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: Novel data indicate that the innate immune system (through activation of Toll-like receptors) is involved in articular pathophysiology, including the recruitment of inflammatory cells, and that periarticular factors such as adipocytokines contribute to the perpetuation of joint inflammation.
Abstract: Rheumatoid arthritis is a complex systemic disease that ultimately leads to the progressive destruction of articular and periarticular structures. Novel data indicate that the innate immune system (through activation of Toll-like receptors) is involved in articular pathophysiology, including the recruitment of inflammatory cells, and that periarticular factors such as adipocytokines contribute to the perpetuation of joint inflammation. The deleterious process of joint destruction is mediated by intracellular signaling pathways involving transcription factors, such as nuclear factor kappaB, cytokines, chemokines, growth factors, cellular ligands, and adhesion molecules. Advances in molecular biology techniques have identified T-cell-independent and B-cell-independent pathways that operate at different stages of the disease. Cytokine-independent pathways appear to be responsible for maintaining basic disease activity that is not affected by currently available therapies. Using this knowledge in combination with gene-transfer and gene-silencing approaches, bench-to-bedside strategies will be developed, thus enabling the creation of novel treatments for rheumatoid arthritis.
306 citations
"Phosphatidylserine-containing lipos..." refers background in this paper
...Pro-inflammatory cytokines produced by macrophages and helper T cells, the major infiltrated cells in the synovium of joints, have pivotal roles in the pathological process of RA.30,31 AA, an animal model of RA, is widely used for studies of both inflammation and bone loss,18,32 because AA rats show unique sequential pathological processes....
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...To clarify the mechanisms underlying PSL-induced phenotypic change of macrophages infiltrated in the ankle joints of AA rats, the effect of PSLs on the secretion of IL-10 and IL-1b from LPS-stimulated macrophages was examined, because LPS is a key component of CFA that activates macrophages in AA rats.(31) Although the mean levels of IL-10 and IL-1b in the culture medium were relatively low in the none treated control macrophages, the mean levels were significantly increased after treatment with LPS (Figure 4a and b)....
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...Pro-inflammatory cytokines produced by macrophages and helper T cells, the major infiltrated cells in the synovium of joints, have pivotal roles in the pathological process of RA.(30,31) AA, an animal model of RA, is widely used for studies of both inflammation and bone loss,(18,32) because AA rats show unique sequential pathological processes....
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TL;DR: It is shown that inhibition of cathepsin K could potently suppress autoimmune inflammation of the joints as well as osteoclastic bone resorption in autoimmune arthritis and mice were resistant to experimental autoimmune encephalomyelitis.
Abstract: Cathepsin K was originally identified as an osteoclast-specific lysosomal protease, the inhibitor of which has been considered might have therapeutic potential. We show that inhibition of cathepsin K could potently suppress autoimmune inflammation of the joints as well as osteoclastic bone resorption in autoimmune arthritis. Furthermore, cathepsin K–/– mice were resistant to experimental autoimmune encephalomyelitis. Pharmacological inhibition or targeted disruption of cathepsin K resulted in defective Toll-like receptor 9 signaling in dendritic cells in response to unmethylated CpG DNA, which in turn led to attenuated induction of T helper 17 cells, without affecting the antigen-presenting ability of dendritic cells. These results suggest that cathepsin K plays an important role in the immune system and may serve as a valid therapeutic target in autoimmune diseases.
289 citations
TL;DR: A dual function for p38α in the regulation of inflammation is suggested and mixed potential for its inhibition as a therapeutic strategy is shown.
Abstract: The mitogen-activated protein kinase p38 mediates cellular responses to injurious stress and immune signaling. Among the many p38 isoforms, p38 alpha is the most widely expressed in adult tissues and can be targeted by various pharmacological inhibitors. Here we investigated how p38 alpha activation is linked to cell type-specific outputs in mouse models of cutaneous inflammation. We found that both myeloid and epithelial p38 elicit inflammatory responses, yet p38 alpha signaling in each cell type served distinct inflammatory functions and varied depending on the mode of skin irritation. In addition, myeloid p38 alpha limited acute inflammation via activation of anti-inflammatory gene expression dependent on mitogen- and stress-activated kinases. Our results suggest a dual function for p38 alpha in the regulation of inflammation and show mixed potential for its inhibition as a therapeutic strategy.
253 citations
"Phosphatidylserine-containing lipos..." refers background in this paper
...macrophages, because p38 MAPK and ERK cross-regulate each other such as the inhibition of one enhances the activation of the other.(47,49) Moreover, PSLs regulated the expression levels of IL-10 and IL-1b in the PB monocytes,...
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Journal Article•
TL;DR: A role for p38 MAPK is demonstrated in the regulation of the IL-1beta cytokine gene in monocytic cell lines using the bicyclic imidazole SB203580 by acting through C/EBP/NFIL-6 transcription factors.
Abstract: Several reports have shown that bicyclic imidazoles, specific inhibitors of the p38 mitogen-activated protein kinase (MAPK), block cytokine synthesis at the translational level In this study, we examined the role of p38 MAPK in the regulation of the IL-1beta cytokine gene in monocytic cell lines using the bicyclic imidazole SB203580 Addition of SB203580 30 min before stimulation of monocytes with LPS inhibited IL-1beta protein and steady state message in a dose-dependent manner in both RAW2647 and J774 cell lines The loss of IL-1beta message was due mainly to inhibition of transcription, since nuclear run-off analysis showed an approximately 80% decrease in specific IL-1 RNA synthesis In contrast, SB203580 had no effect on the synthesis of TNF-alpha message LPS-stimulated p38 MAPK activity in the RAW2647 cells was blocked by SB203580, as measured by the inhibition of MAPKAP2 kinase activity, a downstream target of the p38 MAPK CCAATT/enhancer binding protein (C/EBP)/NFIL-6-driven chloramphenicol acetyltransferase (CAT) reporter activity was sensitive to SB203580, indicating that C/EBP/NFIL-6 transcription factor(s) are also targets of p38 MAPK In contrast, transfected CAT constructs containing NF-kappaB elements were only partially inhibited (approximately 35%) at the highest concentration of SB203580 after LPS stimulation As measured by EMSA, LPS-stimulated NF-kappaB activation was not affected by SB203580 Overall, the results demonstrate, for the first time, a role for p38 MAPK in IL-1beta transcription by acting through C/EBP/NFIL-6 transcription factors
244 citations
TL;DR: Data uncover a new immune evasion strategy, whereby Leishmania differentially modulates CD40-engaged, reciprocally functioning signaling modules, and provide a new conceptual framework for immune homeostasis.
Abstract: Macrophages play host to Leishmania major, a parasite that causes leishmaniasis in 500,000 people annually. Macrophage-expressed CD40, a costimulatory molecule1, induces interleukin-12 (IL-12)-dependent and interferon-γ (IFN-γ)-dependent host-protective immune responses to Leishmania and other intracellular pathogens2,3,4,5,6. Paradoxically, IL-10, another CD40-induced cytokine in macrophages7, promotes Leishmania infection8. How CD40 signaling regulates the secretion of these two counteractive cytokines remains unknown. Here we show that weak CD40 signals induce extracellular stress–related kinase-1/2 (ERK-1/2)-dependent IL-10 expression, whereas stronger signals induce p38 mitogen-activated protein kinase (p38MAPK)-dependent IL-12 production. p38MAPK and ERK-1/2 therefore have counter-regulatory actions. Leishmania skews CD40 signaling toward ERK-1/2, inducing IL-10, which inhibits activation of CD40-induced p38MAPK and expression of inducible nitric oxide synthase-2 (iNOS-2) and IL-12. ERK-1/2 inhibition or IL-10 neutralization restores CD40-induced p38MAPK activation and parasite killing in macrophages and the BALB/c mouse, a susceptible host. These data uncover a new immune evasion strategy, whereby Leishmania differentially modulates CD40-engaged, reciprocally functioning signaling modules, and provide a new conceptual framework for immune homeostasis.
236 citations
"Phosphatidylserine-containing lipos..." refers background in this paper
...macrophages, because p38 MAPK and ERK cross-regulate each other such as the inhibition of one enhances the activation of the other.(47,49) Moreover, PSLs regulated the expression levels of IL-10 and IL-1b in the PB monocytes,...
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...However, PSLinduced increase in IL-10 by LPS-stimulated macrophages may depend on ERK activity, because ERK activity leads to IL-10 production.(47,48) Furthermore, PSLs inhibited the rapid activation of p38 MAPK and may result in the subsequent slow enhancement of ERK activity in LPS-stimulated...
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