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 results suggest that apoptosis induced by glucocorticoid does not require the same zVAD-sensitive caspase steps which are required for Fas/FasL-dependent death induced by anti-CD3 antibody, and that the action of these proteases is also not required for PS externalization.
Abstract: In lymphocytes, an asymmetric distribution of phospholipids across the plasma membrane is maintained by an ATP-dependent translocase which specifically transports aminophospholipids from the outer to the inner leaflet of the bilayer. During apoptosis, this enzyme is down-regulated and a lipid flipsite, termed the scramblase, is activated. Together, these events lead to the appearance of phosphatidylserine (PS) on the cell surface. In DO11.10 T lymphocyte hybridoma cells undergoing apoptosis, the kinetics of PS externalization are paralleled by the development of PS-sensitive phagocytosis by macrophages. This parallel is also observed when PS externalization is effected directly by application of a Ca2+ ionophore, suggesting that PS externalization is not only necessary, but sufficient, to generate a recognition signal. The broad spectrum aspartate-directed cysteine protease (caspase) inhibitor zVAD-fmk blocks externalization of PS and terminal cell lysis after induction of apoptosis by anti-CD3 antibody, but is ineffective when apoptosis is induced in the same cells by treatment with glucocorticoid. These results suggest that apoptosis induced by glucocorticoid does not require the same zVAD-sensitive caspase steps which are required for Fas/FasL-dependent death induced by anti-CD3 antibody, and that the action of these proteases is also not required for PS externalization. Extracellular Ca2+ is required to complete the later stages of apoptosis in DO11.10 cells, and its removal restores normal transport of PS, suggesting that down-regulation of the aminophospholipid translocase and up-regulation of the scramblase are not effected by irreversible protease cleavage.
138 citations
TL;DR: It is suggested that PS exposure provides a sufficient signal to inhibit DC maturation and to modulate adaptive immune responses.
Abstract: Phosphatidylserine (PS), which is exposed on the surface of apoptotic cells, has been implicated in immune regulation. However, the effects of PS on the maturation and function of dendritic cells (DCs), which play a central role in both immune activation and regulation, have not been described. Large unilamellar liposomes containing PS or phosphatidylcholine were used to model the plasma membrane phospholipid composition of apoptotic and live cells, respectively. PS liposomes inhibited the up-regulation of HLA-ABC, HLA-DR, CD80, CD86, CD40, and CD83, as well as the production of IL-12p70 by human DCs in response to LPS. PS did not affect DC viability directly but predisposed DCs to apoptosis in response to LPS. DCs exposed to PS had diminished capacity to stimulate allogeneic T cell proliferation and to activate IFN-γ-producing CD4 + T cells. Exogenous IL-12 restored IFN-γ production by CD4 + T cells. Furthermore, activated CTLs proliferated poorly to cognate Ag presented by DCs exposed to PS. Our findings suggest that PS exposure provides a sufficient signal to inhibit DC maturation and to modulate adaptive immune responses.
109 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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TL;DR: It is found that IL-23 up-regulates receptor activator of NF-κB ligand expression by CD4+ T cells, and thus contributes to osteoclastogenesis, and is a promising therapeutic target for the treatment of arthritis-associated bone destruction.
Abstract: IL-23, a clinically novel cytokine, targets CD4(+) T cells. Recent IL-1Ra(-/-) mouse studies have demonstrated that IL-23 indirectly stimulates the differentiation of osteoclast precursors by enhancing IL-17 release from CD4(+) T cells. IL-17, in turn, stimulates osteoclastogenesis in osteoclast precursor cells. In this study, we found that IL-23 up-regulates receptor activator of NF-kappaB ligand expression by CD4(+) T cells, and thus contributes to osteoclastogenesis. This indirect pathway is mediated by NF-kappaB and STAT3. We have also demonstrated that IL-23 can influence osteoclastogenesis positively under the special conditions in the IL-1-dominant milieu of IL-1Ra(-/-) mice. We propose that IL-23-enhanced osteoclastogenesis is mediated mainly by CD4(+) T cells. The results of this study show that IL-23 is a promising therapeutic target for the treatment of arthritis-associated bone destruction.
89 citations
TL;DR: Observations strongly suggest that leptomeningeal cells release pro-inflammatory cytokines to activate both microglia and astrocytes during systemic inflammation, which may in turn regulate anti-inflammatory response in the brain by providing IL-10.
89 citations
"Phosphatidylserine-containing lipos..." refers 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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TL;DR: Clinical trials in human RA have started with ex vivo retrovirus‐expressing IL‐1 receptor antagonists and have demonstrated the feasibility of the strategy of gene therapy, which targets mainly the players of inflammation or articular destruction.
Abstract: Rheumatoid arthritis (RA) is a severe autoimmune systemic disease. Chronic synovial inflammation results in destruction of the joints. No conventional treatment is efficient in RA. Gene therapy of RA targets mainly the players of inflammation or articular destruction: TNF-α or IL-1 blocking agents (such as anti-TNF-α monoclonal antibodies, soluble TNF-α receptor, type II soluble receptor of IL-1, IL-1 receptor antagonist), antiinflammatory cytokines (such as IL-4, IL-10, IL-1), and growth factors. In this polyarticular disease, the vector expressing the therapeutic protein can be administered as a local (intra-articular injection) or a systemic treatment (extra-articular injection). All the main vectors have been used in experimental models, including the more recent lentivirus and adeno-associated virus. Ex vivo gene transfer was performed with synovial cells, fibroblasts, T cells, dendritic cells, and different cells from xenogeneic origin. In vivo gene therapy is simpler, although a less controlled method. Clinical trials in human RA have started with ex vivo retrovirus-expressing IL-1 receptor antagonists and have demonstrated the feasibility of the strategy of gene therapy. The best target remains to be determined and extensive research has to be conducted in preclinical studies. Copyright © 2002 John Wiley & Sons, Ltd.
74 citations