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
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...[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: These results identify cytokines, antigen-presenting cells and microbial products that promote the polarization of human TH-17 cells and emphasize an important difference in the requirements for the differentiation of TH- 17 cells in humans and mice.
Abstract: Interleukin 17 (IL-17)-producing CD4(+) helper T cells (T(H)-17 cells) have been linked to host defense and autoimmune diseases. In mice, the differentiation of T(H)-17 cells requires transforming growth factor-beta and IL-6 and the transcription factor RORgammat. We report here that for human naive CD4(+) T cells, RORgammat expression and T(H)-17 polarization were induced by IL-1beta and enhanced by IL-6 but were suppressed by transforming growth factor-beta and IL-12. Monocytes and conventional dendritic cells, but not monocyte-derived dendritic cells activated by microbial stimuli, efficiently induced T(H)-17 priming, and this function correlated with antigen-presenting cell production of IL-1beta and IL-6 but not IL-12. Our results identify cytokines, antigen-presenting cells and microbial products that promote the polarization of human T(H)-17 cells and emphasize an important difference in the requirements for the differentiation of T(H)-17 cells in humans and mice.
1,716 citations
"Phosphatidylserine-containing lipos..." refers result in this paper
...This was consistent with the fact that IL-1 β is essential for promoting Th17 cell differentiation and IL-17 production by the differentiated Th17 cells...
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TL;DR: It is suggested that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL -17 is a crucial cytokine for osteoclastic bone resorption in RA patients.
Abstract: IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti-IL-17 antibody significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL-17 is a crucial cytokine for osteoclastic bone resorption in RA patients.
1,705 citations
"Phosphatidylserine-containing lipos..." refers background in this paper
...E-mails: zhouw@dent.kyushu-u.ac.jp or nakan@dent.kyushu-u.ac.jp Laboratory Investigation (2011) 91, 921–931 & 2011 USCAP, Inc All rights reserved 0023-6837/11 $32.00 www.laboratoryinvestigation.org | Laboratory Investigation | Volume 91 June 2011 921 (RANKL) and RANK, which have essential roles in differentiation and the activity of osteoclasts.18 Among pro-inflammatory cytokines, interleukin (IL)-1b is a master regulator of inflammation and inflammatory bone loss, because it can induce other pro-inflammatory cytokines.19,20 Recently, much attention has been paid to IL-17 as a crucial cytokine for inflammatory osteoclastic bone loss because of its marked induction of RANKL.21 Indeed, high levels of IL-1b and IL-17 are found in the plasma and synovial tissues of rheumatoid arthritis (RA) patients, and combined blockade of IL-1b and IL-17 receptors significantly inhibited the rheumatoid arthritic osteoporosis.22 Among anti-inflammatory mediators, including TGF-b1 and PGE2, IL-10 is known as the strongest feedback mediator of inflammatory bone loss.23,24 The paw volume increase of adjuvant arthritic (AA) rat, an animal model of RA,25–27 occurs in two stages: namely an acute inflammation stage from 10 to 21 days after complete Freund’s adjuvant (CFA) injection, and the chronic bone/ joint destruction stage thereafter....
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...First, PSLs decreased the expression levels of IL-1b and IL-17, which can promote the expression of RANKL.38,39 Second, PSL-induced IL-10, which strongly inhibited the expression of RANKL/RANK.23,37 Third, PSLs are phagocytosed by the osteoclast precursor to directly decrease the expression of RANK by osteoclast precursor and the production of RANKL in cultured rat bone marrow cells.17 Therefore, it is considered that the inhibitory effect of PSLs on the trabecular bone loss in AA rats completely depends on the inhibition of the RANKL/RANK pathway....
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...a crucial cytokine for inflammatory osteoclastic bone loss because of its marked induction of RANKL.(21) Indeed, high levels of IL-1b and IL-17 are found in the plasma and...
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TL;DR: Using phage display, a gene that appears to recognize phosphatidylserine on apoptotic cells is cloned and shown to be highly homologous to genes of unknown function in Caenorhabditis elegans and Drosophila melanogaster, suggesting that phosphatido-serine recognition on apoptosis cells during their removal by phagocytes is highly conserved throughout phylogeny.
Abstract: The culmination of apoptosis in vivo is phagocytosis of cellular corpses. During apoptosis, the asymmetry of plasma membrane phospholipids is lost, which exposes phosphatidylserine externally1,2,3,4. The phagocytosis of apoptotic cells can be inhibited stereospecifically by phosphatidylserine and its structural analogues, but not by other anionic phospholipids, suggesting that phosphatidylserine is specifically recognized1,5,6,7,8,9,10. Using phage display, we have cloned a gene that appears to recognize phosphatidylserine on apoptotic cells. Here we show that this gene, when transfected into B and T lymphocytes, enables them to recognize and engulf apoptotic cells in a phosphatidylserine-specific manner. Flow cytometric analysis using a monoclonal antibody suggested that the protein is expressed on the surface of macrophages, fibroblasts and epithelial cells; this antibody, like phosphatidylserine liposomes, inhibited the phagocytosis of apoptotic cells and, in macrophages, induced an anti-inflammatory state. This candidate phosphatidylserine receptor is highly homologous to genes of unknown function in Caenorhabditis elegans and Drosophila melanogaster, suggesting that phosphatidylserine recognition on apoptotic cells during their removal by phagocytes is highly conserved throughout phylogeny.
1,525 citations
TL;DR: Investigating the physiological role of the TNF receptor (TNFR) family member, RANK, revealed that RANK provides critical signals necessary for lymph node organogenesis and osteoclast differentiation.
Abstract: The physiological role of the TNF receptor (TNFR) family member, RANK, was investigated by generating RANK-deficient mice. RANK(-/-) mice were characterized by profound osteopetrosis resulting from an apparent block in osteoclast differentiation. RANK expression was not required for the commitment, differentiation, and functional maturation of macrophages and dendritic cells from their myeloid precursors but provided a necessary and specific signal for the differentiation of myeloid-derived osteoclasts. RANK(-/-) mice also exhibited a marked deficiency of B cells in the spleen. RANK(-/-) mice retained mucosal-associated lymphoid tissues including Peyer's patches but completely lacked all other peripheral lymph nodes, highlighting an additional major role for RANK in lymph node formation. These experiments reveal that RANK provides critical signals necessary for lymph node organogenesis and osteoclast differentiation.
1,421 citations
TL;DR: What makes a protein immunogenic, particularly for strong T cell–mediated immunity?
Abstract: What makes a protein immunogenic, particularly for strong T cell–mediated immunity? To a first approximation, this determination seems to be made by dendritic cells (DCs). Immature DCs, as in skin ([1][1])([2][2])([3][3])([4][4]), lung ([5][5]), blood ([6][6])([7][7]), and spleen ([7][7])([8][8
1,235 citations
"Phosphatidylserine-containing lipos..." refers background in this paper
...PS-dependent phagocytosis of apoptotic cells is believed to trigger the secretion of anti-inflammatory cytokines and restrains that of pro-inflammatory cytokines from macrophages(8,9) and dendritic cells.(10,11) Recently, we and others have found that PS-containing liposomes (PSLs) mimic apoptotic cells to...
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