Different Subsets Of Macrophages Research Articles

USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus

Effective treatment of systemic lupus erythematosus (SLE) remains an unmet need. Different subsets of macrophages play differential roles in SLE and the modulation of macrophage polarization away from M1 status is beneficial for SLE therapeutics. Given the pathogenic roles of type I interferons (IFN-I) in SLE, this study investigated the effects and mechanisms of a mitochondria localization molecule ubiquitin specific peptidase 18 (USP18) preserving anti-IFN effects and isopeptidase activity on macrophage polarization. After observing USP18 induction in monocytes from SLE patients, we studied mouse bone marrow-derived macrophages and showed that USP18 deficiency increased M1signal (LPS + IFN-γ treatment)-induced macrophage polarization, and the effects involved the induction of glycolysis and mitochondrial respiration and the expression of several glycolysis-associated enzymes and molecules, such as hypoxia-inducible factor-1α. Moreover, the effects on mitochondrial activities, such as mitochondrial DNA release and mitochondrial reactive oxygen species production were observed. In contrast, the overexpression of USP18 inhibited M1signal-mediated and enhanced interleukin-4 (IL-4)-mediated polarization of macrophages and the related cellular events. Moreover, the levels of USP18 mRNA expression showed tendency of correlation with the expression of metabolic enzymes in monocytes from patients with SLE. We thus concluded that by preserving anti-IFN effect and downregulating M1 signaling, promoting USP18 activity may serve as a useful approach for SLE therapeutics.

Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia.

Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion (I/R) injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodeling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodeling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodeling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.

The effect of macrophages and their exosomes in ischemic heart disease.

Ischemic heart disease (IHD) is a leading cause of disability and death worldwide, with immune regulation playing a crucial role in its pathogenesis. Various immune cells are involved, and as one of the key immune cells residing in the heart, macrophages play an indispensable role in the inflammatory and reparative processes during cardiac ischemia. Exosomes, extracellular vesicles containing lipids, nucleic acids, proteins, and other bioactive molecules, have emerged as important mediators in the regulatory functions of macrophages and hold promise as a novel therapeutic target for IHD. This review summarizes the regulatory mechanisms of different subsets of macrophages and their secreted exosomes during cardiac ischemia over the past five years. It also discusses the current status of clinical research utilizing macrophages and their exosomes, as well as strategies to enhance their therapeutic efficacy through biotechnology. The aim is to provide valuable insights for the treatment of IHD.

CD47-targeted immunotherapy unleashes antitumour immunity in Epstein-Barr virus-associated gastric cancer

The aims of this study were to enhance the antitumour immunity in Epstein-Barr virus-associated gastric cancer (EBVaGC). We performed RNA-seq analysis to compare the differential expression genes between EBVaGC and EBV-negative gastric cancer (EBVnGC) patients. The expression levels of CD68, CD163 and CD47 were analyzed by immunohistochemistry. Different subsets of macrophages were investigated by a coincubation model. The effects of CD47 blockade were also detected. The expression levels of CD68, CD163 and CD47 were significantly higher in EBVaGC, and were associated with poor prognoses. Macrophages coincubated with EBV+ AGS cells tended to be immunosuppressed, which could be reversed by CD47 deficiency or blocking CD47. EBV resulted in cGAS-STING pathway activation, which stimulated CD47 expression and inhibited macrophage phagocytosis. Anti-CD47 therapy activated cGAS-STING signaling, which was responsible for production of IFN-β, resulting in activation of antitumour immunity. Our results provide a promising new strategy for CD47-targeted immunotherapy in EBVaGC.

Cardiac Macrophages and Their Effects on Arrhythmogenesis.

Cardiac electrophysiology is a complex system established by a plethora of inward and outward ion currents in cardiomyocytes generating and conducting electrical signals in the heart. However, not only cardiomyocytes but also other cell types can modulate the heart rhythm. Recently, cardiac macrophages were demonstrated as important players in both electrophysiology and arrhythmogenesis. Cardiac macrophages are a heterogeneous group of immune cells including resident macrophages derived from embryonic and fetal precursors and recruited macrophages derived from circulating monocytes from the bone marrow. Recent studies suggest antiarrhythmic as well as proarrhythmic effects of cardiac macrophages. The proposed mechanisms of how cardiac macrophages affect electrophysiology vary and include both direct and indirect interactions with other cardiac cells. In this review, we provide an overview of the different subsets of macrophages in the heart and their possible interactions with cardiomyocytes under both physiologic conditions and heart disease. Furthermore, we elucidate similarities and differences between human, murine and porcine cardiac macrophages, thus providing detailed information for researchers investigating cardiac macrophages in important animal species for electrophysiologic research. Finally, we discuss the pros and cons of mice and pigs to investigate the role of cardiac macrophages in arrhythmogenesis from a translational perspective.

The Distributional Characteristics of M2 Macrophages in the Placental Chorionic Villi are Altered Among the Term Pregnant Women With Uncontrolled Type 2 Diabetes Mellitus.

AimNo definite conclusions have been drawn regarding how prolonged exposure to hyperglycemia affects the distribution of macrophages in the placenta, especially in pregnant women with uncontrolled type 2 diabetes mellitus (T2DM). Herein, we explored the distributional characteristics of placental M2 macrophages, including hofbauer cells (HBCs) in the chorionic villi and decidual macrophages, in pregnant women with uncontrolled T2DM.MethodsSix healthy singleton pregnancies and five uncontrolled T2DM singleton pregnancies were collected. Multicolor immunofluorescence and immunohistochemistry were performed to record M1 macrophages by CD80 and CD86, the general M2 macrophages by CD163, M2a macrophages by CD163 and DG-SIGN, M2b macrophages by CD163 and CD86, and M2c macrophages by CD163 and CD206. Meanwhile, the monocyte marker of CD14 and the general macrophage marker of CD68 were also documented on placenta.ResultsIn the chorionic villi and decidua, the most common infiltrated macrophages was the general M2. There were only few M1 and M2b macrophages distributed in the placenta of both the healthy and uncontrolled T2DM groups. The infiltrated degree of M2c macrophages was moderate in chorionic villi and decidua. The uncontrolled T2DM and healthy pregnant women had a comparable amount of M2c macrophages infiltration in the chorionic villi (p = 0.158). Notedly, in both of the healthy and uncontrolled T2DM pregnant women, the predominant subtype of M2 macrophages in the chorionic villi was M2a, where it mainly infiltrated around vessels and syncytiotrophoblasts. The uncontrolled T2DM pregnant women had more M2a macrophage infiltration than the healthy pregnant women (p = 0.016). The M2a macrophages in the decidua of the uncontrolled T2DM group were similar to those of the normal group (p = 0.800). Meanwhile, it was in the chorionic villi but not the decidua, that the CD68+ macrophages and CD14+ M2a macrophages were also elevated in the uncontrolled T2DM group (p = 0.035 and 0.044, respectively).ConclusionThese results confirmed that the M2 macrophages exhibited increased in the chorionic villi of pregnant women with uncontrolled T2DM. The subsets of M2 macrophages in the placental decidua were similar between uncontrolled T2DM pregnant women and normal groups. It may provide a basis for exploring the functions of different subsets of macrophages in the placental chorionic villi.

Human monocyte-derived type 1 and 2 macrophages recognize Ara h 1, a major peanut allergen, by different mechanisms

Evidence has suggested that major peanut allergen Ara h 1 activates dendritic cells (DCs) via interaction with DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin), a C-type lectin receptor, and contributes to development of peanut allergy. Since macrophages, as well as DCs, play a crucial role in innate immunity, we investigated whether natural Ara h 1 (nAra h 1) activates two different subsets of macrophages, human monocyte derived macrophage type 1 (hMDM1: pro-inflammatory model) and type 2 (hMDM2: anti-inflammatory model). hMDM1 and hMDM2 predominantly produced pro-inflammatory cytokines (IL-6 and TNF-α) and an anti-inflammatory cytokine (IL-10) in response to nAra h 1, respectively. hMDM2 took up nAra h 1 and expressed DC-SIGN at higher levels than hMDM1. However, small interfering RNA knockdown of DC-SIGN did not suppress nAra h 1 uptake and nAra h 1-mediated cytokine production in hMDM2. Inhibitors of scavenger receptor class A type I (SR-AI) suppressed the response of hMDM2, but not of hMDM1, suggesting that SR-AI is a major receptor in hMDM2 for nAra h 1 recognition and internalization. nAra h 1 appears to exert stimulatory capacity on DC and macrophages via different receptors. This study advances our understanding how a major peanut allergen interacts with innate immunity.

The Role of Macrophages in Vascular Repair and Regeneration after Ischemic Injury

Macrophage is one of the important players in immune response which perform many different functions during tissue injury, repair, and regeneration. Studies using animal models of cardiovascular diseases have provided a clear picture describing the effect of macrophages and their phenotype during injury and regeneration of various vascular beds. Many data have been generated to demonstrate that macrophages secrete many important factors including cytokines and growth factors to regulate angiogenesis and arteriogenesis, acting directly or indirectly on the vascular cells. Different subsets of macrophages may participate at different stages of vascular repair. Recent findings also suggest a direct interaction between macrophages and other cell types during the generation and repair of vasculature. In this short review, we focused our discussion on how macrophages adapt to the surrounding microenvironment and their potential interaction with other cells, in the context of vascular repair supported by evidences mostly from studies using hindlimb ischemia as a model for studying post-ischemic vascular repair.

From the Editor’s Desk: September 2019

From the Editor’s Desk: September 2019

Ironing out Macrophage Immunometabolism.

Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. In this context, iron metabolism has been recognized as an important component of macrophage plasticity. Since macrophages control the availability of this essential metal, changes in the expression of genes coding for the major proteins of iron metabolism may result in different iron availability for the macrophage itself and for other cells in the microenvironment. In this review, we discuss how macrophage iron can also play a role in immunometabolism.

CD16A-Specific Tetravalent Bispecific Immune Cell Engagers Potently Induce Antibody-Dependent Cellular Phagocytosis (ADCP) on Macrophages

IntroductionAffimed has developed high affinity tetravalent bispecific immune cell engagers for redirected optimized cell killing (ROCK platform). Using anti-CD16A and anti-tumor target-specific antibody domains, the engagers activate NK cells to efficiently kill target cells. The most advanced ROCK-based immune cell engager, AFM13, targeting CD30 on tumor cells and CD16A on immune effectors, is currently being evaluated in several clinical trials to treat CD30-positive malignancies.Based on the fact that CD16A is not exclusively expressed on NK cells, but also on macrophages, we hypothesized that CD16A-specific immune cell engagers would also be able to activate CD16A expressing macrophages through antibody-dependent cellular phagocytosis (ADCP) contributing to anti-tumor response.Macrophages are an essential component of the innate immune system and are a major constituent of normal tissues. They can be broadly classified into different subtypes including M1 (classically activated, generally characterized as pro-inflammatory and immuno-supportive) and M2 (alternatively activated, primarily of an anti-inflammatory profile) subtypes. Those subtypes greatly differ in their phenotype and function and appear to be highly plastic. While M1 macrophages are generally considered to be tumoricidal, M2 macrophages are mostly tumorigenic, depending on their context within the tumor microenvironment. Therapeutic agents focusing on macrophages such as the CD47/SIRPa axis, CSF-1R antibodies and elimination of tumor-associated macrophages (TAMs) have recently come into focus in immuno-oncology.MethodsPeripheral monocytes derived from primary human hematopoietic cells of healthy donors were used to generate various macrophage subtypes (unpolarized macrophages, M1, M2a, M2c) in vitro using well-defined cytokine cocktails. These subtypes were characterized phenotypically for their CD16A expression and a wide number of additional markers. Subsequently, they were used to investigate the ability of a number of different CD16A-specific immune cell engagers derived from Affimed´s ROCK platform and control antibodies in vitro to activate and induce ADCP of target cells by flow cytometry and microscopy.ResultsWe demonstrated that all of the macrophage subtypes generated in this study expressed CD16A and mediated ADCP of tumor cells. In addition, we showed that ADCP of tumor cells by several CD16A-specific engagers was both fast and robust for all investigated macrophage subtypes. Specifically, ADCP was detected as early as 2 hours after co-incubation of tumor cells with M1 or M2 macrophages and CD16A-specific immune cell engagers. Using appropriate control antibodies, it was demonstrated that ADCP mediated by CD16A-specific immune cell engagers was selective and at least as potent as ADCP mediated by classical monoclonal antibodies pan-specific for Fc-gamma receptors.Summary and conclusion:We have demonstrated a new mechanism whereby Affimed´s CD16A-specific immune cell engaging antibodies eliminate tumor cells by ADCP, mediated by different subsets of macrophages. Our data suggest that these antibodies may have the potential to boost tumoricidal function within the tumor microenvironment. Future directions of leveraging innate immunity as a therapeutic option in immuno-oncology will be presented. DisclosuresWingert:Affimed: Employment. Reusch:Affimed: Employment. Beez:Affimed: Employment. Pahl:Affimed: Research Funding. Cerwenka:Affimed: Research Funding; Dragonfly Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Koch:Affimed GmbH: Employment. Treder:Affimed GmbH: Employment.

Increased salt exposure affects both lymphoid and myeloid effector functions, influencing innate-associated disease but not T-cell-associated autoimmunity.

High salt consumption has since long been associated with elevated blood pressure and cardiovascular disease. Recently, mouse studies suggested that a high dietary salt intake exacerbates the clinical manifestations of autoimmunity. Using naïve cells ex vivo after pre-exposure of mice to high salt intake, we showed that increased salt exposure affects the viability and effector functions of immune cells. CD4+ T-cells evidenced a pro-inflammatory phenotype characterized by increased secretion of IFNγ and IL-17A, when exposed to high salt concentrations in vitro. Interestingly, this phenotype was associated with osmotic pressure, as replacing salt for d-mannitol resulted in similar observations. However, high salt intake did not alter the development of T-cell-dependent autoimmunity. Instead, recruitment of peritoneal macrophages was increased in mice pre-exposed to high salt concentrations. These cells had an increased production of both TNFα and IL-10, suggesting that salt stimulates expansion and differentiation of different subsets of macrophages. Moreover, mice pre-exposed to high salt intake developed exacerbated symptoms of colitis, when induced by dextran sulphate sodium. The aggravated colitis in salt-exposed animals was associated with a higher frequency of CD4+ T-cells and CD11b+ CD64+ macrophages producing TNFα. These phenotypes correlated with elevated titres of faecal IgA and higher lymphocytic cellularity in the colon, mesenteric lymph nodes and spleen. In conclusion, we report here that high salt intake affects both lymphoid and myeloid cells ex vivo. However, the effects of high salt intake in vivo seem less pronounced in terms of CD4+ T-cell responses, whereas macrophage-dependent pathologies are significantly influenced.

β2 Integrins Regulate Migratory Properties of M1 and M2 Macrophages during Inflammation

BackgroundThe development of chronic inflammation depends on the balance between accumulation of pro‐inflammatory, classically activated (M1) and alternatively activated (M2) macrophages within the injured tissue. The mesenchymal migration and accumulation of macrophages in the inflamed sites largely depend on myeloid‐specific αMβ2 and αDβ2 integrins, which share similar ligands but have different densities on different subsets of macrophages. The level of integrin expression regulates cell migration. Namely, a low‐intermediate expression supports cell motility, while a high expression generates strong adhesion that prevents cell migration. In this project, we tested how αMβ2 and αDβ2 integrins are involved in the migration and retention of M1 and M2 macrophages at the site of inflammation.Method and ResultsTo test our hypothesis, wild type (WT), αD−/− and αM−/− mice were intraperitoneally injected with thioglycollate to generate macrophages. Isolated macrophages were treated with IFN‐γ and IL‐4 for 4 days to activate M1 and M2 phenotypes, respectively. Integrin levels on macrophages were evaluated by qPCR and FACS. We found that the expression of αD was strongly upregulated on M1 macrophages, but not on M2 macrophages, while the level of αM remained unchanged on both subsets. To test the effect of integrins on the migration of M1 and M2 macrophages, we labeled cells with red and green fluorescent dyes and applied in vitro migration assay in 3D fibrin matrix.Our results showed that WT M2 macrophages possess significantly stronger migratory properties compared to WT M1 macrophages. To understand the contribution of individual integrins we used αD−/− and αM−/− macrophages. The results demonstrated that while αM‐deficiency had no significant effect, αD‐deficiency improved the migration of M1 macrophages. In contrast, both αD‐ and αM‐deficiency reduced the migration of M2 macrophages. To verify these results, we tested in vivo macrophage migration using the model of resolution of peritoneal inflammation. M1 and M2 macrophages, labeled with red and green fluorescent dyes respectively, were injected into the peritoneal cavity of mice with induced peritoneal inflammation. After 3 days, we evaluated the ability of macrophages to emigrate from the peritoneal cavity to lymphatics. Our results corresponded to our in vitro migratory assay. M2 macrophages emigrate significantly faster, αD‐deficiency improves the efflux of M1 macrophages and αD‐ and αM‐deficiency reduced the emigration of M2 macrophages.ConclusionTaken together, these data suggest that integrin αM, which has an intermediate expression on M1 and M2 macrophages, supports macrophage migration. In contrast, integrin αD, which has a high expression on M1 macrophages, prevents the migration of these cells and can promote the retention of M1 macrophages in the inflamed sites. Therefore, integrin αD is a potential therapeutic target to prevent pro‐inflammatory macrophage accumulation and development of chronic inflammation.Support or Funding InformationThis project is funded by NIH and the project number is 5R01DK102020‐05This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Macrophages and Their Contribution to the Development of Atherosclerosis.

Atherosclerosis can be regarded as chronic inflammatory disease driven by lipid accumulation in the arterial wall. Macrophages play a key role in the development of local inflammatory response and atherosclerotic lesion growth. Atherosclerotic plaque is a complex microenvironment, in which different subsets of macrophages coexist executing distinct, although in some cases overlapping functions. According to the classical simplified nomenclature, lesion macrophages can belong to pro-inflammatory or anti-inflammatory or alternatively activated types. While the former promote the inflammatory response and participate in lipid accumulation, the latter are responsible for the inflammation resolution and plaque stabilisation. Atherosclerotic lesion dynamics depends therefore on the balance between these macrophages populations. The diverse functions of macrophages make them an attractive therapeutic target for the development of novel anti-atherosclerotic treatments. In this chapter, we discuss different types of macrophages and their roles in atherosclerotic lesion dynamics and describe the results of several experiments studying macrophage polarisation in atherosclerosis.

A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo

AbstractExtravascular fibrin deposition accompanies many human diseases and causes chronic inflammation and organ damage, unless removed in a timely manner. Here, we used intravital microscopy to investigate how fibrin is removed from extravascular space. Fibrin placed into the dermis of mice underwent cellular endocytosis and lysosomal targeting, revealing a novel intracellular pathway for extravascular fibrin degradation. A C-C chemokine receptor type 2 (CCR2)-positive macrophage subpopulation constituted the majority of fibrin-uptaking cells. Consequently, cellular fibrin uptake was diminished by elimination of CCR2-expressing cells. The CCR2-positive macrophage subtype was different from collagen-internalizing M2-like macrophages. Cellular fibrin uptake was strictly dependent on plasminogen and plasminogen activator. Surprisingly, however, fibrin endocytosis was unimpeded by the absence of the fibrin(ogen) receptors, αMβ2 and ICAM-1, the myeloid cell integrin-binding site on fibrin or the endocytic collagen receptor, the mannose receptor. The study identifies a novel fibrin endocytic pathway engaged in extravascular fibrin clearance and shows that interstitial fibrin and collagen are cleared by different subsets of macrophages employing distinct molecular pathways.

Erythrophagocytosis by plasmacytoid dendritic cells and monocytes is enhanced during inflammation.

Generation of antibodies against red blood cell (RBC) antigens can be a clinically significant problem. The underlying mechanisms that regulate the production of RBC antibodies are only partially understood; however, factors such as inflammation significantly increase the rates of RBC antibody generation. Humoral alloimmunization begins with consumption of transfused RBCs by antigen-presenting cells (APCs). Recently, it has become appreciated that there are multiple different types of APCs. The relative contribution of APC subsets to RBC antibodies has not been described in either the quiescent or the inflamed states. To evaluate the types of APCs that consume RBCs, and how inflammation affects this process, C56Bl/6 mice were treated with polyinosinic-polycytidylic acid (poly(I:C)) to induce an inflammatory response and/or were transfused with 3,3'-dihexadecyloxacarbocyanine perchlorate-labeled syngeneic RBCs. Erythrophagocytosis (both at baseline and during inflammation) was analyzed for different subsets of macrophages (MΦ), dendritic cells (DCs), B cells, and monocytes, by a combined approach using flow cytometry and fluorescent microscopy technology. In four independent experiments, erythrophagocytosis at baseline was predominately performed by red pulp MΦ; however, during inflammation both plasmacytoid DCs (pDCs) and monocytes increased RBC consumption. Furthermore, pDCs up regulated MHC-II and activation markers CD80 and CD86. In addition to changing patterns of erythrophagocytosis, inflammation also led to a significant decrease in CD11c+ conventional DC populations and an increase in granulocytes. The nature of APCs that consume transfused RBCs is changed by inflammation. Given that APCs initiate humoral immune responses, these findings provide potential mechanistic insight into how inflammation regulates RBC alloimmunization.

A Higher Frequency of CD14+ CD169+ Monocytes/Macrophages in Patients with Colorectal Cancer.

ObjectiveMonocytes and macrophages can infiltrate into tumor microenvironment and regulate the progression of tumors. This study aimed at determining the frequency of different subsets of circulating monocytes and tumor infiltrating macrophages (TIMs) in patients with colorectal cancer (CRC).MethodsThe frequency of different subsets of circulating monocytes was characterized in 46 CRC patients and 22 healthy controls (HC) by flow cytometry. The frequency of different subsets of macrophages was analyzed in TIMs from 30 tumor tissues and in lamina propria mononuclear cells (LPMCs) from 12 non-tumor tissues. The concentrations of plasma cytokines and carcinoembryonic antigen (CEA) were determined. The potential association of these measures with the values of clinical parameters was analyzed.ResultsIn comparison with that in the HC, the percentages of circulating CD14+CD169+, CD14+CD169+CD163+ and CD14+CD169+CD206+ monocytes and TIMs CD14+CD169+ as well as IL-10+CD14+CD169+, but not IL-12+ CD14+CD169+ macrophages were significantly increased, accompanied by higher levels of plasma IL-10 in the CRC patients. The percentages of CD14+CD169+ circulating monocytes and TIM macrophages were associated with the stage of disease and correlated positively with the levels of plasma IL-10 and CEA in CRC patients.ConclusionOur data suggest that an increase in the frequency of CD14+CD169+ cells may be associated with the development and progression of CRC and is concomitant rise of both, pro-tumor (M2-like, IL-10 producing) and anti-tumor (M1-like, IL-12 producing) monocytes and infiltrating macrophages. The frequency of CD14+CD169+ circulating monocytes and infiltrating macrophages may serve as a biomarker for evaluating the pathogenic degrees of CRC.

IL-34- and M-CSF-induced macrophages switch memory T cells into Th17 cells via membrane IL-1α.

Macrophages orchestrate the immune response via the polarization of CD4(+) T helper (Th) cells. Different subsets of macrophages with distinct phenotypes, and sometimes opposite functions, have been described. M-CSF and IL-34 induce the differentiation of monocytes into IL-10(high) IL-12(low) immunoregulatory macrophages, which are similar to tumor-associated macrophages (TAMs) in ovarian cancer. In this study, we evaluated the capacity of human macrophages induced in the presence of M-CSF (M-CSF macrophages) or IL-34 (IL-34 macrophages) and ovarian cancer TAMs to modulate the phenotype of human CD4(+) T cells. Taken together, our results show that M-CSF-, IL-34 macrophages, and TAMs switch non-Th17 committed memory CD4(+) T cells into conventional CCR4(+) CCR6(+) CD161(+) Th17 cells, expressing or not IFN-gamma. Contrary, the pro-inflammatory GM-CSF macrophages promote Th1 cells. The polarization of memory T cells into Th17 cells is mediated via membrane IL-1α (mIL-1α), which is constitutively expressed by M-CSF-, IL-34 macrophages, and TAMs. This study elucidates a new mechanism that allows macrophages to maintain locally restrained and smoldering inflammation, which is required in angiogenesis and metastasis.

Dynamic Aspects of Macrophage Polarization during Atherosclerosis Progression and Regression.

It is well recognized that macrophages in many contexts in vitro and in vivo display a spectrum of inflammatory features and functional properties. A convenient system to group together different subsets of macrophages has been the M1 (inflammatory)/M2 (anti-inflammatory) classification. In addition to other sites of inflammation, it is now established that atherosclerotic plaques contain both M1 and M2 macrophages. We review results made possible by a number of recent mouse models of atherosclerotic regression that, taken with other literature, have shown the M1/M2 balance in plaques to be dynamic, with M1 predominating in disease progression and M2 in regression. The regulation of the macrophage phenotype in plaques and the functional consequences of the M1 and M2 states in atherosclerosis will also be discussed.

Different Subsets of Macrophages in Patients with New Onset Tuberculous Pleural Effusion

ObjectiveMacrophages are the infiltrate components of tuberculous pleural effusion (TPE). This study is aimed at examining the role of different subsets of macrophages in pleural fluid (PF) and peripheral blood (PB) from patients with new onset TPE.MethodsThe numbers of PB and PF CD163+, CD206+ and CD115+ macrophages in 25 patients with new onset TPE and 17 healthy controls (HC) were determined by flow cytometry. The concentrations of serum and PF cytokines were determined by cytometric bead array (CBA) and enzyme-linked immunosorbentassay (ELISA). The potential association between the numbers of different subsets of macrophages and the values of clinical measures in TPE patients were analyzed.ResultsThe numbers of PB CD14+CD163− M1-like and CD14+CD163− interleukin (IL)-12+ M1 macrophages were significantly higher than that in the HC, but lower than PF, and the numbers of PF CD14+CD163+, CD14+CD163+CD206+, CD14+CD163+CDll5+ M2-like, and CD14+CD163+IL-10+ M2 macrophages were less than PB in the TPE patients. The levels of serum IL-1, IL-6, IL-8, IL-12, tumor growth factor (TGF)-β1, and tumor necrosis factor (TNF)-α in the TPE patients were significantly higher than that in the HC, but lower than that in the PF. The levels of PF IL-10 were significantly higher than that in the PB of patients and HC. In addition, the levels of serum IL-12 and TNF-α were correlated positively with the values of erythrocyte sedimentation rate (ESR) and the numbers of ESAT-6- and culture filtrate protein 10 (CFP-10)-specific IFN-γ-secreting T cells, and the levels of PF TNF-α were correlated positively with the levels of PF adenosine deaminase (ADA) and lactate dehydrogenase (LDH) in those patients.ConclusionOur data indicate that Mycobacterium tuberculosis (M. tb) infection induces M1 predominant pro-inflammatory responses, contributing to the development of TPE in humans.