Bhi F4/80int Ly-6Clo macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter–diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6Chi monocytes, a common origin with profibrotic Ly-6Chi macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6Clo subset, compared with Ly-6Chi macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process.
744 citations
Cites background from "Phosphatidylserine-containing lipos..."
...Furthermore, recent studies have shown that liposome administration can alter macrophage phenotype in vivo in part by induction of ERK signaling after ingestion (53, 54)....
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TL;DR: This review summarizes new data on inflammatory bone loss obtained in 2011 and describes the molecular pathways by which receptor activator of nuclear factor-κB ligand and RANKL induce osteoclast differentiation.
Abstract: Chronic inflammation including autoimmune disease is an important risk factor for the development of osteoporosis. Receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) play a central role in osteoclast differentiation and function, and the molecular pathways by which M-CSF and RANKL induce osteoclast differentiation have been analyzed in detail. Proinflammatory cytokines directly or indirectly regulate osteoclastogenesis and bone resorption providing a link between inflammation and osteoporosis. Tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17 are the most important proinflammatory cytokines triggering inflammatory bone loss. Inhibition of these cytokines has provided potent therapeutic effects in the treatment of diseases such as rheumatoid arthritis. Further investigation is needed to understand the pathophysiology and to develop new strategies to treat inflammatory bone loss. This review summarizes new data on inflammatory bone loss obtained in 2011.
152 citations
Cites background from "Phosphatidylserine-containing lipos..."
...[77] suggests that this effect is due to increased IL-10 production by macrophages....
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TL;DR: The induction of a uniquely polarized macrophage subset from infected monocytes is described, which is argued to be the ideal cellular environment for the initiation of viral gene expression and replication and, ultimately, viral spread and persistence within the infected host.
Abstract: The wide range of disease pathologies seen in multiple organ sites associated with human cytomegalovirus (HCMV) infection results from the systemic hematogenous dissemination of the virus, which is mediated predominately by infected monocytes. In addition to their role in viral spread, infected monocytes are also known to play a key role in viral latency and life-long persistence. However, in order to utilize infected monocytes for viral spread and persistence, HCMV must overcome a number of monocyte biological hurdles, including their naturally short lifespan and their inability to support viral gene expression and replication. Our laboratory has shown that HCMV is able to manipulate the biology of infected monocytes in order to overcome these biological hurdles by inducing the survival and differentiation of infected monocytes into long-lived macrophages capable of supporting viral gene expression and replication. In this current review, we describe the unique aspects of how HCMV promotes monocyte survival and differentiation by inducing a “finely-tuned” macrophage cell type following infection. Specifically, we describe the induction of a uniquely polarized macrophage subset from infected monocytes, which we argue is the ideal cellular environment for the initiation of viral gene expression and replication and, ultimately, viral spread and persistence within the infected host.
70 citations
TL;DR: The data show that myelin modulates the phenotype of macrophages by PPAR activation, which may subsequently dampen MS lesion progression and the immunoregulatory impact of naturally-occurring myelin lipids may hold promise for future MS therapeutics.
Abstract: Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions. Recent studies have described an altered phenotype of macrophages after myelin internalization. However, mechanisms by which myelin affects the phenotype of macrophages and how this phenotype influences lesion progression remain unclear. We demonstrate that myelin as well as phosphatidylserine (PS), a phospholipid found in myelin, reduce nitric oxide production by macrophages through activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). Furthermore, uptake of PS by macrophages, after intravenous injection of PS-containing liposomes (PSLs), suppresses the production of inflammatory mediators and ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effect of PSLs in EAE animals is associated with a reduced immune cell infiltration into the central nervous system and decreased splenic cognate antigen specific proliferation. Interestingly, PPARβ/δ is activated in foamy macrophages in active MS lesions, indicating that myelin also activates PPARβ/δ in macrophages in the human brain. Our data show that myelin modulates the phenotype of macrophages by PPAR activation, which may subsequently dampen MS lesion progression. Moreover, our results suggest that myelin-derived PS mediates PPARβ/δ activation in macrophages after myelin uptake. The immunoregulatory impact of naturally-occurring myelin lipids may hold promise for future MS therapeutics.
64 citations
Cites background from "Phosphatidylserine-containing lipos..."
...In vivo, PSLs have been described to promote the resolution of inflammation by modulating macrophage function in a model for inflammatory bone loss and myocardial infarction [31,33]....
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...In vitro, clearance of apoptotic cells and PSLs skews macrophages towards a tolerogenic phenotype [21,23,29-35]....
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TL;DR: The findings suggest that the PSL-IL10 has macrophage targeting ability and enhanced anti- inflammatory effect due to the synergistic anti-inflammatory effects of IL-10 and PSL, and can be used as amacrophage-targeted therapeutic material for inflammation-related diseases, including obesity.
55 citations
References
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TL;DR: The present findings suggest that the sensory nerves and the macrophages may be involved in osteophyte formation in the ankle joints of AA rats.
Abstract: To study the mechanism of osteophyte formation in the ankle joints of adjuvant arthritic (AA) rats, the localization of peripheral nerves and immune cells in the synovia were investigated in both axotomized AA rats, whose sciatic nerves were resected before adjuvant injection, and sham-operated ones, using immunohistochemistry for low-affinity nerve growth factor receptor (p75NGFR), growth-associated protein (GAP)-43, calcitonin gene-related peptide (CGRP), helper T cell (W3/25), monocyte/macrophage (ED1), and transforming growth factor (TGF)-beta1 and its receptor, TGF-betaRII. In sham-operated AA rats, dense plexuses of CGRP-positive fibers were observed in the inflamed synovia close to the osteophytes. Most of the CGRP-positive fibers were also positive for p75NGFR and GAP-43. These fibers appeared to be newly sprouted sensory nerves. In axotomized AA rats, the synovia were supplied with no CGRP-positive fibers and the sizes of the osteophytes were smaller than those in sham-operated animals. The ratio of the number of both W3/25- and ED1-positive cells in the inflamed synovia of sham-operated rats peaked at weeks 2-3 after adjuvant injection. The peak, however, lasted until week 4 in axotomized ones. In both animal groups, the macrophages and the osteoblasts were stained for TGF-beta1. The osteoblasts covering the osteophytes were also stained for TGF-betaRII. The present findings suggest that the sensory nerves and the macrophages may be involved in osteophyte formation in the ankle joints of AA rats.
40 citations
"Phosphatidylserine-containing lipos..." refers background or methods in this paper
...We intramuscularly injected PSLs (5 mg/kg/day, PSL-treated AA rats, n1⁄4 27) or PCLs (5 mg/kg/day, PCLtreated AA rats, n1⁄4 27) into the hind limbs from day 10 after CFA injection, when clinical symptoms, such as redness and swelling, were detected in the ankle joints.(28,29) AA rats intramuscularly injected with phosphate-buffered saline (PBS) used as a control (n1⁄4 27)....
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...In the chronic stage, trabecular bone loss occurs, and the number of infiltrated macrophages and helper T cells declines.(26,28) In this study, the expression levels of IL-1b and IL-17 were markedly elevated in the ankle joints during the acute stage in AA rats....
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TL;DR: In the rat model of rheumatoid arthritis, a marked formation of osteoclasts is found in the distal tibia and the metatarsal bone, and it was proposed that osteoclast progenitors would be increased in the bone marrow cavities of rats with adjuvant-induced arthritis (AA rats) to result in the highest recruitment of active osteoclast in the area of marked bone destruction.
40 citations
TL;DR: It is suggested that MRI is likely to be of value for the early diagnosis of arthritis because early soft-tissue changes were detected more frequently by MRI.
Abstract: Arthritis was induced in rats by intradermal injection of Freund's complete adjuvant. MRI was performed with a resistive imager operating at 0.35 T. A spin echo (SE) technique with TR = 0.5 and 2.0 seconds, TE = 28 and 56 msec was used. Transaxial images of hindpaws and knees were obtained at different times after injection of adjuvant. In vitro proton spectroscopy of normal and arthritic hindpaws was also performed. Histologic confirmation was obtained in each case. Inflammatory soft-tissue lesions were seen as focal areas of high intensity on spin echo images obtained with TR = 2.0 seconds and TE = 56 msec and were characterized by long T1 and T2 relaxation times and high spin density. In comparison with both conventional radiography and physical examination, early soft-tissue changes were detected more frequently by MRI. This study suggests that MRI is likely to be of value for the early diagnosis of arthritis.
38 citations
TL;DR: It is assumed that DBD glycoprotein has anti-inflammatory potential, which can modulate proinflammatory signal transduction in LPS-stimulated RAW 264.7 cells.
Abstract: This study was carried out to investigate the anti-inflammatory effects of 30-kDa glycoprotein isolated from Dioscorea batatas Decne (DBD glycoprotein), which consists of carbohydrate content (61%) and protein content (39%) on lipopolysaccharide (LPS, 2 μg/ml)-stimulated RAW 264.7 cells. We found that DBD glycoprotein (200 μg/ml) has an inhibitory effect on the production of intracellular hydrogen peroxide (H2O2), on the phosphorylation of p38 mitogen-activated protein (MAP) kinase, on the DNA binding activity of activator protein-1 (AP-1), and on c-Jun and c-Fos protein expression, respectively. In addition, DBD glycoprotein treatment markedly suppressed the interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase (iNOS) expression and the production of nitric oxide (NO) in LPS-stimulated RAW 264.7 cells. Interestingly, IL-1β, IL-6, and iNOS expression was significantly attenuated by treatment with protein kinase C (PKC) inhibitor (staurosporine) as well as p38 MAP kinase inhibitor (SKF86002) in LPS-stimulated RAW 264.7 cells. On the basis of these results, we assume that DBD glycoprotein has anti-inflammatory potential, which can modulate proinflammatory signal transduction in LPS-stimulated RAW 264.7 cells.
32 citations
"Phosphatidylserine-containing lipos..." refers background in this paper
...The inhibitory effects of PSLs on IL-1b secretion from LPS-activated macrophages may depend on the reduction of p38 MAPK activity, because p38 MAPK activity has crucial roles in the regulation of IL-1b biosynthesis(45) and p38 MAPK inhibitor blocks IL-1b production.(46) PSL-induced inhibition of NF-kB activity may be involved in the inhibition of IL-1b, because NF-kB activity is required for pro-inflammatory cytokine production, including IL-1b....
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TL;DR: IL-17 produced by Th17 plays an important role in the pathogenesis of rat EAM, and IL-17 inhibition might be a possible mechanism of the amelioration of EAM by IL-10-Ig treatment.
29 citations
"Phosphatidylserine-containing lipos..." refers background in this paper
...It was considered that IL-10 secreted from macrophages after phagocytosis of PSLs can inhibit IL-1b production and the differentiation of Th17 cells, thus resulting in a decrease in the IL-17 levels.(34) This PSL-induced phenotypic change of infiltrated macrophages also contributed to the inhibition of AA-induced trabecular bone loss through the inhibition of RANKL/RANK expression, which have essential roles in osteoclastogenesis(18,35,36) and osteoclastic bone loss in RA as well as in AA....
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