Aberrant Polarization Research Articles

Inhibition of differentiation of monocyte-derived macrophages toward an M2-Like phenotype May Be a neglected mechanism of β-AR receptor blocker therapy for atherosclerosis.

The clinical efficacy of adrenergic β-receptor (β-AR) blockers in significantly stabilizing atherosclerotic plaques has been extensively supported by evidence-based medical research; however, the underlying mechanism remains unclear. Recent findings have highlighted the impact of lipid-induced aberrant polarization of macrophages during normal inflammatory-repair and regenerative processes on atherosclerosis formation and progression. In this review, we explore the relationship between macrophage polarization and atherosclerosis, as well as the influence of β-AR blockers on macrophage polarization. Based on the robust evidence supporting the use of β-AR blockers for treating atherosclerosis, we propose that their main mechanism involves inhibiting monocyte-derived macrophage differentiation towards an M2-like phenotype.

Spatial Engineering of Mammary Epithelial Cell Cultures with 3D Bioprinting Reveals Growth Control by Branch Point Proximity

The three-dimensional (3D) structure of the ductal epithelium and the surrounding extracellular matrix (ECM) are integral aspects of the breast tissue, and they have important roles during mammary gland development, function and malignancy. However, the architecture of the branched mammary epithelial network is poorly recapitulated in the current in vitro models. 3D bioprinting is an emerging approach to improve tissue-mimicry in cell culture. Here, we developed and optimized a protocol for 3D bioprinting of normal and cancerous mammary epithelial cells into a branched Y-shape to study the role of cell positioning in the regulation of cell proliferation and invasion. Non-cancerous cells formed continuous 3D cell networks with several organotypic features, whereas the ductal carcinoma in situ (DCIS) –like cancer cells exhibited aberrant basal polarization and defective formation of the basement membrane (BM). Quantitative analysis over time demonstrated that both normal and cancerous cells proliferate more at the branch tips compared to the trunk region of the 3D-bioprinted cultures, and particularly at the tip further away from the branch point. The location-specific rate of proliferation was independent of TGFβ signaling but invasion of the DCIS-like breast cancer cells was reduced upon the inhibition of TGFβ. Thus, our data demonstrate that the 3D-bioprinted cells can sense their position in the branched network of cells and proliferate at the tips, thus recapitulating this feature of mammary epithelial branching morphogenesis. In all, our results demonstrate the capacity of the developed 3D bioprinting method for quantitative analysis of the relationships between tissue structure and cell behavior in breast morphogenesis and cancer.

M6A-Mediated Upregulation of Imprinted in Prader-Willi Syndrome Induces Aberrant Apical-Basal Polarization and Oxidative Damage in RPE Cells.

To reveal the clinical significance, pathological involvement and molecular mechanism of imprinted in Prader-Willi syndrome (IPW) in RPE anomalies that contribute to AMD. IPW expression under pathological conditions were detected by microarrays and qPCR assays. In vitro cultured fetal RPE cells were used to study the pathogenicity induced by IPW overexpression and to analyze its upstream and downstream regulatory networks. We showed that IPW is upregulated in the macular RPE-choroid tissue of dry AMD patients and in fetal RPE cells under oxidative stress, inflammation and dedifferentiation. IPW overexpression in fetal RPE cells induced aberrant apical-basal polarization as shown by dysregulated polarized markers, disrupted tight and adherens junctions, and inhibited phagocytosis. IPW upregulation was also associated with RPE oxidative damages, as demonstrated by intracellular accumulation of reactive oxygen species, reduced cell proliferation, and accelerated cell apoptosis. Mechanically, N6-methyladenosine level of the IPW transcript regulated its stability with YTHDC1 as the reader. IPW mediated RPE features by suppressing MEG3 expression to sequester its inhibition on the AKT serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) pathway. We also noticed that the mTOR inhibitor rapamycin suppresses the AKT/mTOR pathway to alleviate the IPW-induced RPE anomalies. We revealed that IPW overexpression in RPE induces aberrant apical-basal polarization and oxidative damages, thus contributing to AMD progression. We also annotated the upstream and downstream regulatory networks of IPW in RPE. Our findings shed new light on the molecular mechanisms of RPE dysfunctions, and indicate that IPW blockers may be a promising option to treat RPE abnormalities in AMD.

Advancements in Macrophage-Targeted Drug Delivery for Effective Disease Management.

Macrophages play a crucial role in tissue homeostasis and the innate immune system. They perform essential functions such as presenting antigens, regulating cytokines, and responding to inflammation. However, in diseases like cancer, cardiovascular disorders, and autoimmune conditions, macrophages undergo aberrant polarization, which disrupts tissue regulation and impairs their normal behavior. To address these challenges, there has been growing interest in developing customized targeted drug delivery systems specifically designed for macrophage-related functions in different anatomical locations. Nanomedicine, utilizing nanoscale drug systems, offers numerous advantages including improved stability, enhanced pharmacokinetics, controlled release kinetics, and precise temporal drug delivery. These advantages hold significant promise in achieving heightened therapeutic efficacy, specificity, and reduced side effects in drug delivery and treatment approaches. This review aims to explore the roles of macrophages in major diseases and present an overview of current strategies employed in targeted drug delivery to macrophages. Additionally, this article critically evaluates the design of macrophage-targeted delivery systems, highlighting limitations and discussing prospects in this rapidly evolving field. By assessing the strengths and weaknesses of existing approaches, we can identify areas for improvement and refinement in macrophage-targeted drug delivery.

Resveratrol-loaded nanoplatform RSV@DTPF promote alveolar bone regeneration in OVX rat through remodeling bone-immune microenvironment

The reconstruction of alveolar bone defect is essential for periodontal regenerative therapy or subsequent prosthetic/implant therapy, particularly in individuals with systemic diseases, such as osteoporosis. ROS accumulation, coupled with aberrant macrophage polarization, is pivotal in the pathogenesis of osteoporosis and contributes to the disequilibrium between bone and the immune system. Consequently, therapeutic strategies targeting the immune microenvironment present a promising approach to the treatment of in situ alveolar bone regeneration in osteoporotic condition. Herein, we present a novel nano platform denoted as RSV@DTPF, designed to target macrophage and facilitate the controllable release of resveratrol in a ROS-responsive behavior. This approach aims to modulate the tampered immune microenvironment. The conjugated folate moiety selectively interacts with the folate receptors expressed on the macrophage surface, thereby augmenting cellular uptake. While the thioketal bond would break down when sensing a high level of intracellular ROS and release the encapsulated RSV. In vitro experiments suggested that designated nanoparticles could scavenge ROS effectively and restore the M1/M2 ratio in a lipopolysaccharide (LPS) -stimulated inflammation environment; The co-culture experiment provided evidence substantiating the adeptness of the modified immune milieu in fostering osteoblast differentiation, while concurrently impeding osteoclast maturation. Furthermore, through comprehensive imaging and histopathological evaluations, we elucidate the potential of RSV@DTPF in promoting osteogenesis within a periodontal defect model utilizing ovariectomized (OVX) rats. This in vivo study substantiates the advantageous impact of the nanoplatform on alveolar bone regeneration and its associated immunomodulatory effects. In summary, the RSV@DTPF nanoplatform exhibited the capacity to orchestrate immune microenvironmental shifts and enhance alveolar bone generation ability in osteoporosis and also could be expected to be applied in other biomedical fields associated with redox metabolism imbalance.

CTRP6 regulates M1 macrophage polarization via the PPAR-γ/NF-κB pathway and reprogramming glycolysis in recurrent spontaneous abortion

Aberrant polarization and functions of decidual macrophages are closely related to recurrent spontaneous abortion (RSA). C1q/tumor necrosis factor-related protein 6 (CTRP6) is a member of the adiponectin paralog family, and plays indispensable roles in inflammation, glucose uptake and tumor metastasis. However, the regulatory effect of CTRP6 on macrophage polarization and glycolysis in RSA and the underlying mechanisms have not been fully elucidated. In the present study, we first found that CTRP6 expression was positively correlated with the M1 macrophage marker (CD86) in decidual tissues by dual immunofluorescence analysis. In vitro experiments indicated that CTRP6 could facilitate M1 macrophage activation through the PPAR-γ/NF-κB pathway and manipulate the glycolysis of macrophages. Notably, in addition to silencing CTRP6, treatment with a PPAR-γ agonist (GW1929) inhibited M1 macrophage polarization and rescued embryo absorption in vivo. Taken together, these results identify previously unrevealed functions of CTRP6 in macrophage transformation during RSA.

Loss of polarity regulators initiates gasdermin-E-mediated pyroptosis in syncytiotrophoblasts.

The syncytiotrophoblast is a human epithelial cell that is bathed in maternal blood on the maternal-facing surface of the human placenta. It therefore acts as a barrier and exchange interface between the mother and fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy pathologies, like preeclampsia. Dysfunctional syncytiotrophoblasts display a loss of microvilli, which is a marker of aberrant apical-basal polarization, but little data exist about the regulation of syncytiotrophoblast polarity. Atypical PKC isoforms are conserved polarity regulators. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using human placental explant culture and primary trophoblasts, we found that loss of aPKC activity or expression induces syncytiotrophoblast gasdermin-E-dependent pyroptosis, a form of programmed necrosis. We also establish that TNF-α induces an isoform-specific decrease in aPKC expression and gasdermin-E-dependent pyroptosis. Therefore, aPKCs are homeostatic regulators of the syncytiotrophoblast function and a pathogenically relevant pro-inflammatory cytokine leads to the induction of programmed necrosis at the maternal-fetal interface. Hence, our results have important implications for the pathobiology of placental disorders like preeclampsia.

Proliferation, Plasticity, and Migration: Exploring the synergistic relationship between eosinophils and TH2 cells in development of HES-like syndrome

Abstract Aberrancies in eosinophil proliferation, activation and chemotaxis can lead to acute eosinophilic leukemia, paraneoplastic eosinophilia associated with T cell lymphoma and carcinomas, and Hypereosinophilic Syndrome (HES), respectively. HES is an idiopathic disease affecting humans and veterinary patients characterized by persistent eosinophilia (>1,500 cells/uL) and eosinophilic infiltration of solid organs leading to increased morbidity and mortality. Previous studies have demonstrated the role of NF-κB inducing kinase, NIK, an upstream regulator of the noncanonical NF-κB signaling pathway, in development of a HES-like syndrome due to aberrant TH2 polarization in the Nik−/−murine model. However, the intricacies of eosinophilic granulopoiesis, eosinophil/neutrophil plasticity, and chemotactic ability has not been assessed during development of HES-like syndrome in Nik−/−mice. Here we show that loss of NIK potentially enhances eosinophilic chemotaxis to CCL11, enhances eosinophilic/neutrophilic plasticity, and affects granulopoiesis in the bone marrow and spleen beginning at the level of eosinophilic metamyelocytes, despite potentially decreasing the proliferative potential of these cells. Taken together, these results suggest that NIK and the noncanonical NF-κB signaling pathway plays a role in dictating the hematopoietic and chemotactic potential of eosinophils and highlights a synergistic relationship with TH2 cells and their respective cytokines during development of HES-like syndrome in Nik−/−mice. Overall, these findings warrant further study to better characterize the synergistic relationship described above to better understand development of HES and HES-like diseases. Virginia-Maryland College of Veterinary Medicine and the Institute for Critical Technology and Applied Science

Aryl polyenes expressed by Uropathogenic Escherichia colicontribute to pathogenesis in a mouse model with an aberrant macrophage polarization

Abstract Uropathogenic Escherichia coli (UPEC) is a causative agent of urinary tract infections (UTIs), and one of the most common causes of pyelonephritis. Interestingly, UPEC is often found as a non-pathobiont in the gut flora. The transition from gut flora to pathogen for UPEC is dependent upon a flexible tropism, and a number of virulence factors that aid in UPEC’s colonization and invasion of the urinary tract. We recently demonstrated a role for the E. coli aryl polyenes (APEs) as a potential UPEC fitness factor. The current hypothesis is that APEs contribute to UPEC virulence in the host system. APEs are encoded by a biosynthetic gene cluster (BGC) family identified among many gram-negative bacteria. The products of this BGC family are lipids comprised of an aryl head group and conjugated double bond system, which are structurally reminiscent of established virulence factors found in gram-positives. In addition to the structural mimicry, UPEC APE expression conferred resistance to reactive oxygen species and enhanced biofilm formation. In a UTI mouse model, infection with UPEC that constitutively expressed APEs (UPEC APE+) increased pathogenicity. Transcriptomic analyses of in vitro co-incubation experiments indicates that UPEC APE+exposure influences the macrophage gene transcription profile differently as compared to UPEC WT. Taken together, our findings suggest that APE expression aids in bacterial virulence and immune modulation during infection. Therefore, targeting the biosynthetic gene product APE may be a viable therapeutic approach to reduce fitness of pathogenic populations while leaving commensal gut microflora unharmed and minimize tissue damage. NIAID RO1AI153173 Cleveland Clinic Foundation

Aberrant Naive CD4-Positive T Cell Differentiation in Systemic Juvenile Idiopathic Arthritis Committed to B Cell Help.

Systemic juvenile idiopathic arthritis (JIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. In this study, we hypothesized that aberrant or incomplete polarization of T helper cells contributes to disease pathology. Cells or serum samples were obtained from healthy controls (n=72) and systemic JIA patients (n=171). Isolated naive T helper cells were cultured under Th1, Th17, and T follicular helper (Tfh) or T peripheral helper (Tph)-polarizing conditions and were partly cocultured with allogenic memory B cells. Cell samples were then analyzed for surface marker, transcription factor, and cytokine expression, as well as plasmablast generation. Serum samples were subjected to multiplexed bead and self-antigen arrays and enzyme-linked immunosorbent assays, and all data were compared to retrospective RNA profiling analyses. Differentiation of systemic JIA-naive T helper cells toward Th1 cells resulted in low expression levels of interferon-γ (IFNγ) and eomesodermin, which was associated in part with disease duration. In contrast, developing Th1 cells in patients with systemic JIA were found to produce elevated levels of interleukin-21 (IL-21), which negatively correlated with cellular expression of IFNγ and eomesodermin. In both in vitro and ex vivo analyses, IL-21 together with programmed cell death 1 (PD-1), inducible T cell costimulator (ICOS), and CXCR5 expression induced naive T helper cells from systemic JIA patients to polarize toward a Tfh/Tph cell phenotype. Retrospective analysis of whole-blood RNA-sequencing data demonstrated that Bcl-6, a master transcription factor in Tfh/Tph cell differentiation, was overexpressed specifically in patients with systemic JIA. Naive T helper cells from systemic JIA patients which were stimulated in vitro promoted B cellular plasmablast generation, and self-antigen array data indicated that IgG reactivity profiles of patients with systemic JIA differed from those of healthy controls. In the pathogenesis of systemic JIA, skewing of naive T helper cell differentiation toward a Tfh/Tph cell phenotype may represent an echo of autoimmunity, which may indicate the mechanisms driving progression toward chronic destructive arthritis.

PlGF/FLT-1 deficiency leads to reduced STAT3-C/EBPβ signaling and aberrant polarization in decidual macrophages during early spontaneous abortion.

Dysregulated macrophage polarization (excessive M1-like or limited M2-like macrophages) in the early decidua contributes to allogeneic fetal rejection and thus early spontaneous abortion. However, the modulators of M1/M2 balance at the early maternal-fetal interface remain mostly unknown. First-trimester decidual tissues were collected from normal pregnant women undergoing elective pregnancy terminations and patients with spontaneous abortion. We measured the expression of placental growth factor (PlGF) and Fms-like-tyrosine-kinase receptor 1 (FLT-1), and characterized the profiles of macrophages in decidua. Notably, we investigated the effect of recombinant human PlGF (rhPlGF) on decidual macrophages (dMφs) from normal pregnancy and revealed the underlying mechanisms both in vitro and in vivo. The downregulated expression of PlGF/ FLT-1 may result in spontaneous abortion by inducing the M1-like deviation of macrophages in human early decidua. Moreover, the CBA/J×DBA/2 abortion-prone mice displayed a lower FLT-1 expression in uterine macrophages than did CBA/J×BALB/c control pregnant mice. In in vitro models, rhPlGF treatment was found to drive the M2-like polarization of dMφs via the STAT3/CEBPB signaling pathway. These findings were further supported by a higher embryo resorption rate and uterine macrophage dysfunction in Pgf knockout mice, in addition to the reduced STAT3 transcription and C/EBPβ expression in uterine macrophages. PlGF plays a key role in early pregnancy maintenance by skewing dMφs toward an M2-like phenotype via the FLT-1-STAT3-C/EBPβ signaling pathway. Excitingly, our results highlight a rationale that PlGF is a promising target to prevent early spontaneous abortion.

Targeting Drug to MACROPHAGES for Enhance Healing Efficacy of Enclosed Drug : AIDS

Targeted drug shipping to the macrophages seems to be an appealing proposition to enhance healing efficacy of enclosed drug. Thus, macrophages may be exploited as Trojan horses for centered drug shipping. Nanocarriers can migrate throughout the specific membrane barriers and launch their drug shipment at sites of infection. Macrophages play a key function in protecting in opposition to overseas pathogens, recuperation wounds, and regulating tissue homeostasis. Driving this versatility is their phenotypic plasticity, which permits macrophages to reply to subtle cues in tightly coordinated ways. However, whilst this coordination is disrupted, macrophages can resource the development of severa diseases, which includes cancer, cardiovascular disease, and autoimmune disease. The central hyperlink among those problems is aberrant macrophage polarization, which misguides their purposeful programs, secretory products, and law of the encircling tissue microenvironment. As a end result in their crucial and deterministic roles in each fitness and disease, macrophages have received large interest as targets for drug shipping. Here, we speak the function of macrophages withinside the initiation and development of diverse inflammatory diseases, summarize the main capsules used to alter macrophages, and evaluate drug shipping structures designed to goal macrophages. We emphasize techniques which are authorised for medical use or are poised for medical investigation. Finally, we offer a prospectus of the destiny of macrophage-centered drug shipping structures. Destruction of CD4 T cells is taken into consideration to be the principal reason of immunodeficiency manifested through opportunistic infections in HIV-1-inflamed humans, as properly as in SIV-inflamed macaques. We recommend that monocyte/ macrophage lineage cells additionally play an crucial function in the pathogenesis of AIDS, primarily based totally on our current work with the SIV/rhesus macaque animal model. We recommend that harm to CD4 T cells is crucial and simply apparent, however harm to monocyte/macrophage lineage cells, despite the fact that much less obvious, may also offer the lacking hyperlink to are expecting the onset of opportunistic infections and development to AIDS.

Role of spindle pole body component 25 in neurodegeneration.

BackgroundAberrant growth and polarization of microglia are critical for pathological initiation and progression of neurodegenerative conditions like Alzheimer’s disease (AD). However, the molecular signals that govern the outgrowth of microglia have not yet been fully determined. Spindle pole body component 25 (SPC25) is an important part for forming NDC80 complex, which plays a key role in the assembly of the microtubule-binding domain of kinetochores. Nevertheless, the role of SPC25 in microglial growth during neurodegeneration has not been described before, and was thus addressed in the current study.MethodsWe generated an adeno-associated virus (AAV) serotype PHP.B carrying short hairpin RNA (shRNA) for SPC25 (shSPC25) under a microglia-specific TMEM119 promoter (AAV-pTMEM-shSPC25). Serotype PHP.B allowed the virus to cross blood-brain barrier, while TMEM119 promoter allowed specific targeting microglia in vitro and in vivo. We intravenously administrated AAV-pTMEM-shSPC25 to AD-prone APP/PS1 male and female mice and determined this effect on microglia proliferation and mouse behavior.ResultsDepletion of SPC25 did not alter polarization of microglia cell polarization in vitro. On the other hand, AD-prone APP/PS1 mice that had received AAV-pTMEM-shSPC25 significantly decreased SPC25 levels in microglia and attenuated microglia proliferation, resulting in significant improvement of the performance of the mice in behavior tests.ConclusionsSpecific depletion of SPC25 in microglia may prevent AD development through suppression of microglia outgrowth. SPC25 may be a promising novel target for preventing AD through microglia.

MiRNA Landscape in Pathogenesis and Treatment of Vogt-Koyanagi-Harada Disease.

miRNAs, one of the members of the noncoding RNA family, are regulators of gene expression in inflammatory and autoimmune diseases. Changes in miRNA pool expression have been associated with differentiation of CD4+ T cells toward an inflammatory phenotype and with loss of self-tolerance in autoimmune diseases. Vogt–Koyanagi–Harada (VKH) disease is a chronic multisystemic pathology, affecting the uvea, inner ear, central nervous system, and skin. Several lines of evidence support an autoimmune etiology for VKH, with loss of tolerance against retinal pigmented epithelium-related self-antigens. This deleterious reaction is characterized by exacerbated inflammation, due to an aberrant TH1 and TH17 polarization and secretion of their proinflammatory hallmark cytokines interleukin 6 (IL-6), IL-17, interferon γ, and tumor necrosis factor α, and an impaired CD4+ CD25high FoxP3+ regulatory T cell function. To restrain inflammation, VKH is pharmacologically treated with corticosteroids and immunosuppressive drugs as first and second line of therapy, respectively. Changes in the expression of miRNAs related to immunoregulatory pathways have been associated with VKH development, whereas some genetic variants of miRNAs have been found to be risk modifiers of VKH. Furthermore, the drugs commonly used in VKH treatment have great influence on miRNA expression, including those miRNAs associated to VKH disease. This relationship between response to therapy and miRNA regulation suggests that these small noncoding molecules might be therapeutic targets for the development of more effective and specific pharmacological therapy for VKH. In this review, we discuss the latest evidence regarding regulation and alteration of miRNA associated with VKH disease and its treatment.

Soluble CD83 suppresses experimental food allergy via regulating aberrant T helper 2 responses.

Aberrant T helper-2 (Th2) responses play a critical role in the pathogenesis of allergic diseases. The underlying mechanism is to be further investigated. It is reported that soluble CD83 (sCD83) has immune-regulatory effects. This study aims to investigate the role of sCD83 in the regulation of Th2 polarization. Blood samples were collected from pediatric patients with food allergy (FA). The Th2 response was analyzed by pertinent immunological approaches. An FA murine model was developed to test the role of sCD83 in the regulation of FA response. We found that the serum sCD83 levels were lower in FA patients. A negative correlation was detected between serum sCD83 levels and serum Th2 cytokine levels. The presence of sCD83 suppressed Th2 cell differentiation and antigen-specific Th2 cell activation. sCD83 upregulated the T-bet expression and suppressed the GATA3 expression in CD4+ T cells. Administration of sCD83 suppressed experimental FA. Pediatric FA patients have low serum sCD83 levels. Administration of sCD83 can alleviate experimental FA via suppression of aberrant Th2 polarization.

Drug delivery to macrophages: A review of targeting drugs and drug carriers to macrophages for inflammatory diseases.

Macrophages play a key role in defending against foreign pathogens, healing wounds, and regulating tissue homeostasis. Driving this versatility is their phenotypic plasticity, which enables macrophages to respond to subtle cues in tightly coordinated ways. However, when this coordination is disrupted, macrophages can aid the progression of numerous diseases, including cancer, cardiovascular disease, and autoimmune disease. The central link between these disorders is aberrant macrophage polarization, which misguides their functional programs, secretory products, and regulation of the surrounding tissue microenvironment. As a result of their important and deterministic roles in both health and disease, macrophages have gained considerable attention as targets for drug delivery. Here, we discuss the role of macrophages in the initiation and progression of various inflammatory diseases, summarize the leading drugs used to regulate macrophages, and review drug delivery systems designed to target macrophages. We emphasize strategies that are approved for clinical use or are poised for clinical investigation. Finally, we provide a prospectus of the future of macrophage-targeted drug delivery systems.

Correction: Bcl2L12 Contributes to Th2-Biased Inflammation in the Intestinal Mucosa by Regulating CD4+ T Cell Activities.

The Th2-biased inflammation and immune deregulation play a critical role in the pathogenesis of ulcerative colitis (UC). Recent studies indicate that the Bcl2-like protein 12 (Bcl2L12) is associated with immune deregulation of UC. This study aims to investigate the role of Bcl2L12 in the induction of aberrant Th2-biased inflammation. In this study, peripheral blood samples were collected from patients with inflammatory bowel disease. The Th2 cell activities were analyzed by flow cytometry, real-time quantitative RT-PCR, and Western blotting. Mice with Bcl2L12-knockout CD4+ T cells were used in the experiments. The results showed that the expression of Bcl2L12 was detected in peripheral CD4+ T cells, which was significantly higher in UC patients than in healthy subjects. A positive correlation between the expression of Bcl2L12 and Th2 cytokines was detected in CD4+ T cells from UC patients. Naive CD4+ T cells with Bcl2L12 overexpression were prone to differentiate into Th2 cells. Mice with Bcl2L12 deficiency failed to induce the Th2-biased inflammation in the intestine. Bcl2L12 bound GATA3 to form a complex to enhance the binding between GATA3 and the Il4 promoter to enhance the expression of IL-4 in CD4+ T cells. CD4+ T cells with Bcl2L12 overexpression were resistant to apoptosis. In conclusion, the Bcl2L12 is a critical factor in the induction of aberrant Th2 polarization by upregulating Th2 responses and downregulating Th2 cell apoptosis. Bcl2L12 may be a novel therapeutic target in the management of the disorders with Th2-biased inflammation.

Oxidative stress and macrophages: driving forces behind exacerbations of asthma and chronic obstructive pulmonary disease?

Oxidative stress is a common feature of obstructive airway diseases like asthma and chronic obstructive pulmonary disease (COPD). Lung macrophages are key innate immune cells that can generate oxidants and are known to display aberrant polarization patterns and defective phagocytic responses in these diseases. Whether these characteristics are linked in one way or another and whether they contribute to the onset and severity of exacerbations in asthma and COPD remain poorly understood. Insight into oxidative stress, macrophages, and their interactions may be important in fully understanding acute worsening of lung disease. This review therefore highlights the current state of the art regarding the role of oxidative stress and macrophages in exacerbations of asthma and COPD. It shows that oxidative stress can attenuate macrophage function, which may result in impaired responses toward exacerbating triggers and may contribute to exaggerated inflammation in the airways.

Bcl2-Like Protein 12 Is Required for the Aberrant T Helper-2 Polarization in the Heart by Enhancing Interleukin-4 Expression and Compromising Apoptotic Machinery in CD4+ T Cells.

The biased T helper-2 (Th2) response plays a critical role in myocarditis. Bcl2-like protein 12 (Bcl2L12) is associated with the Th2 pattern of inflammation. This study aims to elucidate the role of Bcl2L12 in the pathogenesis of Th2-biased inflammation in the heart. Mice were treated with the myosin heavy-chain-α peptides to induce inflammation in the heart. Human hearts were collected from the surgically removed hearts of patients who had undergone heart transplantation. The expression of Bcl2L12 was detected in CD4+ T cells of the hearts, which was markedly higher in the hearts with myocarditis at the advanced stage of heart failure compared with the control (dilated cardiomyopathy) hearts without myocarditis. Mice with Bcl2L12-deficient CD4+ T cells failed to induce the Th2-biased inflammation in the heart. CD4+ T cells with a higher expression of Bcl2L12 were prone to differentiate into Th2 cells. Bcl2L12 formed a complex with GATA3 in CD4+ T cells to enhance the binding between GATA3 and the Il4 promoter, which promoted the Il4 gene transcription. Bcl2L12 compromised the apoptotic machinery by inhibiting the expression of p53 in CD4+ T cells to reduce the activation-induced CD4+ T cell death. CD4+ T cells isolated from hearts with myocarditis at the end stage of heart failure express high levels of Bcl2L12, and the latter is required for the development of aberrant Th2 polarization in the heart. The Bcl2L12 may be a novel target in the treatment of myocarditis as well as other Th2-biased inflammation.

Bcl2-like protein 12 plays a critical role in development of airway allergy through inducing aberrant TH2 polarization

Bcl2-like protein 12 plays a critical role in development of airway allergy through inducing aberrant TH2 polarization