Macrophages In Inflammatory Diseases Research Articles

Arginine-assembly as NO nano-donor prevents the negative feedback of macrophage repolarization by mitochondrial dysfunction for cancer immunotherapy

Repolarizing the tumor-associated macrophages (TAMs) towards the antitumoral M1-like phenotype has been a promising approach for cancer immunotherapy. However, the anti-cancer immune response is severely limited mainly by the repolarized M1-like macrophages belatedly returning to the M2-like phenotype (i.e., negative feedback). Inspired by nitric oxide (NO) effectively preventing repolarization of inflammatory macrophages in inflammatory diseases, herein, we develop an arginine assembly, as NO nano-donor for NO generation to prevent the negative feedback of the macrophage repolarization. The strategy is to first apply reversible tagging of hydrophobic terephthalaldehyde to create an arginine nano-assembly, and then load a toll-like receptor 7/8 agonist resiquimod (R848) (R848@Arg). Through this strategy, a high loading efficiency of 40 % for the arginine and repolarization characteristics for TAMs can be achieved. Upon the macrophage repolarization by R848, NO can be intracellularly generated from the released arginine by the upregulated inducible nitric oxide synthase. Mechanistically, NO effectively prevented the negative feedback of the repolarized macrophage by mitochondrial dysfunction via blocking oxidative phosphorylation. Notably, R848@Arg significantly increased the tumor inhibition ratio by 3.13-fold as compared to the free R848 by maintaining the M1-like phenotype infiltrating into tumor. The Arg-assembly as NO nano-donor provides a promising method for effective repolarization of macrophages.

Adenine is an anti-inflammatory metabolite found to be more abundant in M-CSF over GM-CSF-differentiated human macrophages

Immunometabolism has been unveiled in the last decade to play a major role in controlling macrophage metabolism and inflammation. There has been a constant effort to understand the immunomodulating properties of regulated metabolites during inflammation with the aim of controlling and re-wiring aberrant macrophages in inflammatory diseases. M-CSF and GM-CSF-differentiated macrophages play a key role in mounting successful innate immune responses. When a resolution phase is not achieved however, GM-CSF macrophages contribute substantially more towards an adverse inflammatory milieu than M-CSF macrophages, consequently driving disease progression. Whether there are specific immunometabolites that determine the homoeostatic or inflammatory nature of M-CSF and GM-CSF-differentiated macrophages is still unknown. As such, we performed metabolomics analysis on LPS and IL-4-stimulated M-CSF and GM-CSF-differentiated human macrophages to identify differentially accumulating metabolites. Adenine was distinguished as a metabolite significantly higher in M-CSF-differentiated macrophages after both LPS or IL-4 stimulation. Human macrophages treated with adenine before LPS stimulation showed a reduction in inflammatory gene expression, cytokine secretion and surface marker expression. Adenine caused macrophages to become more quiescent by lowering glycolysis and OXPHOS which resulted in reduced ATP production. Moreover, typical metabolite changes seen during LPS-induced macrophage metabolic reprogramming were absent in the presence of adenine. Phosphorylation of metabolic signalling proteins AMPK, p38 MAPK and AKT were not responsible for the suppressed metabolic activity of adenine-treated macrophages. Altogether, in this study we highlight the immunomodulating capacity of adenine in human macrophages and its function in driving cellular quiescence.

Molecular scale study on the interactions of biocompatible nanoparticles with macrophage membrane and blood proteins

AbstractMacrophage targeting and researches centered on immunological responses have received interest thanks to studies unveiling the significant role of macrophages in inflammatory diseases and cancer. In this regard, we have selected four types of nanoparticles (NPs), including acetalated dextran‐based nano‐carrier functionalized with atrial natriuretic peptide and linTT1(AcDEX‐PEG‐TT1‐ANP), PEGylated acetalated dextran (AcDEX‐PEG), acetalated dextran (AcDEX), and hyaluronic acid (HA) to investigate their interactions with macrophage membrane. Using microsecond coarse‐grained molecular dynamics (MD) simulations, we studied the interactions between the NPs and the macrophage membrane and subsequent immunological reactions that occur after the penetration of the NPs within the macrophage cell. Different parameters that determine the strength and amount of macrophage membrane interaction were measured and compared for all four types of NPs. The results showed that AcDEX‐PEG‐TT1‐ANP has the most favorable interaction with the macrophage membrane while HA has the least favorable results by comparison. Moreover, drug encapsulation and release in different pH conditions showed the pH‐responsivity of the considered NPs for drug delivery in acidic environments. On the other hand, evaluations with human serum albumin (HSA), fibrinogen (Fib), and transferrin (Tf) declared that peptide modified AcDEX polymers are the most probable NPs to absorb a layer of the protein corona.

Effects of l-arginine and l-ornithine supplementations on the treatment of chronic periodontitis: A preliminary randomized short-term clinical trial

The growing interest in the possibilities of modulating macrophages in inflammatory diseases with therapeutic purpose has prompted the development of new approaches for the treatment of periodontitis. This randomized add-on open preliminary clinical study evaluated the short-term effects of L-arginine or L-ornithine as an adjuvant to scaling and root planing (SRP) in patients with chronic periodontitis. Materials and methodsSeventy-five periodontitis patients were recruited and monitored clinically and immunologically at baseline (before SRP) and 30 ± 5 days after SRP. All patients were assigned by stratified randomization to SRP (SRP only, n = 25), Arg (SRP + L-arginine, n = 25) or Control (SRP + L-ornithine, n = 25) Group. The medicines were used according to available instructions for 10 and 15 days, respectively. During the study, all patients were on a stable diet, without changing their rations and regiments. As immunological monitoring immunohistochemical study of CD68+ and CD163 + single positive gingival macrophages for 5 patients per group in the same time-point was conducted. The data were statistically analyzed. ResultsReduction of periodontal pocket depth (PPD) and bleeding on probing (BoP) was observed in all groups, with significant between-group differences for BoP in the Arg Group (p < 0.0001) at 30 days. The SRP and Arg groups demonstrated nonsignificantly increased density of CD68+ and CD163 + cells. The Orn Group showed an increase in the density of CD68+ and CD163 + macrophages at intragroup (p = 0.0066 and p < 0.0001) and between-group levels (p = 0.001 and p < 0.0001), and these changes corresponded to clinical PPD and BoP reduction. In the Arg and Orn groups at 30 days, CD163 + macrophages significantly predominated over CD68+ (p = 0.013, p < 0.0001). ConclusionThe use of L-arginine and L-ornithine as an adjunct to SRP promotes additional limited immunological benefit in the treatment of periodontitis. Metabolic stimulation with L-ornithine, but not L-arginine, is preferable for CD163+ Mφs subpopulation in periodontitis-affected gingiva.

A Novel Role of Nogo Proteins: Regulating Macrophages in Inflammatory Disease

Nogo proteins, also known as Reticulon-4, have been identified as myelin-derived inhibitors of neurite outgrowth in the central nervous system (CNS). There are three Nogo variants, Nogo-A, Nogo-B and Nogo-C. Recent studies have shown that Nogo-A/B is abundant in macrophages and may have a wider effect on inflammation. In this review, we focus mainly on the possible roles of Nogo-A/B on polarization and recruitment of macrophages and their involvement in a variety of inflammatory diseases. We then discuss the Nogo receptor1 (NgR1), a common receptor for Nogo proteins that is also abundant in microglia/macrophage in the CNS. Interaction of Nogo and NgR1 in microglia/macrophage may affect the adhesion and polarization of macrophages that are involved in multiple neurodegenerative diseases, including Alzheimer's disease and multiple sclerosis. Overall, this review provides insights into the roles of Nogo proteins in regulating macrophage functions and suggests that, potentially, Nogo proteins maybe a new target in the treatment of inflammatory diseases.

Editorial introductions

Current Opinion in Lipidology was launched in 1990. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of lipidology is divided into six sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editor for this issue. Section Editor Mohamad NavabMohamad NavabMohamad Navab is a Faculty and a co-project leader at David Geffen school of medicine, University of California Los Angeles. He obtained his PhD in biochemistry from Columbia University, in 1976. Subsequently, he served as an Assistant Professor and Head of Clinical Labs at the National University School of Medicine in Tehran, Iran. He started his research and teaching first at the UCLA Cancer Center in 1981 and subsequently at the Division of Cardiology at UCLA where he has been since 1983. Prof. Navab has received research support from NIH and has served as grant reviewer for the National Heart, Lung & Blood Institute at NIH and the American Heart Association. He serves on the editorial board and advisory board of a dozen scientific journals. Prof. Navab has authored or been a coauthor for 203 papers indexed at PubMed and has presented 171 invited national and international medical lectures. Menno de WintherMenno de WintherMenno de Winther is a Professor of vascular immune cell biology at the AMC of the Amsterdam-University Medical Centers, Amsterdam, Netherlands. Prof. de Winther graduated in biology at Utrecht University, Netherlands, and obtained his PhD in 1999 at Leiden University, Netherlands with a thesis on macrophage scavenger receptors in atherosclerosis. After completing the PhD, he was a postdoc in Oxford University, UK and Maastricht University, Netherlands and became a principal investigator studying the role of macrophages in cardiovascular disease. In 2011, Prof. de Winther was appointed as a Professor of vascular immune cell biology at the Academic Medical Center of the University of Amsterdam. Using cellular and animal models for disease, his group studies the molecular regulation of macrophages in inflammatory disease. His research particularly focuses on the transcriptional regulation of monocytes and macrophages in atherosclerosis, characterizing environmental factors (e.g. dyslipidemia, metabolic triggers, cytokines) that drives signaling pathways influencing cellular function in disease. Prof. de Winther's group was the first to define the role of the transcription factor NF-κB in atherosclerosis and more recently identified the epigenetic enzyme HDAC3 a major regulator of macrophage gene programs in atherosclerosis. Significant efforts in his group are now running on further delineating epigenetic pathways in atherosclerostic diseases. His group thrives on a combination of human and mouse cell- and animal models combined with patient studies through close interactions with the clinic. Dr de Winther is an established investigator of the Netherlands Heart Foundation and together with Dr Glass (UCSD) is currently coordinating a Leducq Transatlantic Network on epigenetics in atherosclerosis.

Modulating inflammatory macrophages with an apoptotic body-inspired nanoparticle

Macrophages play a critical role in the initiation, maintenance, and resolution of inflammation because of their diverse and plastic phenotypic responses to extracellular stimuli. Inflammatory stimuli drive the recruitment and activation of inflammatory (M1) macrophages, capable of significant cytokine production that potentiates inflammation. Local environmental signals including apoptotic cell efferocytosis drive a phenotypic transition toward pro-reparative (M2) macrophages to facilitate the resolution of inflammation. However, prolonged or dysregulated inflammatory macrophage response contributes to many disease states and tissue damage. We have developed a nanoparticle to help resolve macrophage-mediated inflammation by mimicking the anti-inflammatory effect of apoptotic cell engulfment. The nanoparticle, comprised of a poly(lactide-co-glycolide) core, is coated in phosphatidylserine (PS)-supplemented cell plasma membrane to emulate key characteristics of the apoptotic cell surface. These apoptotic body-inspired PS/membrane-coated nanoparticles (PS-MNPs) reduce inflammatory cytokine expression to promote an anti-inflammatory, phenotypic shift in macrophages in vitro, without the use of small molecule inhibitors or other drugs. Specifically, PS-MNP treatment before lipopolysaccharide (LPS)-induced inflammatory challenge resulted in a 2.5-fold reduction in secreted tumor necrosis factor α (TNFα) at 24 h, with co-treatment of PS-MNPs and LPS demonstrating a 5-fold TNFα reduction compared to LPS alone. Reduced TNFα production, as well as gene expression of several pro-inflammatory cytokines, correlated with a reduction in NFκB activation from PS-MNP treatment. The development of a nanoparticle to reduce the production of multiple inflammatory cytokines and transition away from an inflammatory macrophage phenotype, through the use of a physiologic anti-inflammatory pathway, illustrates a new potential strategy in creating anti-inflammatory therapeutics. Statement of SignificanceMacrophages propagate inflammation as the major source of cytokine production in the body. In inflammatory diseases, pro-inflammatory macrophages persist in the site of inflammation and exacerbate tissue destruction. Current anti-inflammatory drugs have significant drawbacks, including variable response rates and off-target effects. Here, we have developed an apoptotic-body inspired nanoparticle to modulate inflammatory macrophage phenotype. This polymeric nanoparticle is coated with phosphatidylserine-supplemented cell plasma membrane to mimic the anti-inflammatory effect of apoptotic cell engulfment. Nanoparticle delivery reduces inflammatory cytokine production and promotes an anti-inflammatory phenotypic macrophage shift. The capacity of these nanoparticles to help resolve macrophage-mediated inflammation may be a useful tool to study macrophage-apoptotic cell interactions, the role of macrophages in inflammatory diseases, and in the design of anti-inflammatory therapeutics.

Editorial introductions

Current Opinion in Lipidology was launched in 1990. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of lipidology is divided into six sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Mohamad NavabMohamad NavabMohamad Navab is a Faculty and a co-project leader at David Geffen school of medicine, University of California Los Angeles. He obtained his PhD in biochemistry from Columbia University, in 1976. Subsequently, he served as an Assistant Professor and Head of Clinical Labs at the National University School of Medicine in Tehran, Iran. He started his research and teaching first at the UCLA Cancer Center in 1981 and subsequently at the Division of Cardiology at UCLA where he has been since 1983. Prof. Navab has received research support from NIH and has served as grant reviewer for the National Heart, Lung & Blood Institute at NIH and the American Heart Association. He serves on the editorial board and advisory board of a dozen scientific journals. Prof. Navab has authored or been a coauthor for 203 papers indexed at PubMed and has presented 171 invited national and international medical lectures. Menno de WintherMenno de WintherMenno de Winther is a Professor of vascular immune cell biology at the AMC of the Amsterdam-University Medical Centers, Amsterdam, Netherlands. Prof. de Winther graduated in biology at Utrecht University, Netherlands, and obtained his PhD in 1999 at Leiden University, Netherlands with a thesis on macrophage scavenger receptors in atherosclerosis. After completing the PhD, he was a postdoc in Oxford University, UK and Maastricht University, Netherlands and became a principal investigator studying the role of macrophages in cardiovascular disease. In 2011, Prof. de Winther was appointed as a Professor of vascular immune cell biology at the Academic Medical Center of the University of Amsterdam. Using cellular and animal models for disease, his group studies the molecular regulation of macrophages in inflammatory disease. His research particularly focuses on the transcriptional regulation of monocytes and macrophages in atherosclerosis, characterizing environmental factors (e.g. dyslipidemia, metabolic triggers, cytokines) that drives signaling pathways influencing cellular function in disease. Prof. de Winther's group was the first to define the role of the transcription factor NF-κB in atherosclerosis and more recently identified the epigenetic enzyme HDAC3 a major regulator of macrophage gene programs in atherosclerosis. Significant efforts in his group are now running on further delineating epigenetic pathways in atherosclerostic diseases. His group thrives on a combination of human and mouse cell- and animal models combined with patient studies through close interactions with the clinic. Dr de Winther is an established investigator of the Netherlands Heart Foundation and together with Dr Glass (UCSD) is currently coordinating a Leducq Transatlantic Network on epigenetics in atherosclerosis.

Editorial introductions

Current Opinion in Lipidology was launched in 1990. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of lipidology is divided into six sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Mohamad NavabMohamad NavabMohamad Navab is a Professor of medicine and cardiology and a co-project leader at David Geffen school of Medicine, University of California Los Angeles (UCLA), USA. He obtained his PhD in biochemistry from Columbia University, New York, USA, in 1976. Subsequently, he served as an Assistant Professor and Head of Clinical Labs at the National University School of Medicine, Tehran, Iran. He started his research and teaching first at the UCLA Cancer Center in 1981 and subsequently at the Division of Cardiology at UCLA where he has been since 1983. Prof. Navab has received research support from NIH and has served as grant reviewer for the National Heart, Lung & Blood Institute at NIH and the American Heart Association. He serves on the editorial board and advisory board of a dozen scientific journals. Prof. Navab has authored or been a coauthor for 203 papers indexed at PubMed and has presented 171 invited national and international medical lectures. Menno de WintherMenno de WintherMenno de Winther is a Professor of Vascular Immune Cell Biology at the AMC of the Amsterdam-University Medical Centers, Amsterdam, Netherlands. Prof. de Winther graduated in biology at Utrecht University, Netherlands, and obtained his PhD in 1999 at Leiden University, Netherlands with a thesis on macrophage scavenger receptors in atherosclerosis. After completing the PhD, he was a postdoc in Oxford University, UK and Maastricht University, Netherlands and became a principal investigator studying the role of macrophages in cardiovascular disease. In 2011, Prof. de Winther was appointed as a Professor of Vascular Immune Cell Biology at the Academic Medical Center of the University of Amsterdam. Using cellular and animal models for disease, his group studies the molecular regulation of macrophages in inflammatory disease. His research particularly focuses on the transcriptional regulation of monocytes and macrophages in atherosclerosis, characterizing environmental factors (e.g. dyslipidemia, metabolic triggers, cytokines) that drives signaling pathways influencing cellular function in disease. Prof. de Winther's group was the first to define the role of the transcription factor NF-κB in atherosclerosis and more recently identified the epigenetic enzyme HDAC3 a major regulator of macrophage gene programs in atherosclerosis. Significant efforts in his group are now running on further delineating epigenetic pathways in atherosclerostic diseases. His group thrives on a combination of human and mouse cell- and animal models combined with patient studies through close interactions with the clinic. Dr de Winther is an established investigator of the Netherlands Heart Foundation and together with Dr Glass (UCSD) is currently coordinating a Leducq Transatlantic Network on epigenetics in atherosclerosis.

The Peritoneal Macrophages in Inflammatory Diseases and Abdominal Cancers.

Peritoneal macrophages (PMs) are the major cell type of peritoneal cells that participate in multiple aspects of innate and acquired immunity in the peritoneal cavity. PMs have an ability to release a large amount of proinflammatory and anti-inflammatory cytokines and therefore play a critical role in regulating the differentiation of innate immune cells and inflammatory T cells. Accumulating studies demonstrate that the immunological reactions and inflammatory responses of PMs are strongly related to the pathogenic processes of various inflammatory diseases and abdominal cancers. Consequently, the regulation of PM activation has gradually emerged as a promising target for immunotherapy, and better understanding of the distinctly biological function of PMs in individual diseases is crucial for designing specific and effective therapeutic agents. This review covers the characterization and immunological function of PMs in hosts with inflammatory diseases and abdominal cancers.

Metabolic features of macrophages in inflammatory diseases and cancer

Macrophages are now considered to be important players in various inflammatory diseases as well as tumor progression. Emerging evidence reveals that macrophage metabolic features are deeply associated with their immune functions. Understanding the interaction between cellular metabolism and immune signaling pathways in macrophages can help us to develop appropriate therapeutic approaches for inflammatory diseases. In this review, we briefly summarize key metabolic features of M1 and M2 macrophages as well as signaling interactions between major metabolic molecules with TLRs and NLRs. Current knowledges of cellular metabolism are focused on macrophages in various disease situations including sepsis, atherosclerosis, obesity, tuberculosis and cancer. Novel insights and present targets for regulating macrophage metabolism are also discussed.

Analysis of Antifolate Drugs with Disease Tissue Specificity

Antifolates, analogues of the essential vitamin folic acid, are used in the clinic to treat cancers and inflammatory diseases. Antifolates are primarily transported into cells via the endogenously expressed reduced folate carrier (RFC). Conversely, our collaborators in Aleem Gangjee's group at Duquesne University have synthesized antifolates (AG antifolates) that transport poorly by the RFC, but are efficiently transported by the folate receptor (hFR). The GPI-anchored hFR is lowly expressed on the apical surface in a subset of normal epithelial lineages, but is highly expressed in many cancers of epithelial origin and on activated macrophages in inflammatory disease. Therefore, AG antifolate molecules have specificity for transport into disease cells over healthy cells. These newly developed AG antifolates cause cell death via inhibition of an enzyme involved in de novo purine synthesis, glycinamide ribonucleotide (GAR) transformylase.We analyzed a series of AG antifolates using biophysical and biochemical techniques to understand both the specificity for transport by the folate receptor as well as the inhibition of the GAR transformylase in order to drive informed, hypothesis-based drug design. Our data, including pH-dependent binding profiles, enzyme inhibition data, and crystallographic models of protein in complex with AG molecules will be presented in the context of drug design and development.

Distribution and Presumed Proliferation of Macrophages in Inflammatory Diseases of the Ocular Adnexae

ABSTRACTPurpose: The aim of this article is to investigate whether macrophages show a proliferative activity (as indicated by Ki67 expression) and their distribution at the site of inflammation.Materials and Methods: Six different macrophage-containing lesions from six different patients (four females, two males; age range: 16–58 years) were stained for macrophage markers (CD68, CD163) and Ki67 by immunohistochemistry. Immunofluorescence techniques were used to investigate dual-labeling of the specimens for CD68, CD163 and Ki67, respectively.Results: With immunofluorescence staining, scattered cells in all specimens were dual-labeled for CD68–Ki67 and CD163–Ki67. All lesions were composed of mixed infiltrates of M1 (CD68+CD163−) and M2 (CD68+CD163+) macrophages. The center of epithelioid-cell granulomas and foreign body giant cells was exclusively composed of M1 macrophages.Conclusions: This study shows that CD68+ and CD163+ cells express Ki67, a marker for proliferative activity at the site of inflammation. Until recently, macrophages were regarded as end-differentiated cells without mitotic activity. Since self-renewal of M1 and M2 macrophages has been described in the literature, staining of macrophages with Ki67 may indicate proliferative activity or at least an activation state. The distribution of macrophages in classic granulomatous lesions with only M1 macrophages in the avascular center represents an immune response to foreign body material, whereas the proangiogenic M2 macrophages are located mostly in the surrounding inflammatory tissue and seem to be mandatory for the vascularization of the inflammatory tissue.

NR4A1 (Nur77) dependent monocytes patrol the lung vasculature and inhibit tumor cell invasion (P5068)

Abstract The nuclear receptor NR4A1 (Nur77) is expressed in monocytes and macrophages, yet its function in regulating inflammation associated with cancer is uncertain. Our previous studies identified that Nur77 regulates the development of patrolling Ly6C- monocytes and is involved in the resolution of inflammation. In the current study, we sought to determine how absence of Nur77 in hematopoietic cells impacts tumor growth and metastasis. Mice deficient in Nur77 showed a significant increase in growth and lung metastasis of syngeneic B16F10 melanoma. Increased tumor seeding of the lung was visible after only 4 days post IV tumor transfer, and appears to be specific to the lung. In vivo imaging reveals that Nur77-defficient mice have a drastic reduction in cells patrolling the lung vasculature, and that these patrolling monocytes establish early immune interactions with tumor cells and granulocytes in the lung. Furthermore, over-expression of Nur77 in human monocytes inhibited angiogenesis and invasion of human tumor cells in co-culture assays. We conclude that the absence of Nur77-regulated patrolling monocytes in combination with polarization of myeloid cells towards a pro-inflammatory and pro-angiogenic phenotype contributes to early tumor cell invasion of the vasculature and growth in the lung. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages in inflammatory diseases, including cancers.

Novel Therapy for Atherosclerosis Using Recombinant Immunotoxin Against Folate Receptor β–Expressing Macrophages

BackgroundFolate receptor β (FRβ) is induced during macrophage activation. A recombinant immunotoxin consisting of the truncated Pseudomonas exotoxin A (PE38) conjugated to an anti-FRβ antibody (anti–FRβ-PE38) has been reported to kill activated macrophages in inflammatory diseases. To elucidate the effect of an immunotoxin targeting FRβ on atherosclerosis, we determined the presence of FRβ-expressing macrophages in atherosclerotic lesions and administered the FRβ immunotoxin in apolipoprotein E–deficient mice.Methods and ResultsThe FRβ-expressing macrophages were observed in atherosclerotic lesions of apolipoprotein E–deficient mice. At 15 or 35 weeks of age, the apolipoprotein E–deficient mice were divided into 3 groups and were intravenously administered 0.1 mg/kg of anti–FRβ-PE38 (immunotoxin group), 0.1 mg/kg of PE38 (toxin group), or 0.1 mL of saline (control group) every 3 days, for a total of 5 times for each age group. The mice were analyzed at 21 or 41 weeks of age. Treatment with the immunotoxin resulted in 31% and 22% reductions in atherosclerotic lesions of the 21- and 41-week-old mice, respectively (P<0.05). Administration of immunotoxin reduced the numbers of FRβ- and tumor necrosis factor-α–expressing macrophages, reduced cell proliferation, and increased the number of apoptotic cells (P<0.05). Real-time polymerase chain reaction demonstrated that the expression of FRβ and tumor necrosis factor-α mRNA was significantly decreased in the immunotoxin group (P<0.05).ConclusionsThese results suggest that FRβ-expressing macrophages exist in the atherosclerotic lesions of apolipoprotein E–deficient mice and that FRβ immunotoxin administration reduces the progression of atherosclerotic lesions in younger and older individuals. The recombinant FRβ immunotoxin targeting activated macrophages could provide a novel therapeutic tool for atherosclerosis. (J Am Heart Assoc. 2012;1:e003079 doi: 10.1161/JAHA.112.003079.)

Biodegradable Polyoxalate and Copolyoxalate Particles for drug-delivery Applications

Polyoxalate and copolyoxalate were developed in the 1970s and have been used for biomedical applications such as suture coating purposes, owing to their biocompatibility and biodegradability. They are known to degrade into diols and oxalic acid, which are considered biocompatible. One of the advantages of oxalate-based polymer is the ease of control of physicochemical properties, such as biodegradability, crystallinity and mechanical strength. The composition and hydrophobicity of diols greatly influenced their hydrolytic stability and mechanical properties. Oxalate-based polymers have faster hydrolytic-degradation kinetics than the commercial biodegradable polymers, poly(lactide-co-glycolide) and poly(caprolactone). Recently, our group has developed fully biodegradable polymer drug carriers based on oxalate-based polymers that are composed of various diols. The hydrophobicity of the oxalate-based polymers allowed them to be formulated into nano- or micro-particles, which are suitable for targeting macrophages in inflammatory diseases. The nano- or micro-particles exhibited excellent cytotoxicity profiles and fast drug-release kinetics, suggesting great potential as drug-delivery systems for the treatment of acute inflammatory diseases. In this article, we discuss the synthesis and physicochemical properties of oxalate-based polymers which can be used as a drug-delivery vehicle for the treatment of inflammatory diseases.

Neurons and neuroblastoma as a source of macrophage colony-stimulating factor.

Accumulation of macrophages in brain tissue as observed in nervous system injury may be due to local production of hematopoietic colony-stimulating factors (CSF). The present work shows human neuroblastoma cells and murine neurons, namely granule cells of the cerebellum, to produce macrophage (M)-CSF which guides expansion and differentiation of macrophage lineage cells. The mRNA-encoding M-CSF but not the respective protein is present in mouse brain including cerebellum. Neither granulocyte M-CSF nor IL-3 is produced by cerebellar neurons or neuroblastoma. By their production of M-CSF, neurons may regulate the macrophage response and lead to local expansion and enhanced function of macrophages in inflammatory diseases of the central nervous system.