Influence Macrophage Polarization Research Articles

Role of miRNAs in macrophage-mediated kidney injury.

Macrophages, crucial components of the human immune system, can be polarized into M1/M2 phenotypes, each with distinct functions and roles. Macrophage polarization has been reported to be significantly involved in the inflammation and fibrosis observed in kidney injury. MicroRNA (miRNA), a type of short RNA lacking protein-coding function, can inhibit specific mRNA by partially binding to its target mRNA. The intricate association between miRNAs and macrophages has been attracting increasing interest in recent years. This review discusses the role of miRNAs in regulating macrophage-mediated kidney injury. It shows how miRNAs can influence macrophage polarization, thereby altering the biological function of macrophages in the kidney. Furthermore, this review highlights the significance of miRNAs derived from exosomes and extracellular vesicles as a crucial mediator in the crosstalk between macrophages and kidney cells. The potential of miRNAs as treatment applications and biomarkers for macrophage-mediated kidney injury is also discussed.

Pathogenic Autoimmunity in Atherosclerosis Evolves from HSP60-Reactive CD4 + T Cells.

Clinical evidence suggests anti-Hsp60 antibodies could contribute to atherosclerosis (AS) development, with unclear mechanisms. This study aims to explore the role of anti-HSP60-mediated autoimmunity in AS progression. HSP60-MHC tetramers were used to characterize HSP60-specific CD4 + T cells and assess TCR responses in mice. These cells were transplanted into AS mice to examine immune cell differentiation and infiltration in plaques and blood. Mice were injected with recombinant HSP60 or anti-HSP60 sera to evaluate effects on plaque progression and macrophage activity. Experiments with muMT-/-Apoe-/- mice examined humoral immunity's role in this autoimmunity. HSP60-reactive CD4 + T cells in AS mice differentiated into follicular helper cells, not Th1/Th17. Anti-HSP60 treatments increased macrophage infiltration and M1 polarization, indicating an anti-HSP60-driven inflammatory progression, dependent on humoral immunity. Anti-HSP60 influences macrophage infiltration, polarization, and plaque formation via humoral immunity, shedding light on its potential role in AS progression.

Exosomal miR-182-5p from breast cancer cells reprogram tumor-associated macrophages and promotes TNBC progression by targeting Notch1 in macrophages

IntroductionThe regulatory role of miR-182 in breast cancer malignancy and macrophage reprogramming is well-established. However, the mechanisms through which miR-182 overexpression in tumor cells influences macrophage polarization remain elusive.Material and methodsAfter transfection with miR-182-5p mimics, inhibitors, and controls for 24 hours, exosomes were extracted by differential centrifugation from transfected MDA-MB-231. Macrophages co-cultured with these exosomes to illustrate the regulative effects of exo-miR-182-5p reprogram macrophage. Furthermore, breast cancer cells co-cultured with exo-miR-182-5p reprogrammed M2 macrophages to demonstrate the effects of reprogrammed M2 macrophages to influence breast cancer progression. After all, these findings were validated in cell derived xenograft (CDX) BALB/C nude-mice model.ResultsIn this study, we demonstrate that exosome-derived miR-182-5p from TNBC cells reprograms M2 macrophage polarization through direct combined with Notch1, thereby enhancing breast cancer progression in vitro and in vivo. When co-cultured with exosomes from TNBC cells transfected with miR-182-5p mimics or inhibitors, macrophages showed altered Notch1/Hes1 pathway expression, leading to M2 polarization and subsequent changes in reactive oxygen species (ROS), inflammation, and other biochemical markers. Furthermore, breast cancer cells co-cultured with exosomes reprogrammed macrophages exhibited increased colony formation, migration, and invasion, as well as reduced apoptosis. These findings were validated in a BALB/C nude-mice model.ConclusionsThis study pioneers the elucidation of the feedback loop mechanism between breast cancer cells and macrophages mediated by the exosome-derived miR-182-5p/Notch1 pathway, highlighting its role in macrophage reprogramming. Although the therapeutic application of miR-182-5p inhibitors as anticancer agents remains in the early stages, targeting macrophage polarization represents a promising avenue for breast cancer therapy.

Mechanisms underlying aryl hydrocarbon receptor-driven divergent macrophage function.

Macrophages play an essential role in the innate immune system by differentiating into functionally diverse subsets in order to fight infection, repair damaged tissues, and regulate inappropriate immune responses. This functional diversity stems from their ability to adapt and respond to signals in the environment, which is in part mediated through aryl hydrocarbon receptor (AHR)-signaling. AHR, an environmental sensor, can be activated by various ligands, ranging from environmental contaminants to microbially derived tryptophan metabolites. This review discusses what is currently known about how AHR-signaling influences macrophage differentiation, polarization, and function. By discussing studies that are both consistent and divergent, our goal is to highlight the need for future research on the mechanisms by which AHR acts as an immunological switch in macrophages. Ultimately, understanding the contexts in which AHR-signaling promotes and/or inhibits differentiation, proinflammatory functions, and immunoregulatory functions, will help uncover functional predictions of immunotoxicity following exposure to environmental chemicals as well as better design AHR-targeted immunotherapies.

Macrophage Polarization Dynamics in Biomaterials: Implications for in Vitro Wound Healing.

The interaction between biomaterials and the immune system plays a pivotal role in determining the success or failure of implantable devices. Macrophages, as key orchestrators of immune responses, exhibit diverse reactions that influence tissue integration or lead to implant failure. This study focuses on unraveling the intricate relationship between macrophage phenotypes and biomaterials, specifically hydrogels, by employing THP-1 cells as a model. Through a comprehensive investigation using polysaccharide, polymer, and protein-based hydrogels, our research sheds light on how the properties of hydrogels influence macrophage polarization. Phenotypic observations, biochemical assays, surface marker expression, and gene expression profiles collectively demonstrate the differential macrophage polarization abilities of polysaccharide-, polymer-, and protein-based hydrogels. Moreover, our indirect coculture studies reveal that hydrogels fostering M2 polarization exhibit exceptional wound-healing capabilities. These findings highlight the crucial role of the hydrogel microenvironment in adjusting macrophage polarization, offering a fresh avenue for refining biomaterials to bolster advantageous immune responses and improve tissue integration. This research contributes valuable insights for designing biomaterials with tailored properties that can guide macrophage behavior, ultimately improving the overall success of implantable devices.

Multifunctional Hydrogel Enhances Inflammatory Control, Antimicrobial Activity, and Oxygenation to Promote Healing in Infectious Wounds.

Chronic infected wounds often fail to heal through normal repair mechanisms, and the persistent response of reactive oxygen species (ROS) and inflammation is a major contributing factor to the difficulty in their healing. In this context, we developed an ROS-responsive injectable hydrogel. This hydrogel is composed of ε-polylysine grafted (EPL) with caffeic acid (CA) and hyaluronic acid (HA) grafted with phenylboronic acid (PBA). Before the gelation process, a mixture CaO2@Cur-PDA (CCP) consisting of calcium peroxide (CaO2) coated with polydopamine (PDA) and curcumin (Cur) is embedded into the hydrogel. Under the conditions of chronic refractory wound environments, the hydrogel gradually dissociates. HA mimics the function of the extracellular matrix, while the released caffeic acid-grafted ε-polylysine (CE) effectively eliminates bacteria in the wound vicinity. Additionally, released CA also clears ROS and influences macrophage polarization. Subsequently, CCP further decomposes, releasing Cur, which promotes angiogenesis. This multifunctional hydrogel accelerates the repair of diabetic skin wounds infected with Staphylococcus aureus in vivo and holds promise as a candidate dressing for the healing of chronic refractory wounds.

Extracellular Matrix-Bioinspired Anisotropic Topographical Cues of Electrospun Nanofibers: A Strategy of Wound Healing through Macrophage Polarization.

The skin serves as the body's outermost barrier and is the largest organ, providing protection not only to the body but also to various internal organs. Owing to continuous exposure to various external factors, it is susceptible to damage that can range from simple to severe, including serious types of wounds such as burns or chronic wounds. Macrophages play a crucial role in the entire wound-healing process and contribute significantly to skin regeneration. Initially, M1 macrophages infiltrate to phagocytose bacteria, debris, and dead cells in fresh wounds. As tissue repair is activated, M2 macrophages are promoted, reducing inflammation and facilitating restoration of the dermis and epidermis to regenerate the tissue. This suggests that extracellular matrix (ECM) promotes cell adhesion, proliferation, migrationand macrophage polarization. Among the numerous strategies, electrospinning is a versatile technique for obtaining ECM-mimicking structures with anisotropic and isotropic topologies of micro/nanofibers. Various electrospun biomaterials influence macrophage polarization based on their isotropic or anisotropic topologies. Moreover, these fibers possess a high surface-area-to-volume ratio, promoting the effective exchange of vital nutrients and oxygen, which are crucial for cell viability and tissue regeneration. Micro/nanofibers with diverse physical and chemical properties can be tailored to polarize macrophages toward skin regeneration and wound healing, depending on specific requirements. This review describes the significance of micro/nanostructures for activating macrophages and promoting wound healing.

Tumor Pigmentation Does Not Affect Light-Activated Belzupacap Sarotalocan Treatment but Influences Macrophage Polarization in a Murine Melanoma Model.

Pigmentation in uveal melanoma is associated with increased malignancy and is known as a barrier for photodynamic therapy. We investigated the role of pigmentation in tumor behavior and the response to light-activated Belzupacap sarotalocan (Bel-sar) treatment in a pigmented (wild type) and nonpigmented (tyrosinase knock-out [TYR knock-out]) cell line in vitro and in a murine model. The B16F10 (TYR knock-out) was developed using CRISPR/Cas9. After the treatment with light-activated Bel-sar, cytotoxicity and exposure of damage-associated molecular patterns (DAMPs) were measured by flow cytometry. Treated tumor cells were co-cultured with bone marrow-derived macrophages (BMDMs) and dendritic cells (DCs) to assess phagocytosis and activation. Both cell lines were injected subcutaneously in syngeneic C57BL/6 mice. Knock-out of the tyrosinase gene in B16F10 led to loss of pigmentation and immature melanosomes. Pigmented tumors contained more M1 and fewer M2 macrophages compared with amelanotic tumors. Bel-sar treatment induced near complete cell death, accompanied with enhanced exposure of DAMPs in both cell lines, resulting in enhanced phagocytosis of BMDMs and maturation of DCs. Bel-sar treatment induced a shift to M1 macrophages and delayed tumor growth in both in vivo tumor models. Following treatment, especially the pigmented tumors and their draining lymph nodes contained IFN-gamma positive CD8+T cells. Pigmentation influenced the type of infiltrating macrophages in the tumor, with more M1 macrophages in pigmented tumors. Belzupacap sarotalocan treatment induced immunogenic cell death and tumor growth delay in pigmented as well as in nonpigmented models and stimulated M1 macrophage influx in both models.

Heparin-binding hemagglutinin of Mycobacterium tuberculosis inhibits autophagy via TLR4 and drives M2 polarization in macrophages.

Tuberculosis (TB), predominantly caused by Mycobacterium tuberculosis (MTB) infection, remains a prominent global health challenge. Macrophages are the frontline defense against MTB, relying on autophagy for intracellular bacterial clearance. However, MTB can combat and evade autophagy, and it influences macrophage polarization, facilitating immune evasion and promoting infection. We previously found that heparin-binding hemagglutinin (HBHA) inhibits autophagy in A549 cells; however, its role in macrophage autophagy and polarization remains unclear. Bacterial cultures, cell cultures, western blotting, immunofluorescence, macrophage infection assays, siRNA knockdown, and ELISA were used to investigate HBHA's impact on macrophages and its relevance in Mycobacterium infection. HBHA inhibited macrophage autophagy. Expression of recombinant HBHA in Mycobacterium smegmatis (rMS-HBHA) inhibited autophagy, promoting bacterial survival within macrophages. Conversely, HBHA knockout in the Mycobacterium bovis Bacillus Calmette-Guérin (BCG) mutant (BCG-ΔHBHA) activated autophagy and reduced bacterial survival. Mechanistic investigations revealed that HBHA may inhibit macrophage autophagy through the TLR4-dependent PI3K-AKT-mTOR signaling pathway. Furthermore, HBHA induced macrophage M2 polarization. Mycobacterium may exploit HBHA to suppress the antimicrobial immune response in macrophages, facilitating intracellular survival, and immune evasion through autophagy inhibition and M2 polarization induction. Our findings may help identify novel therapeutic targets and develop more effective treatments against MTB infection.

Sublethal heat treatment enhances lactic acid uptake in macrophages via MCT1, leading to reduced paraspeckle formation and a subsequent decrease in macrophage pyroptosis.

Heat ablation is one of the key modalities in treating liver cancer, yet the residual cancer tissues suffering sublethal heat treatment possess a potential for increased malignancy. This study conducts a comprehensive analysis of cellular dynamics, metabolic shifts, and macrophage polarization within the tumor microenvironment following sublethal heat treatment. We observed significant acidification in tumor cell supernatants, attributed to increased lactic acid production. The study focused on how this pH shift, crucial in tumor progression and resistance, influences macrophage polarization, especially towards the M2 phenotype known for tumor-promoting functions. We also examined the upregulation of MCT1 expression post sublethal heat treatment and its primary role in lactic acid transport. Notably, the study found minimal disparity in MCT1 expression between hepatocellular carcinoma patients and healthy liver tissues, highlighting the complexity of cancer biology. The research further revealed an intricate relationship between lactic acid, MCT1, and the inhibition of macrophage pyroptosis, offering significant insights for therapeutic strategies targeting the tumor immune environment. Post sublethal heat treatment, a reduction in paraspeckle under lactic acid exposure was observed, indicating diverse cellular impacts. Additionally, PKM2 was identified as a key molecule in this context, with decreased levels after sublethal heat treatment in the presence of lactic acid. Collectively, these findings illuminate the intertwined mechanisms of sublethal heat treatments, metabolic alterations, and immune modulation in the tumor milieu, providing a deeper understanding of the complex interplay in cancer biology and treatment.

Glycolysis Induced by METTL14 Is Essential for Macrophage Phagocytosis and Phenotype in Cervical Cancer.

N 6-methyladenosine (m6A) is the most abundant mRNA modification in mammals and it plays a vital role in various biological processes. However, the roles of m6A on cervical cancer tumorigenesis, especially macrophages infiltrated in the tumor microenvironment of cervical cancer, are still unclear. We analyzed the abnormal m6A methylation in cervical cancer, using CaSki and THP-1 cell lines, that might influence macrophage polarization and/or function in the tumor microenvironment. In addition, C57BL/6J and BALB/c nude mice were used for validation invivo. In this study, m6A methylated RNA immunoprecipitation sequencing analysis revealed the m6A profiles in cervical cancer. Then, we discovered that the high expression of METTL14 (methyltransferase 14, N6-adenosine-methyltransferase subunit) in cervical cancer tissues can promote the proportion of programmed cell death protein 1 (PD-1)-positive tumor-associated macrophages, which have an obstacle to devour tumor cells. Functionally, changes of METTL14 in cervical cancer inhibit the recognition and phagocytosis of macrophages to tumor cells. Mechanistically, the abnormality of METTL14 could target the glycolysis of tumors invivo and vitro. Moreover, lactate acid produced by tumor glycolysis has an important role in the PD-1 expression of tumor-associated macrophages as a proinflammatory and immunosuppressive mediator. In this study, we revealed the effect of glycolysis regulated by METTL14 on the expression of PD-1 and phagocytosis of macrophages, which showed that METTL14 was a potential therapeutic target for treating advanced human cancers.

C-C Motif Chemokine 2 Regulates Macrophage Polarization and Contributes to Myocardial Infarction Healing.

Macrophages are crucial immune cells that play essential roles in the healing of myocardial infarction (MI), undergoing continuous polarization throughout this process. C-C motif chemokine 2 (CCL2) is a chemokine that regulates inflammatory responses during MI. However, the extent to which CCL2 influences macrophage polarization and MI healing remains incompletely understood. In this study, we investigate the role of CCL2 in macrophage polarization and MI healing. Our findings reveal that CCL2 is differentially expressed in lipopolysaccharide (LPS)-induced M1 and interleukin (IL)-4-induced M2 RAW264.7 macrophages. Knockdown of CCL2 attenuates TNF-α secretion stimulated by LPS, while overexpression of CCL2 mitigates IL-10 production triggered by IL-4 in these macrophages. Moreover, CCL2 deficiency disrupts LPS-induced M1 polarization, whereas CCL2 overexpression reduces M2 polarization of RAW264.7 macrophages induced by IL-4. Further exploration indicates that the promotion of M1 polarization by CCL2 is significantly impaired by inhibition of the p38-mediated MAPK pathway and NF-κB pathway. In a MI mouse model, CCL2 knockdown remarkably reduces infarct size, collagen synthesis, and the expression of cardiac fibrosis and hypertrophy markers. The activity of the p38-mediated MAPK pathway and NF-κB pathway is downregulated by CCL2 knockdown as well. Additionally, the number of total macrophages and M1 macrophages in the infarct decreases, while the number of M2 macrophages increases upon CCL2 deficiency. In conclusion, these results suggest that CCL2 is a key regulator of macrophage polarization, controlling MI healing in vivo.

Marine-Fungi-Derived Gliotoxin Promotes Autophagy to Suppress Mycobacteria tuberculosis Infection in Macrophage.

The Mycobacterium tuberculosis (MTB) infection causes tuberculosis (TB) and has been a long-standing public-health threat. It is urgent that we discover novel antitubercular agents to manage the increased incidence of multidrug-resistant (MDR) or extensively drug-resistant (XDR) strains of MTB and tackle the adverse effects of the first- and second-line antitubercular drugs. We previously found that gliotoxin (1), 12, 13-dihydroxy-fumitremorgin C (2), and helvolic acid (3) from the cultures of a deep-sea-derived fungus, Aspergillus sp. SCSIO Ind09F01, showed direct anti-TB effects. As macrophages represent the first line of the host defense system against a mycobacteria infection, here we showed that the gliotoxin exerted potent anti-tuberculosis effects in human THP-1-derived macrophages and mouse-macrophage-leukemia cell line RAW 264.7, using CFU assay and laser confocal scanning microscope analysis. Mechanistically, gliotoxin apparently increased the ratio of LC3-II/LC3-I and Atg5 expression, but did not influence macrophage polarization, IL-1β, TNF-a, IL-10 production upon MTB infection, or ROS generation. Further study revealed that 3-MA could suppress gliotoxin-promoted autophagy and restore gliotoxin-inhibited MTB infection, indicating that gliotoxin-inhibited MTB infection can be treated through autophagy in macrophages. Therefore, we propose that marine fungi-derived gliotoxin holds the promise for the development of novel drugs for TB therapy.

Surface immobilized α-1 acid glycoprotein and collagen VI modulate mouse macrophage polarization and reduce the foreign body capsule.

Macrophages are widely recognized in modulating the foreign body response, and the manner in which they do so largely depends on their activation state, often referred to as their polarization. This preliminary study demonstrates that surface immobilized α-1 acid glycoprotein (AGP), as well as collagen VI (Col6) in conjunction with AGP, can direct macrophages towards the M2 polarization state in vitro and modify the foreign body response in vivo. AGP and Col6 are immobilized onto poly(2-hydroxyethyl methacrylate) (pHEMA) surfaces using carbonyl diimidazole chemistry. Mouse bone marrow derived macrophages are cultured on modified surfaces with or without lipopolysaccharide stimulation. Surface modified pHEMA discs are implanted subcutaneously into mice to observe differences in the foreign body response. After stimulation with lipopolysaccharide, macrophages cultured on AGP or Col6 modified surfaces showed a reduction in TNF-α expression compared to controls. Arg1 expression was also increased in macrophages cultured on modified surfaces. Explanted tissues showed that the foreign body capsule around implants with AGP or AGP and Col6 modification had reduced thickness, while also being more highly vascularized. These data demonstrate that α-1 acid glycoprotein and collagen VI could potentially be used for the surface modification of medical devices to influence macrophage polarization leading to a reduced and modulated foreign body response.

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

Impact of Lipid Metabolism on Macrophage Polarization: Implications for Inflammation and Tumor Immunity.

Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages' responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid β-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of lipid-metabolism-related factors can potentially serve as a targeted approach against tumor cells. Cyclooxygenase inhibitors, which block the conversion of arachidonic acid into various inflammatory mediators, influence macrophage polarization and have generated attention in cancer research.

Manipulating macrophage polarization through gene manipulation techniques in lung injury

Macrophages play a critical role in lung injury and repair processes. Their functions can be broadly classified into two polarized phenotypes. The M1 macrophages promote inflammation and defense against pathogens, while the M2 macrophages are involved in tissue repair and resolution of inflammation.Gene manipulation techniques can be used to modulate macrophage polarization during lung injury. 1. Transcription factors: Transcription factors are proteins that regulate gene expression. Manipulating the expression or activity of specific transcription factors can influence macrophage polarization. 2. Cytokines and chemokines: Cytokines and chemokines are small signaling molecules that mediate immune responses. They can be used to manipulate macrophage polarization by inducing the expression of specific cytokines. 3. MicroRNAs (miRNAs): miRNAs are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level. Certain miRNAs have been identified as regulators of macrophage polarization. 4. Genetic engineering: Genetic engineering techniques, such as CRISPR-Cas9, can be used to directly modify genes involved in macrophage polarization. By introducing specific genetic modifications, researchers can enhance or suppress the expression of genes associated with M1 or M2 polarization.Manipulating macrophage polarization through gene manipulation techniques holds promise for modulating immune responses and promoting lung repair during injury.

Regulation of polarization of lung macrophages by Nur77/Nr4a1

Nur77, also known as NR4A1 (nuclear receptor subfamily 4 group A member 1), is a transcription factor belonging to the NR4A subfamily of nuclear receptors. Emerging evidence suggests its involvement in modulating macrophage polarization states.Macrophages are versatile immune cells that can adopt distinct functional states depending on the signals they receive from their microenvironment. Two main polarization states are commonly recognized: the classically activated (M1) phenotype, associated with pro-inflammatory responses, and the alternatively activated (M2) phenotype, linked to tissue repair and immunoregulation. The balance between M1 and M2 polarization is critical for maintaining immune homeostasis in the lung.Several studies have indicated that Nur77/NR4A1 may influence macrophage polarization towards the M1 phenotype. Also, other studies have also indicated a potential role for Nur77 in regulating M2 polarization of macrophages. Research findings suggest a dual role for Nur77 in modulating macrophage polarization, potentially promoting both M1 and M2 phenotypes depending on the context and specific signaling cues.It's important to note that the exact mechanisms underlying Nur77's regulation of macrophage polarization in the lung are still being elucidated. Further research is needed to fully understand the complex interplay between Nur77, other transcription factors, and the signaling pathways involved in lung macrophage polarization. Nonetheless, the current evidence suggests that Nur77/NR4A1 is a key player in orchestrating the immune responses of lung macrophages and may have a role in regulating their polarization towards both M1 and M2 phenotypes.

Bio-inspired Glycosylated Nano-hydroxyapatites Enhance Endogenous Bone Regeneration by Modulating Macrophage M2 Polarization.

A macrophage-associated immune response is vital in bone regeneration. Mannose receptor (MR), a macrophage pattern-recognition receptor, is crucial for the maintenance of immune homeostasis. Here, we designed MR-targeted glycosylated nano-hydroxyapatites (GHANPs) to reprogram macrophages into polarized M2s, promoting bone regeneration by improving the osteoimmune microenvironment. The prepared GHANPs induced macrophage M2 polarization, which then promoted osteoblastic differentiation of stem cells. Further, the mechanistic study showed that GHANPs might influence macrophage polarization by modulating cell metabolism, including enhancing mitochondrial oxidative phosphorylation and activating autophagy. Finally, a rat cranial defect model was used to verify the effect of GHANPs on endogenous bone regeneration in vivo, revealing that GHANPs promoted bone regeneration within the defect and increased the ratio of M2/M1 macrophages in early bone repair. Our results indicate that the MR-targeted macrophage M2 polarization strategy is promising in endogenous bone regeneration. STATEMENT OF SIGNIFICANCE: Macrophage is a pivotal immunity component for bone regeneration. A switch to M2 macrophage has been considered to contribute to osteogenesis. For inducing macrophage M2 polarization, an effective strategy to overcome off-target effects and insufficient specificity is a critical challenge. The mannose receptor on the surface of macrophages has been involved in regulating macrophage directional polarization. The glucomannan presented on the nano-hydroxyapatite rods acts as ligands targeting macrophage mannose receptors to promote their M2 polarization, improving the immunomicroenvironment and achieving bone regeneration. This approach has the advantage of easy preparation, specific regulation, and safety.

Identifying mechanisms driving macrophage differentiation and function in colorectal cancer.

Abstract The tumor microenvironment (TME) plays a critical role in cancer proliferation, metastasis, & responses of patients to treatment. Within the TME, tumor-initiated signaling results in aberrant activation of stromal & immune cell populations to suppress immune surveillance, induce angiogenesis, & establish premetastatic niches. Macrophages, a subset of antigen presenting myeloid cells, are the most abundant immune cell in the TME & participate in immune regulation during tumorigenesis. They functionally exhibit both anti & pro-tumorigenic properties as well as demonstrate the plasticity to repolarize between phenotypes based on environmental cues. Additionally, macrophage subset predominance within the TME & tumors have been correlated to favorable prognoses in some cancers. However, there is a lack of consensus for their role in colorectal cancer (CRC) progression. In this study, we investigated CRCs with distinct mutations, grade, & origin for their ability to drive macrophage differentiation & function in vitro. Human CRC cells were used to create multicellular tumor spheroids to better recapitulate in vivo tumor biology. CD14 +monocytes were polarized into macrophage subsets (M 0/M1/M2) by cytokine/growth-factor exposure (GMCSF/MCSF/IFNγ/IL4/IL6/IL10) & co-cultured with each model. Spheroid proliferation & inflammatory profiles alone/in co-culture were assessed by live-cell microscopy, viability, & multiplex assays. Macrophage polarization, spheroid infiltration, & anti-tumor activity were examined by flow-cytometry, live-cell microscopy, & functional assessments. Overall, this study demonstrates that it may be useful to direct targeted therapies to influence macrophage polarization in CRC patients. Supported by funding from Janssen Pharmaceutical Companies of Johnson & Johnson, Inc. under the direction of the DPDS Postdoctoral Fellowship Program and Biologics Discovery Division - Exploratory Biology Department.