Activation State Of Macrophages Research Articles

Cellular uptake of mesoporous silica particles is governed by activation state of macrophages

Cellular uptake of mesoporous silica particles is governed by activation state of macrophages

Identification of multiple cellular uptake pathways of polystyrene nanoparticles and factors affecting the uptake: Relevance for drug delivery systems

Nanoparticles may address challenges by human diseases through improving diagnosis, vaccination and treatment. The uptake mechanism regulates the type of threat a particle poses on the host cells and how a cell responds to it. Hence, understanding the uptake mechanisms and cellular interactions of nanoparticles at the cellular and subcellular level is a prerequisite for their effective biomedical applications. The present study shows the uptake mechanisms of polystyrene nanoparticles and factors affecting their uptake in bone marrow-derived macrophages, 293T kidney epithelial cells and L929 fibroblasts. Labeling with the endocytic marker FM4-64 and transmission electron microscopy studies show that the nanoparticles were internalized rapidly via endocytosis and accumulated in intracellular vesicles. Soon after their internalizations, nanoparticles trafficked to organelles with acidic pH. Analysis of the ultrastructural morphology of the plasma membrane invaginations or extravasations provides clear evidence for the involvement of several uptake routes in parallel to internalize a given type of nanoparticles by mammalian cells, highlighting the complexity of the nanoparticle–cell interactions. Blocking the specific endocytic pathways by different pharmacological inhibitors shows similar outcomes. The potential to take up nanoparticles varies highly among different cell types in a particle sizes-, time- and energy-dependent manner. Furthermore, infection and the activation status of bone marrow-derived macrophages significantly affect the uptake potential of the cells, indicating the need to understand the diseases’ pathogenesis to establish effective and rational drug-delivery systems. This study enhances our understanding of the application of nanotechnology in biomedical sciences.

Generation of BTNL8+ Inducible Tregs By Allogeneic Human Regulatory Macrophages Is IDO- and B7-Dependent.

Purpose: This study identifies the phenotypic and functional changes that human T cells undergo when exposed to regulatory macrophages. Methods: Human regulatory macrophages (M regs) represent a unique and stable state of macrophage activation, characterized by their ability to suppress activated T cells. M regs arise from CD14+ monocytes over a 6-day culture period in the presence of M-CSF, human serum, and a final 24-hour pulse of IFN-γ. In preclinical models, pre-transplant administration of donor-derived M regs prolonged allograft survival. This graft-protective effect initially depended upon metabolically-competent cells, but persisted beyond the lifespan of the M regs, implying regulation of recipient T cells by M regs. Here, mechanisms by which human M regs influence allogeneic T cell responses in vitro are examined. Results: Phenotypic and functional changes imposed by human M regs on allogeneic T cells were investigated by flow cytometry, whole-genome gene expression profiling, and secondary suppression assays. After exposure to M regs, CD4+ T cells were induced to express FoxP3, CD25, CTLA4, OX40, GITR, ICOS, EBI3, and BTNL8. Such FoxP3+ T cells generated in M reg cocultures suppressed polyclonal T cell proliferation and inhibited TNFα-induced dendritic cell maturation. The Treg-specific demethylated region (TSDR) of the FOXP3 gene in M reg-cocultured CD4+ T cells was 5% demethylated. The M reg-induced regulatory T cell (Treg) phenotype was not alloantigen-dependent, but was contact-dependent, and could be abolished by B7 blockade with CTLA4-Ig or by indoleamine 2,3-dioxygenase (IDO) inhibition with 1 mM 1-L-methyltryptophan. Tacrolimus and rapamycin did not affect FoxP3+ T cell development. Conclusions: M regs drive an antigen non-specific, B7- and contact-dependent induction of activated induced Tregs through a mechanism partially dependent on IDO. This finding supports the concept that pre-transplant treatment of recipients with donor-derived M regs engenders a pro-tolerogenic state and hints at a feedforward mechanism by which it could be perpetuated. Clinical applications of M reg immunosuppressive therapy are currently being pursued within The ONE Study framework.

Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma.

BackgroundThe mechanisms by which viruses cause asthma exacerbations are not precisely known. Previously, we showed that, in ovalbumin (OVA)-sensitized and -challenged mice with allergic airway inflammation, rhinovirus (RV) infection increases type 2 cytokine production from alternatively-activated (M2) airway macrophages, enhancing eosinophilic inflammation and airways hyperresponsiveness. In this paper, we tested the hypothesis that IL-4 signaling determines the state of macrophage activation and pattern of RV-induced exacerbation in mice with allergic airways disease.MethodsEight week-old wild type or IL-4 receptor knockout (IL-4R KO) mice were sensitized and challenged with OVA and inoculated with RV1B or sham HeLa cell lysate.ResultsIn contrast to OVA-treated wild-type mice with both neutrophilic and eosinophilic airway inflammation, OVA-treated IL-4R KO mice showed increased neutrophilic inflammation with few eosinophils in the airways. Like wild-type mice, IL-4R KO mice showed OVA-induced airway hyperreactivity which was further exacerbated by RV. There was a shift in lung cytokines from a type 2-predominant response to a type 1 response, including production of IL-12p40 and TNF-α. IL-17A was also increased. RV infection of OVA-treated IL-4R KO mice further increased neutrophilic inflammation. Bronchoalveolar macrophages showed an M1 polarization pattern and ex vivo RV infection increased macrophage production of TNF-α, IFN-γ and IL-12p40. Finally, lung cells from OVA-treated IL-4R KO mice showed reduced CD206+ CD301+ M2 macrophages, decreased IL-13 and increased TNF-α and IL-17A production by F4/80+, CD11b+ macrophages.ConclusionsOVA-treated IL-4R KO mice show neutrophilic airway inflammation constituting a model of allergic, type 1 cytokine-driven neutrophilic asthma. In the absence of IL-4/IL-13 signaling, RV infection of OVA-treated mice increased type 1 cytokine and IL-17A production from conventionally-activated macrophages, augmenting neutrophilic rather than eosinophilic inflammation. In mice with allergic airways inflammation, IL-4R signaling determines macrophage activation state and the response to subsequent RV infection.

Neuroinflammation and M2 microglia: the good, the bad, and the inflamed.

The concept of multiple macrophage activation states is not new. However, extending this idea to resident tissue macrophages, like microglia, has gained increased interest in recent years. Unfortunately, the research on peripheral macrophage polarization does not necessarily translate accurately to their central nervous system (CNS) counterparts. Even though pro- and anti-inflammatory cytokines can polarize microglia to distinct activation states, the specific functions of these states is still an area of intense debate. This review examines the multiple possible activation states microglia can be polarized to. This is followed by a detailed description of microglial polarization and the functional relevance of this process in both acute and chronic CNS disease models described in the literature. Particular attention is given to utilizing M2 microglial polarization as a potential therapeutic option in treating diseases.

Expression of P2X family receptors in peritoneal macrophages of mouse with acute T lymphoblastic leukemia

This study was aimed at exploring the expression pattern of P2X family receptors (P2XR) in peritoneal macrophages and their relationship with the activation states of macrophages in Notch1-induced mouse T-ALL model. After establishment of the leukemia model, F4/80(+) peritoneal macrophages, F4/80(+)CD206(+) M2-like and F4/80(+)CD206(-) M1-like peritoneal macrophages were sorted by flow cytometry based on F4/80 and CD206 surface markers. The expression of P2XR in each cell population was detected by real time RT-PCR. The results showed that macrophages,M1-like and M2-like macrophages moderately expressed P2XR except for P2X5R. The expression of P2XR varied with the development of leukemia. The expression of P2X1R and P2X7R in peritoneal macrophages increased steadily; the expression of P2X2R and P2X3R decreased at late stage of leukemia;the expression of P2X4R slightly decreased at intermediate stage;the expression of P2X6R kept unchanged. At intermediate stage of leukemia, the expression of P2XR in M1-like and M2-like peritoneal macrophages varied. M1-like macrophages expressed higher level of P2X1R than M2-like macrophages, whereas M2-like macrophages expressed higher level of P2X7R than M1-like macrophages, which suggested that the expression of P2XR were related to the activation states. It is concluded that the expression of P2XR in peritoneal macrophages from leukemia mice is related to the progression of leukemia and the activation states of macrophages, which lay a foundation for further studying the role of macrophages in the development of leukemia.

Human macrophage polarization in vitro: Maturation and activation methods compared

Macrophages form a heterogeneous cell population displaying multiple functions, and can be polarized into pro- (M1) or anti-inflammatory (M2) macrophages, by environmental factors. Their activation status reflects a beneficial or detrimental role in various diseases. Currently several in vitro maturation and activation protocols are used to induce an M1 or M2 phenotype. Here, the impact of different maturation factors (NHS, M-CSF, or GM-CSF) and activation methods (IFN-γ/LPS, IL-4, dexamethason, IL-10) on the macrophage phenotype was determined. Regarding macrophage morphology, pro-inflammatory (M1) activation stimulated cell elongation, and anti-inflammatory (M2) activation induced a circular appearance. Activation with pro-inflammatory mediators led to increased CD40 and CD64 expression, whereas activation with anti-inflammatory factors resulted in increased levels of MR and CD163. Production of pro-inflammatory cytokines was induced by activation with IFN-γ/LPS, and TGF-β production was enhanced by the maturation factors M-CSF and GM-CSF. Our data demonstrate that macrophage marker expression and cytokine production in vitro is highly dependent on both maturation and activation methods. In vivo macrophage activation is far more complex, since a plethora of stimuli are present. Hence, defining the macrophage activation status ex vivo on a limited number of markers could be indecisive. From this study we conclude that maturation with M-CSF or GM-CSF induces a moderate anti- or pro-inflammatory state respectively, compared to maturation with NHS. CD40 and CD64 are the most distinctive makers for human M1 and CD163 and MR for M2 macrophage activation and therefore can be helpful in determining the activation status of human macrophages ex vivo.

NOX2 protects against progressive lung injury and multiple organ dysfunction syndrome.

Systemic inflammatory response syndrome (SIRS) is a common clinical condition in patients in intensive care units that can lead to complications, including multiple organ dysfunction syndrome (MODS). MODS carries a high mortality rate, and it is unclear why some patients resolve SIRS, whereas others develop MODS. Although oxidant stress has been implicated in the development of MODS, several recent studies have demonstrated a requirement for NADPH oxidase 2 (NOX2)-derived oxidants in limiting inflammation. We recently demonstrated that NOX2 protects against lung injury and mortality in a murine model of SIRS. In the present study, we investigated the role of NOX2-derived oxidants in the progression from SIRS to MODS. Using a murine model of sterile systemic inflammation, we observed significantly greater illness and subacute mortality in gp91(phox-/y) (NOX2-deficient) mice compared with wild-type mice. Cellular analysis revealed continued neutrophil recruitment to the peritoneum and lungs of the NOX2-deficient mice and altered activation states of both neutrophils and macrophages. Histological examination showed multiple organ pathology indicative of MODS in the NOX2-deficient mice, and several inflammatory cytokines were elevated in lungs of the NOX2-deficient mice. Overall, these data suggest that NOX2 function protects against the development of MODS and is required for normal resolution of systemic inflammation.

Identification of Candida glabrata genes involved in pH modulation and modification of the phagosomal environment in macrophages.

Candida glabrata currently ranks as the second most frequent cause of invasive candidiasis. Our previous work has shown that C. glabrata is adapted to intracellular survival in macrophages and replicates within non-acidified late endosomal-stage phagosomes. In contrast, heat killed yeasts are found in acidified matured phagosomes. In the present study, we aimed at elucidating the processes leading to inhibition of phagosome acidification and maturation. We show that phagosomes containing viable C. glabrata cells do not fuse with pre-labeled lysosomes and possess low phagosomal hydrolase activity. Inhibition of acidification occurs independent of macrophage type (human/murine), differentiation (M1-/M2-type) or activation status (vitamin D3 stimulation). We observed no differential activation of macrophage MAPK or NFκB signaling cascades downstream of pattern recognition receptors after internalization of viable compared to heat killed yeasts, but Syk activation decayed faster in macrophages containing viable yeasts. Thus, delivery of viable yeasts to non-matured phagosomes is likely not triggered by initial recognition events via MAPK or NFκB signaling, but Syk activation may be involved. Although V-ATPase is abundant in C. glabrata phagosomes, the influence of this proton pump on intracellular survival is low since blocking V-ATPase activity with bafilomycin A1 has no influence on fungal viability. Active pH modulation is one possible fungal strategy to change phagosome pH. In fact, C. glabrata is able to alkalinize its extracellular environment, when growing on amino acids as the sole carbon source in vitro. By screening a C. glabrata mutant library we identified genes important for environmental alkalinization that were further tested for their impact on phagosome pH. We found that the lack of fungal mannosyltransferases resulted in severely reduced alkalinization in vitro and in the delivery of C. glabrata to acidified phagosomes. Therefore, protein mannosylation may play a key role in alterations of phagosomal properties caused by C. glabrata.

Alternatively activated macrophages as therapeutic agents for kidney disease: in vivo stability is a key factor

Infusing ex vivo-generated alternatively activated macrophages (AAM) has shown promise in experimental systems as a therapeutic strategy for inflammatory kidney disease. In the mouse Adriamycin nephropathy model, however, Cao et al. report that AAM derived from bone marrow precursors fail to ameliorate disease severity. Absence of the anticipated protective effect resulted from a loss of macrophage anti-inflammatory (M2) phenotype following trafficking to injured kidney-an effect that was mediated by localized colony-stimulating factor-1-dependent macrophage proliferation.

Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation

SummaryMacrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.

Macrophage-mediated injury and repair after ischemic kidney injury

Acute ischemic kidney injury is a common complication in hospitalized patients. No treatment is yet available for augmenting kidney repair or preventing progressive kidney fibrosis. Animal models of acute kidney injury demonstrate that activation of the innate immune system plays a major role in the systemic response to ischemia/reperfusion injury. Macrophage depletion studies suggest that macrophages, key participants in the innate immune response, augment the initial injury after reperfusion but also promote tubular repair and contribute to long-term kidney fibrosis after ischemic injury. The distinct functional outcomes seen following macrophage depletion at different time points after ischemia/reperfusion injury suggest heterogeneity in macrophage activation states. Identifying the pathways that regulate the transitions of macrophage activation is thus critical for understanding the mechanisms that govern both macrophage-mediated injury and repair in the postischemic kidney. This review examines our understanding of the complex and intricately controlled pathways that determine monocyte recruitment, macrophage activation, and macrophage effector functions after renal ischemia/reperfusion injury. Careful delineation of repair and resolution pathways could provide therapeutic targets for the development of effective treatments to offer patients with acute kidney injury.

Macrophage Activation and Patterns of Inflammation in Obese and Non-Obese Women with Breast Carcinoma

Tumor-associated macrophages (TAMs) with M2 phenotype provide an immunosuppressive microenvironment for tumor growth. In contrast, A great deal of evidence indicates that macrophages in obese patients' adipose tissue undergo a phenotypic change from M2 to Ml polarization accelerating adipose tissue inflammation. Interestingly, obesity is considered a major risk factor for breast cancer. Here, we report a case-control study comparing normal-weight and obese women with breast cancer. Activation states of macrophages and patterns of inflammation associated to breast invasive ductal carcinoma were analyzed by immunohistochemistry. iNOS positive macrophages were counted as a Ml polarized population. Our study demonstrates that classically activated macrophages in obese patients outnumber classically activated macrophages in the breast of non-obese patients with infiltrating ductal carcinoma. However, cancer cell linked factors may strongly antagonize Ml macrophages' positive effects by both stimulating their switching to M2 TAMs and inhibiting their effects.

Macrophages migrate in an activation-dependent manner to chemokines involved in neuroinflammation

BackgroundIn neuroinflammatory diseases, macrophages can play a dual role in the process of tissue damage, depending on their activation status (M1 / M2). M1 macrophages are considered to exert damaging effects to neurons, whereas M2 macrophages are reported to aid regeneration and repair of neurons. Their migration within the central nervous system may be of critical importance in the final outcome of neurodegeneration in neuroinflammatory diseases e.g. multiple sclerosis (MS). To provide insight into this process, we examined the migratory capacity of human monocyte-derived M1 and M2 polarised macrophages towards chemoattractants, relevant for neuroinflammatory diseases like MS.MethodsPrimary cultures of human monocyte-derived macrophages were exposed to interferon gamma and lipopolysaccharide (LPS) to evoke proinflammatory (M1) activation or IL-4 to evoke anti-inflammatory (M2) activation. In a TAXIScan assay, migration of M0, M1 and M2 towards chemoattractants was measured and quantified. Furthermore the adhesion capacity and the expression levels of integrins as well as chemokine receptors of M0, M1 and M2 were assessed. Alterations in cell morphology were analysed using fluorescent labelling of the cytoskeleton.ResultsSignificant differences were observed between M1 and M2 macrophages in the migration towards chemoattractants. We show that M2 macrophages migrated over longer distances towards CCL2, CCL5, CXCL10, CXCL12 and C1q compared to non-activated (M0) and M1 macrophages. No differences were observed in the adhesion of M0, M1 and M2 macrophages to multiple matrix components, nor in the expression of integrins and chemokine receptors. Significant changes were observed in the cytoskeleton organization upon stimulation with CCL2, M0, M1 and M2 macrophages adopt a spherical morphology and the cytoskeleton is rapidly rearranged. M0 and M2 macrophages are able to form filopodia, whereas M1 macrophages only adapt a spherical morphology.ConclusionsTogether our results indicate that the alternative activation status of macrophages promotes their migratory properties to chemoattractants relevant for neuroinflammatory diseases like MS. Conversely, classically activated, proinflammatory macrophages have reduced migratory properties. Based on our results, we postulate that the activation status of the macrophage influences the capacity of the macrophages to rearrange their cytoskeleton. This is the first step in understanding how modulation of macrophage activation affects macrophage migration in neuroinflammatory diseases like MS.

Effect of low-level laser therapy on the modulation of the mitochondrial activity of macrophages.

BACKGROUND: Macrophages play a major role among the inflammatory cells that invade muscle tissue following an injury. Low-level laser therapy (LLLT) has long been used in clinical practice to accelerate the muscle repair process. However, little is known regarding its effect on macrophages. OBJECTIVE: This study evaluated the effect of LLLT on the mitochondrial activity (MA) of macrophages. METHOD: J774 macrophages were treated with lipopolysaccharide (LPS) and interferon - gamma (IFN-γ) (activation) for 24 h to simulate an inflammatory process, then irradiated with LLLT using two sets of parameters (780 nm; 70 mW; 3 J/cm2 and 660 nm; 15 mW; 7.5 J/cm2). Non-activated/non-irradiated cells composed the control group. MA was evaluated by the cell mitochondrial activity (MTT) assay (after 1, 3 and 5 days) in three independent experiments. The data were analyzed statistically. RESULTS: After 1 day of culture, activated and 780 nm irradiated macrophages showed lower MA than activated macrophages, but activated and 660 nm irradiated macrophages showed MA similar to activated cells. After 3 days, activated and irradiated (660 nm and 780 nm) macrophages showed greater MA than activated macrophages, and after 5 days, the activated and irradiated (660 nm and 780 nm) macrophages showed similar MA to the activated macrophages. CONCLUSIONS: These results show that 660 nm and 780 nm LLLT can modulate the cellular activation status of macrophages in inflammation, highlighting the importance of this resource and of the correct determination of its parameters in the repair process of skeletal muscle.

Identification of a Unique Hybrid Macrophage-Polarization State following Recovery from Lipopolysaccharide Tolerance

LPS tolerance is an essential immune-homeostatic response to repeated exposure to LPS that prevents excessive inflammatory responses. LPS tolerance induces a state of altered responsiveness in macrophages, resulting in repression of proinflammatory gene expression and increased expression of factors that mediate the resolution of inflammation. In this study, we analyzed the transcriptional plasticity of macrophages following LPS tolerance using genome-wide transcriptional profiling. We demonstrate that LPS tolerance is a transient state and that the expression of proinflammatory genes is restored to levels comparable to the acute response to LPS. However, following recovery from LPS tolerance a number of genes remained locked in a tolerizable state, including IL-33, CD86, IL-10, and NFIL3. Furthermore, we identified of a number of genes uniquely induced following recovery from LPS tolerance. Thus, macrophages adopt a unique transcriptional profile following recovery from LPS tolerance and have a distinct expression pattern of regulators of Ag presentation, antiviral responses, and transcription factors. Our data suggest that recovery from LPS tolerance leads to a hybrid macrophage activation state that is proinflammatory and microbicidal in nature but that possesses a regulatory anti-inflammatory profile distinct from that of LPS-tolerant and LPS-activated macrophages.

Nutritional impacts on gene expression in the surface mucosa of blue catfish (Ictalurus furcatus)

Short-term feed deprivation is a common occurrence in both wild and farmed fish species, due to reproductive processes, seasonal variations in temperature, or in response to a disease outbreak. Fasting can have dramatic physiological and biological consequences for fish, including impacts on mucosal immunity which can, in turn, change host susceptibility to pathogens. Culture and selection of blue catfish (Ictalurus furcatus) has gained importance as the production of a channel catfish×blue catfish (Ictalurus punctatus×I. furcatus) hybrid has increased in the Southeast US. Following a recent examination of fasting-induced impacts on mucosal immunity in channel catfish, here we utilized Illumina-based RNA-seq expression profiling to compare changes in blue catfish gill and skin after a brief (7day) period of fasting. Transcriptome sequencing and de novo assembly of over 194million 100base-pair transcript reads was followed by differential expression analysis. Fasting altered a total of 530genes in the surface mucosa, including genes regulating the immune response, energy metabolism, mucus production, cellular cytoskeletal structure, cell proliferation, and antioxidant responses. In particular, fasting perturbed arginine synthesis and metabolism pathways in a manner likely altering macrophage activation states and immune readiness. Our findings highlight key mediators of the critical interaction between nutrition and immunity at points of pathogen adherence and entry.

Macrophage–Cryptococcus Interactions: An Update

Cryptococcus species are fungal pathogens that are a leading cause of mortality. Initial inoculation is through the pulmonary route and, if disseminated, results in severe invasive infection including meningoencephalitis. Macrophages are the dominant phagocytic cell that interacts with Cryptococcus. Emerging theories suggest that Cryptococcus microevolution in macrophages is linked to survival and virulence within the host. In addition, Cryptococcus elaborates virulence factors as well as usurps host machinery to establish macrophage activation states that are permissive to intracellular survival and replication. In this review, we provide an update of the recent findings pertaining to macrophage interaction with Cryptococcus and focus on new avenues for biomedical research.

Metabolic syndrome: variations on the theme of inflammation

“It is too violent to gather up the four movements of such different characters under the name of Sonata! But this piece is incredibly beautiful...” This historic quote was made by Robert Schumann in reference to the second piano sonata by Frederic Chopin that contains the famous funeral march. When experiencing the sonata for the first time, one may feel that this piece is somewhat “slippery”, as the association between the movements appears obscure due to the musical independency and distinctive color of each movement. However, after having heard the whole piece, one will no longer find any cracks in the artistic structure and will be fully convinced that the four movements form a definite complex. In fact, this is brought about by the common motif with a minor third , which is used throughout the sonata in the form of various metaphors; thus, it is not obvious at first glance. This motif links all the movements, thereby providing unity to the masterpiece. The prominent increase in the incidence of obesity in modern society has been caused by rapid and extreme changes in lifestyle, particularly eating habits. Obesity induces multiple diseases, each of which threatens our health and is a burden on medical expenses. Examples includes type 2 diabetes, atherosclerosis followed by cardiovascular complications, fatty liver diseases giving rise to liver fibrosis and cancer, and, interestingly, autoimmune diseases. At a glance, these diseases appear independent of each other: the pathogenesis of each disease is distinctive, the major affected organ in each disease is different, and each disease is treated and studied by its own specialists. However, all these diseases are manifestations of metabolic syndrome, which is the most talked about disease complex in modern society. In this sense, the relationship between metabolic syndrome and its associated diseases is reminiscent of the second sonata by Chopin and its four movements. Then, what is the minor third motif that mechanistically links all these different diseases? Accumulating evidence indicates that the answer to this question is inflammation. The breakthrough in understanding the events which bridge obesity and its associated diseases was brought about by the discovery that the chronic, low-grade inflammation observed in obese adipose tissue is responsible for triggering insulin resistance. In recent years, it has become clear that infiltration of a large number of classically activated inflammatory macrophages (M1 macrophages) into adipose tissue is responsible for obesity-associated inflammation. Lean adipose tissue contains a resident population of alternatively activated macrophages (M2 macrophages), which can suppress inflammation in both adipocytes and macrophages themselves, partly via secreting interleukin 10. Hence, obesity induces a switch in the macrophage activation state in adipose tissue toward M1 polarization, which induces inflammation. Such subclinical inflammation of adipose tissue is closely associated with insulin resistance not only in adipose tissue, but also systemically, thus contributing to the development of multiple obesity-induced metabolic and cardiovascular diseases. In this issue, the authors introduce eight variations of obesity-associated disease linked by the motif of inflammation. Arai et al. discuss adipose tissue macrophage recruitment with a focus on the newly identified role of apoptosis inhibitor of macrophage (AIM), a macrophage-derived blood protein initially identified as an apoptosis inhibitor that supports macrophage survival. Under obese conditions, augmented blood AIM is incorporated into adipocytes via CD36-mediated endocytosis and induces vigorous lipolysis. The authors show how this AIM-induced lipolytic response influences the This article is a contribution to the special issue onMetabolic Syndrome Guest Editor: T. Miyazaki

Comparative analysis of resistant and susceptible macrophage gene expression response to Leishmania majorparasite

BackgroundLeishmania are obligated intracellular pathogens that replicate almost exclusively in macrophages. The outcome of infection depends largely on parasite pathogenicity and virulence but also on the activation status and genetic background of macrophages. Animal models are essential for a better understanding of pathogenesis of different microbes including Leishmania.ResultsHere we compared the transcriptional signatures of resistant (C57BL/6) and susceptible (BALB/c) mouse bone marrow-derived macrophages in response to Leishmania major (L. major) promastigotes infection.Microarray results were first analyzed for significant pathways using the Kyoto Encylopedia of Genes and Genomes (KEGG) database. The analysis revealed that a large set of the shared genes is involved in the immune response and that difference in the expression level of some chemokines and chemokine receptors could partially explain differences in resistance. We next focused on up-regulated genes unique to either BALB/c or C57BL/6 derived macrophages and identified, using KEGG database, signal transduction pathways among the most relevant pathways unique to both susceptible and resistant derived macrophages. Indeed, genes unique to C57BL/6 BMdMs were associated with target of rapamycin (mTOR) signaling pathway while a range of genes unique to BALB/c BMdMs, belong to p53 signaling pathway. We next investigated whether, in a given mice strain derived macrophages, the different up-regulated unique genes could be coordinately regulated. Using GeneMapp Cytoscape, we showed that the induced genes unique to BALB/c or C57BL/6 BMdMs are interconnected. Finally, we examined whether the induced pathways unique to BALB/c derived macrophages interfere with the ones unique to C57BL/6 derived macrophages. Protein-protein interaction analysis using String database highlights the existence of a cross-talk between p53 and mTOR signaling pathways respectively specific to susceptible and resistant BMdMs.ConclusionsTaken together our results suggest that strains specific pathogenesis may be due to a difference in the magnitude of the same pathways and/or to differentially expressed pathways in the two mouse strains derived macrophages. We identify signal transduction pathways among the most relevant pathways modulated by L. major infection, unique to BALB/c and C57BL/6 BMdM and postulate that the interplay between these potentially interconnected pathways could direct the macrophage response toward a given phenotype.