Metabolic Reprogramming Of Macrophages Research Articles

IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages

In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.

Maresin-1 promotes neuroprotection and prevents disease progression in experimental models of multiple sclerosis through metabolic reprogramming and shaping innate and adaptive disease-associated cell types.

MaR1 expedited inflammation resolution and prevented neurological impairments in RR-EAE.IL-10 plays a role in mediating the protective effect of MaR1 on EAE.MaR1 repaired CD4, macrophage, and microglia metabolic abnormalities.MaR1 therapy restored efferocytosis in EAE.MaR1 preserved myelin and improved O4+ oligodendrocyte metabolism.

LncRNA CRNDE promotes hepatoma cell proliferation by regulating the metabolic reprogramming of M2 macrophages via ERK pathway

BackgroundLncRNA colorectal neoplasia differentially expressed (CRNDE) was found to be an important regulator in many cancers. This project focuses on the function of CRNDE on macrophage metabolic reprogramming and Hepatocellular carcinoma (HCC).MethodqRT-PCR and Immunofluorescence were used to analyze Arg-1, IL-10, CD163, CCL-18, CD206, and CRNDE expression in HCC tissues and macrophages. Western Blotting was used to analyze ERK and p-ERK expression. Edu assay, transwell assay and xenograft experiments were carried out to study cell viability, migrated and invasive capability. Immunohistochemical staining was used to evaluate Ki67 expression. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed for macrophages metabolites analysis.ResultsArg-1, IL-10, CD163, CD206, and CRNDE were significantly up-regulated in HCC tissues, M2 macrophage and M0 macrophage with CRNDE overexpressed (OV-CRNDE-M0), which downregulated in M0 macrophage with CRNDE knockdown (sh-CRNDE-M0). The conditioned medium (CM) of M2 cells and OV-CRNDE-M0 cells promoted cell viability, invasion, and migration of HCC cells, the effect was reversed by sh-CRNDE-M0 cells CM. OV-CRNDE-M0 cells promoted tumor growth, Ki67 and CD206 expression in xenograft model. 61 metabolites were detected, of which 18 metabolites changed significantly in OV-CRNDE-M0 group compared to M0 group, with 9 upregulated and 9 downregulated. KEGG analysis showed the enrichment pathways were biosynthesis, glyoxylate and dicarboxylate metabolism. SMPDB analysis showed the enrichment pathways were hypoacetylaspartia, canavan disease, and aspartate metabolism.ConclusionCRNDE regulated the metabolic reprogramming of M2 macrophage via ERK pathway, which thereby contributed to HCC proliferation, migration, and invasion.

Immunometabolic checkpoint-mediated macrophage metabolic reprogramming accelerates infected wound healing

Immunometabolic disorders, triggered by excessive oxidative stress, lead to macrophage dysfunction, consequently impeding the healing of infected wounds. The uncontrolled accumulation of reactive oxygen species (ROS) in infected wounds is primarily attributed to persistent bacterial infections, excess exudate, and hypoxia. Herein, an immunometabolic checkpoint-mediated macrophage metabolic reprogramming strategy based on a nanofiber aerogel loaded with catalase (CAT) and tannic acid (TA) is proposed. The three-dimensional porous network of the nanofiber aerogel effectively absorbs exudates, maintains wound dryness, and prevents tissue saturation. CAT catalyzes oxygen generation, alleviates hypoxia, and reduces ROS, while TA acts as a natural antioxidant and antibacterial agent, collaboratively mitigating oxidative stress and bacterial infections. More importantly, the CAT-TA nanofiber aerogel, as an immunometabolic checkpoint regulator, can reshape the glutathione (GSH) metabolic pathway, enhancing intrinsic antioxidative capacity, allowing the reversion of macrophage functions, and ultimately promoting wound healing. This macrophage metabolism therapy (MMT), centered on the modulation of immunometabolic checkpoint, effectively enhances the regenerative capacity of infected wounds and provides a pioneering perspective for the treatment of regeneration disorders in infected tissues.

A simplified herbal decoction attenuates myocardial infarction by regulating macrophage metabolic reprogramming and phenotypic differentiation via modulation of the HIF-1α/PDK1 axis

BackgroundMyocardial infarction (MI) poses a global public health challenge, often associated with elevated mortality rates and a grim prognosis. A crucial aspect of the inflammatory injury and healing process post-MI involves the dynamic differentiation of macrophages. A promising strategy to alleviate myocardial damage after MI is by modulating the inflammatory response and orchestrating the shift from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages, aiming to achieve a reduced M1/M2 ratio. Nuanxinkang (NXK), a simplified herbal decoction, has demonstrated noteworthy cardioprotective, inflammation-regulating, and myocardial energy metabolism-regulating properties.MethodsIn this study, we constructed an MI model by ligating coronary arteries to investigate the efficacy of NXK in improving ventricular remodeling and cardiac function. Mice were administered NXK (1.65 g/kg/d) or an equivalent volume of regular saline via gavage for 28 consecutive days, commencing the day after surgery. Then, we conducted echocardiography to assess the cardiac function, Masson staining to illustrate the extent of myocardial fibrosis, TUNEL staining to reveal myocardial apoptosis, and flow cytometry to analyze the polarization of M1 and M2 macrophages in the hearts. Besides, a lipopolysaccharide (LPS)-induced pro-inflammatory macrophage (M1) polarization model was implemented in RAW264.7 cells to elucidate the underlying mechanism of NXK in regulating macrophage polarization. RAW264.7 cells were pre-treated with or without NXK-containing serum. Oxidative stress was detected by MitoSox staining, followed by Seahorse energy metabolism assay to evaluate alterations in mitochondrial metabolic patterns and ATP production. Both In vivo and in vitro, HIF-1α and PDK1 were detected by fluorescent quantitative PCR and Western blotting.ResultsIn vivo, MI mice exhibited a decline in cardiac function, adverse ventricular remodeling, and an increase in glycolysis, coupled with M1-dominant polarization mediated by the HIF-1α/PDK1 axis. Notably, robust responses were evident with high-dose NXK treatment (1.65 g/kg/day), leading to a significant enhancement in cardiac function, inhibition of cardiac remodeling, and partial suppression of macrophage glycolysis and the inflammatory phenotype in MI mice. This effect was achieved through the modulation of the HIF-1α/PDK1 axis. In vitro, elevated levels of mitochondrial ROS production and glycolysis were observed in LPS-induced macrophages. Conversely, treatment with NXK notably reduced the oxidative stress damage induced by LPS and enhanced oxidative phosphorylation (OXPHOS). Furthermore, NXK demonstrated the ability to modify the energy metabolism and inflammatory characteristics of macrophages by modulating the HIF-1α/PDK1 axis. The influence of NXK on this axis was partially counteracted by the HIF-1α agonist DMOG. And NXK downregulated PDK1 expression, curtailed glycolysis, and reversed LPS-induced M1 polarization in macrophages, similar to the PDK1 inhibitor DCA.ConclusionIn conclusion, NXK protects against MI-induced cardiac remodeling by inducing metabolic reprogramming and phenotypic differentiation of macrophages, achieved through the modulation of the HIF-1α/PDK1 axis. This provides a novel and promising strategy for the treatment of MI.

Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues.

It is commonly known that different macrophage phenotypes play specific roles in different pathophysiological processes. In recent years, many studies have linked the phenotypes of macrophages to their characteristics in different metabolic pathways, suggesting that macrophages can perform different functions through metabolic reprogramming. It is now gradually recognized that lactate, previously overlooked as a byproduct of glycolytic metabolism, acts as a signaling molecule in regulating multiple biological processes, including immunological responses and metabolism. Recently, lactate has been found to mediate epigenetic changes in macrophages through a newfound lactylation modification, thereby regulating their phenotypic transformation. This novel finding highlights the significant role of lactate metabolism in macrophage function. In this review, we summarize the features of relevant metabolic reprogramming in macrophages and the role of lactate metabolism therein. We also review the progress of research on the regulation of macrophage metabolic reprogramming by lactylation through epigenetic mechanisms.

Distinct metabolic responses to heme in inflammatory human and mouse macrophages – Role of nitric oxide

Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and pro-inflammatory effects in murine macrophages, but has been associated with polarization towards an anti-inflammatory phenotype in human macrophages. In the current study, we compared the regulatory responses to heme and the prototypical Toll-like receptor (TLR)4 ligand lipopolysaccharide (LPS) in human and mouse macrophages with a particular focus on alterations of cellular bioenergetics. In human macrophages, bulk RNA-sequencing analysis indicated that heme led to an anti-inflammatory transcriptional profile, whereas LPS induced a classical pro-inflammatory gene response. Co-stimulation of heme with LPS caused opposing regulatory patterns of inflammatory activation and cellular bioenergetics in human and mouse macrophages. Specifically, in LPS-stimulated murine, but not human macrophages, heme led to a marked suppression of oxidative phosphorylation and an up-regulation of glycolysis. The species-specific alterations in cellular bioenergetics and inflammatory responses to heme were critically dependent on the availability of nitric oxide (NO) that is generated in inflammatory mouse, but not human macrophages. Accordingly, studies with an inducible nitric oxide synthase (iNOS) inhibitor in mouse, and a pharmacological NO donor in human macrophages, reveal that NO is responsible for the opposing effects of heme in these cells. Taken together, the current findings indicate that NO is critical for the immunomodulatory role of heme in macrophages.

Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues

Background and aimsObesity-induced chronic inflammation and metabolic abnormalities are highly relevant to the functional dysregulation of macrophages, especially under obese conditions. Hyperglycemia and hyperlipidemia, central to obesity, directly alter macrophage activity. However, the impacts of different nutritional cues on the intricate metabolic networks in macrophages remain unclear. Materials and methodsIn this study, we employed metabolomic approaches to examine the metabolic responses of macrophages to high glucose, high fat and their coexistence, aiming to delineate the molecular mechanisms of nutritional factors on macrophage activation and obesity-related diseases from a metabolic perspective. ResultsOur findings revealed that different nutritional conditions could reprogram key metabolism in macrophages. Additionally, we identified a metabolite derived from macrophages, Long-Chain Phosphatidylcholine (LPC), which exerts beneficial effects on obese mice. It ameliorates the obesity phenotype and improves glucose metabolism profiles. This discovery suggests that LPC has a significant therapeutic potential in the context of obesity-induced metabolic dysfunctions. Our study unveils the metabolic phenotype of macrophages in high-fat and high-sugar environments and uncovers a macrophage-derived metabolite that significantly ameliorates the obesity phenotype. ConclusionThis finding reveals a potential dialogue mechanism between macrophages and adipocytes, shedding light on the complex interplay of immune and metabolic systems in obesity. This discovery not only enhances our understanding of obesity’s underlying mechanisms but also opens up new avenues for therapeutic interventions targeting macrophage-adipocyte interactions.

From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.

Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor-associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche-derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype-specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.

Decoding the Cell Atlas and Inflammatory Features of Human Intracranial Aneurysm Wall by Single-Cell RNA Sequencing.

Intracranial aneurysm (IA) is common and occasionally results in life-threatening hemorrhagic strokes. However, the cell architecture and inflammation in the IA dome remain less understood. Single-cell RNA sequencing was performed on ruptured and unruptured human IA domes for delineating the cell atlas, gene expression perturbations, and inflammation features. Two external bulk mRNA sequencing-based data sets and serological results of 126 patients were collected for validation. As a result, a total of 21 332 qualified cells were captured. Vascular cells, including endothelial cells, smooth muscle cells, fibroblasts, and pericytes, were assigned in extremely sparse numbers (4.84%), and were confirmed by immunofluorescence staining. Pericytes, characterized by ABCC9 and HIGD1B, were identified in the IA dome for the first time. Abundant immune cells were identified, with the proportion of monocytes/macrophages and neutrophils being remarkably higher in ruptured IA. The lymphocyte compartment was also thoroughly categorized. By leveraging external data sets and machine learning algorithms, macrophages were robustly associated with IA rupture, irrespective of their polarization status. The single nucleotide polymorphism rs2280543, which is identified in East Asian populations, was associated with macrophage metabolic reprogramming through regulating TALDO1 expression. This study provides insights into the cellular architecture and inflammatory features in the IA dome and may enlighten novel therapeutics for unruptured IA.

Quercitrin improves cardiac remodeling following myocardial infarction by regulating macrophage polarization and metabolic reprogramming

The death and disability caused by myocardial infarction is a health problem that needs to be addressed worldwide, and poor cardiac repair and fibrosis after myocardial infarction seriously affect patient recovery. Postmyocardial infarction repair by M2 macrophages is of great significance for ventricular remodeling. Quercitrin (Que) is a common flavonoid in fruits and vegetables that has antioxidant, anti-inflammatory, antitumor and other effects, but whether it has a role in the treatment of myocardial infarction is unclear. In this study, we constructed a mouse myocardial infarction model and administered Que. We found through cardiac ultrasound that Que administration improved cardiac ejection fraction and reduced ventricular remodeling. Staining of heart sections and detection of fibrosis marker protein levels revealed that Que administration slowed fibrosis after myocardial infarction. Flow cytometry showed that the proportion of M2 macrophages in the mouse heart was increased and that the expression levels of M2 macrophage markers were increased in the Que-treated group. Finally, we identified by metabolomics that Que reduces glycolysis, increases aerobic phosphorylation, and alters arginine metabolic pathways, polarizing macrophages toward the M2 phenotype. Our research lays the foundation for the future application of Que in myocardial infarction and other cardiovascular diseases.

Metabolic reprogramming of immune cells by mitochondrial division inhibitor-1 to prevent post-vascular injury neointimal hyperplasia

Background and aimsNew treatments are needed to prevent neointimal hyperplasia that contributes to post-angioplasty and stent restenosis in patients with coronary artery disease (CAD) and peripheral arterial disease (PAD). We investigated whether modulating mitochondrial function using mitochondrial division inhibitor-1 (Mdivi-1) could reduce post-vascular injury neointimal hyperplasia by metabolic reprogramming of macrophages from a pro-inflammatory to anti-inflammatory phenotype. Methods and ResultsIn vivo Mdivi-1 treatment of Apoe−/− mice fed a high-fat diet and subjected to carotid-wire injury decreased neointimal hyperplasia by 68%, reduced numbers of plaque vascular smooth muscle cells and pro-inflammatory M1-like macrophages, and decreased plaque inflammation, endothelial activation, and apoptosis, when compared to control. Mdivi-1 treatment of human THP-1 macrophages shifted polarization from a pro-inflammatory M1-like to an anti-inflammatory M2-like phenotype, reduced monocyte chemotaxis and migration to CCL2 and macrophage colony stimulating factor (M-CSF) and decreased secretion of pro-inflammatory mediators. Finally, treatment of pro-inflammatory M1-type-macrophages with Mdivi-1 metabolically reprogrammed them to an anti-inflammatory M2-like phenotype by inhibiting oxidative phosphorylation and attenuating the increase in succinate levels and correcting the decreased levels of arginine and citrulline. ConclusionsWe report that treatment with Mdivi-1 inhibits post-vascular injury neointimal hyperplasia by metabolic reprogramming macrophages towards an anti-inflammatory phenotype thereby highlighting the therapeutic potential of Mdivi-1 for preventing neointimal hyperplasia and restenosis following angioplasty and stenting in CAD and PAD patients.

M2 macrophage exosome-derived lncRNA AK083884 protects mice from CVB3-induced viral myocarditis through regulating PKM2/HIF-1α axis mediated metabolic reprogramming of macrophages

Viral myocarditis (VM) is a clinically common inflammatory disease. Accumulating literature has indicated that M2 macrophages protect mice from Coxsackievirus B3 (CVB3)-induced VM. However, mechanisms that underlie M2 macrophages alleviating myocardial inflammation remain largely undefined. We found that M2 macrophage-derived exosomes (M2-Exo) can effectively attenuate VM. The long non-coding RNA (lncRNA) AK083884 in M2-Exo was found to be involved in the regulation of macrophage polarization by exosome lncRNA sequencing combined with in vitro functional assays. M2-Exo-derived AK083884 promotes macrophage M2 polarization and protects mice from CVB3-induced VM. Furthermore, we identified pyruvate kinase M2 (PKM2) as a protein target binding to AK083884 and found that PKM2 knockdown could promote macrophages to polarize to M2 phenotype. Intriguingly, functional assay revealed that downregulation of AK083884 promotes metabolic reprogramming in macrophages. In addition, co-immunoprecipitation was performed to reveal AK083884 could interact with PKM2 and inhibition of AK083884 can facilitate the binding of PKM2 and HIF-1α. Collectively, our findings uncovered an important role of M2-Exo-derived AK083884 in the regulation of macrophage polarization through metabolic reprogramming, identified a new participant in the development of VM and provided a potential clinically important therapeutic target.

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

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

Macrophage-hitchhiking interleukin-10 plasmid DNA delivery system modulates rheumatoid arthritis microenvironment via the re-polarization of macrophages

Rheumatoid arthritis (RA) is a common chronic inflammatory disease and the current treatments for RA are unsatisfactory due to the buffer barrier from the RA microenvironment. Interleukin-10 (IL-10) was found to be able to modulate rheumatoid arthritis microenvironment (RAM) by the metabolic reprogramming of macrophages. However, its clinical application has proven challenging mainly due to its short half-life, non-ideal targeting efficiency via systemic administration and poor tissue penetration. Taking advantage of the recruitment of macrophages, we constructed an innovative macrophage-hitchhiking IL-10 pDNA delivery system using the peptides bearing nuclear localization signal (NLS) and tuftsin-modified disulfide-crosslinked polymers (bPEI-SS-PEG-T) which was responsive to the intracellular glutathione concentration. Firstly, we formed NLS/DNA complexes via electrostatic interactions to enhance the nuclear entry efficiency. Then NLS/DNA complexes were combined with bPEI-SS-PEG-T to construct bPEI-SS-PEG-T/NLS/DNA NPs with sizes of 168.4 nm and zeta potentials of + 10.9 mV. As the bPEI-SS-PEG-T was biodegradable and the tuftsin peptides enhanced macrophage-mediated phagocytosis, the nanoparticles exhibited lower cytotoxicity and better cellular uptake in addition to higher nuclear entry efficiency, leading to better IL-10 plasmid transfection. In addition, these macrophage-hitchhiking nanoparticles could effectively accumulate at inflammatory sites of RA via intra-peritoneal injection due to the macrophage migration to the inflammatory joints and alleviate symptoms of inflammation in vivo by inducing the re-polarization of macrophages, which might be mediated by the inhibition of mammalian target of rapamycin (mTOR) and the induction of arginase-2 (Arg2). As a result, this macrophage-hitchhiking gene delivery system demonstrated excellent inflammation targeting ability, good nuclear entry ability, high IL-10 plasmid transfection efficiency and great therapeutic efficacy in vivo, which is promising for the treatment of rheumatoid arthritis. Besides, this delivery system also provides a novel strategy for the gene therapy and the gene delivery system design for rheumatoid arthritis and other similar inflammatory diseases from the perspective of the inflammatory microenvironment.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming

BackgroundSepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PurposeThis investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. Methods/ResultsFrom a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. ConclusionThese results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Activation of BZW1 by CEBPB in macrophages promotes eIF2α phosphorylation-mediated metabolic reprogramming and endoplasmic reticulum stress in MRL/lpr lupus-prone mice

BackgroundLupus nephritis (LN) is associated with significant mortality and morbidity, while effective therapeutics and biomarkers are limited since the pathogenesis is complex. This study investigated the roles of the CEBPB/BZW1/eIF2α axis in metabolic reprogramming and endoplasmic reticulum stress in LN.MethodThe differentially expressed genes in LN were screened using bioinformatics tools. The expression of CEBPB in the renal tissue of patients with LN and its correlation with the levels of creatinine and urinary protein were analyzed. We used adenoviral vectors to construct LN mice with knockdown CEBPB using MRL/lpr lupus-prone mice and analyzed the physiological and autoimmune indices in mice. Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP–qPCR) and dual-luciferase reporter assays were conducted to explore the regulation of BZW1 by CEBPB, followed by glycolytic flux analysis, glucose uptake, and enzyme-linked immunosorbent assay (ELISA). Finally, the role of eIF2α phosphorylation by BZW1 in bone marrow-derived macrophages (BMDM) was explored using eIF2α phosphorylation and endoplasmic reticulum stress inhibitors.ResultsCEBPB was significantly increased in renal tissues of patients with LN and positively correlated with creatinine and urine protein levels in patients. Downregulation of CEBPB alleviated the autoimmune response and the development of nephritis in LN mice. Transcriptional activation of BZW1 by CEBPB-mediated glucose metabolic reprogramming in macrophages, and upregulation of BZW1 reversed the mitigating effect of CEBPB knockdown on LN. Regulation of eIF2α phosphorylation levels by BZW1 promoted endoplasmic reticulum stress-amplified inflammatory responses in BMDM.ConclusionTranscriptional activation of BZW1 by CEBPB promoted phosphorylation of eIF2α to promote macrophage glycolysis and endoplasmic reticulum stress in the development of LN.

Soybean polyenylphosphatidylcholine (PPC) is beneficial in liver and extrahepatic tissue injury: An update in experimental research.

Polyenylphosphatidylcholine (PPC) is a purified polyunsaturated phosphatidylcholine extract of soybeans. This article updates PPC's beneficial effects on various forms of liver cell injury and other tissues in experimental research. PPC downregulates hepatocyte CYP2E1 expression and associated hepatotoxicity, as well as attenuates oxidative stress, apoptosis, lipoprotein oxidation and steatosis in alcoholic and nonalcoholic liver injury. PPC inhibits pro-inflammatory cytokine production, while stimulating anti-inflammatory cytokine secretion in ethanol or lipopolysaccharide-stimulated Kupffer cells/macrophages. It promotes M2-type macrophage polarization and metabolic reprogramming of glucose and lipid metabolism. PPC mitigates steatosis in NAFLD through inhibiting polarization of pro-inflammatory M1-type Kupffer cells, alleviating metabolic inflammation, remodeling hepatic lipid metabolism, correcting imbalances between lipogenesis and lipolysis and enhancing lipoprotein secretion from hepatocytes. PPC is antifibrotic by preventing progression of alcoholic hepatic fibrosis in baboons and also prevents CCl4-induced fibrosis in rats. PPC supplementation replenishes the phosphatidylcholine content of damaged cell membranes, resulting in increased membrane fluidity and functioning. Phosphatidylcholine repletion prevents increased membrane curvature of the endoplasmic reticulum and Golgi and decreases sterol regulatory element binding protein-1-mediated lipogenesis, reducing steatosis. PPC remodels gut microbiota and affects hepatic lipid metabolism via the gut-hepatic-axis and also alleviates brain inflammatory responses and cognitive impairment via the gut-brain-axis. Additionally, PPC protects extrahepatic tissues from injury caused by various toxic compounds by reducing oxidative stress, inflammation, and membrane damage. It also stimulates liver regeneration, enhances sensitivity of cancer cells to radiotherapy/chemotherapy, and inhibits experimental hepatocarcinogenesis. PPC's beneficial effects justify it as a supportive treatment of liver disease.

Impact of Airborne Pathogen-Derived Extracellular Vesicles on Macrophages Revealed by Raman Spectroscopy and Multiomics.

Long-term exposure to the indoor environment may pose threats to human health due to the presence of pathogenic bacteria and their byproducts. Nanoscale extracellular vesicles (EVs) extensively secreted from pathogenic bacteria can traverse biological barriers and affect physio-pathological processes. However, the potential health impact of EVs from indoor dust and the underlying mechanisms remain largely unexplored. Here, Raman spectroscopy combined with multiomics (genomics and proteomics) was used to address these issues. Genomic analysis revealed that Pseudomonas was an efficient producer of EVs that harbored 68 types of virulence factor-encoding genes. Upon exposing macrophages to environmentally relevant doses of Pseudomonas aeruginosa PAO1-derived EVs, macrophage internalization was observed, and release of inflammatory factors was determined by RT-PCR. Subsequent Raman spectroscopy and unsupervised surprisal analysis of EV-affected macrophages distinguished metabolic alterations, particularly in proteins and lipids. Proteomic analysis further revealed differential expression of proteins in inflammatory and metabolism-related pathways, indicating that EV exposure induced macrophage metabolic reprogramming and inflammation. Collectively, our findings revealed that pathogen-derived EVs in the indoor environments can act as a new mediator for pathogens to exert adverse health effects. Our method of Raman integrated with multiomics offers a complementary approach for rapid and in-depth understanding of EVs' impact.

MiR-182/183-Rasa1 axis induced macrophage polarization and redox regulation promotes repair after ischemic cardiac injury

Few therapies have produced significant improvement in cardiac structure and function after ischemic cardiac injury (ICI). Our possible explanation is activation of local inflammatory responses negatively impact the cardiac repair process following ischemic injury. Factors that can alter immune response, including significantly altered cytokine levels in plasma and polarization of macrophages and T cells towards a pro-reparative phenotype in the myocardium post-MI is a valid strategy for reducing infarct size and damage after myocardial injury.Our previous studies showed that cortical bone stem cells (CBSCs) possess reparative effects after ICI. In our current study, we have identified that the beneficial effects of CBSCs appear to be mediated by miRNA in their extracellular vesicles (CBSC-EV). Our studies showed that CBSC-EV treated animals demonstrated reduced scar size, attenuated structural remodeling, and improved cardiac function versus saline treated animals. These effects were linked to the alteration of immune response, with significantly altered cytokine levels in plasma, and polarization of macrophages and T cells towards a pro-reparative phenotype in the myocardium post-MI. Our detailed in vitro studies demonstrated that CBSC-EV are enriched in miR-182/183 that mediates the pro-reparative polarization and metabolic reprogramming in macrophages, including enhanced OXPHOS rate and reduced ROS, via Ras p21 protein activator 1 (RASA1) axis under Lipopolysaccharides (LPS) stimulation. In summary, CBSC-EV deliver unique molecular cargoes, such as enriched miR-182/183, that modulate the immune response after ICI by regulating macrophage polarization and metabolic reprogramming to enhance repair.