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2 pages, 517 KiB  
Correction
Correction: Yun et al. Rhusflavone Modulates Osteoclastogenesis Through RANKL-Induced AKT Signaling in Bone Marrow-Derived Macrophages. Int. J. Mol. Sci. 2025, 26, 3025
by Hyung-Mun Yun, Bomi Kim, Eonmi Kim and Kyung-Ran Park
Int. J. Mol. Sci. 2025, 26(15), 7354; https://doi.org/10.3390/ijms26157354 - 30 Jul 2025
Viewed by 125
Abstract
In the original publication [...] Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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22 pages, 11171 KiB  
Article
Artesunate Ameliorates SLE Atherosclerosis Through PPARγ-Driven Cholesterol Efflux Restoration and Disruption of Lipid Raft-Organized TLR9/MyD88 Signaling Pathway
by Miao Zhang, Xinyu Pan, Yuanfang He, Kairong Sun, Zhiyu Wang, Weiyu Tian, Haonan Qiu, Yiqi Wang, Chengping Wen and Juan Chen
Biomolecules 2025, 15(8), 1078; https://doi.org/10.3390/biom15081078 - 25 Jul 2025
Viewed by 280
Abstract
Systemic lupus erythematosus (SLE) is characterized by autoimmune dysregulation, elevated autoantibody production, and persistent inflammation, predisposing patients to atherosclerosis (AS). Atherogenesis is dependent on lipid homeostasis and inflammatory processes, with the formation of lipid-laden, macrophage-derived foam cells (MDFC) essential for atherosclerotic lesion progression. [...] Read more.
Systemic lupus erythematosus (SLE) is characterized by autoimmune dysregulation, elevated autoantibody production, and persistent inflammation, predisposing patients to atherosclerosis (AS). Atherogenesis is dependent on lipid homeostasis and inflammatory processes, with the formation of lipid-laden, macrophage-derived foam cells (MDFC) essential for atherosclerotic lesion progression. Elevated cholesterol levels within lipid rafts trigger heightened pro-inflammatory responses in macrophages via Toll-like receptor 9 (TLR9). Artesunate (ART), an artemisinin derivative sourced from Artemisia annua, exhibits therapeutic potential in modulating inflammation and autoimmune conditions. Nonetheless, its impact and mechanisms in SLE-associated AS (SLE-AS) remain largely unexplored. Our investigation demonstrated that ART could effectively ameliorate lupus-like symptoms and atherosclerotic plaque development in SLE-AS mice. Moreover, ART enhanced cholesterol efflux from MDFC by upregulating ABCA1, ABCG1, and SR-B1 both in vivo and in vitro. Moreover, ART reduced cholesterol accumulation in bone marrow-derived macrophages (BMDMs), thereby diminishing TLR9 recruitment to lipid rafts. ART also suppressed TLR9 expression and its downstream effectors in the kidney and aorta of SLE-AS mice, attenuating the TLR9-mediated inflammatory cascade in CPG2395 (ODN2395)-stimulated macrophages. Through bioinformatics analysis and experimental validation, PPARγ was identified as a pivotal downstream mediator of ART in macrophages. Depleting PPARγ levels reduced the expression of ABCA1, ABCG1, and SR-B1 in macrophages, consequently impeding cholesterol efflux. In conclusion, these findings suggest that ART ameliorates SLE-AS by restoring cholesterol homeostasis through the PPARγ-ABCA1/ABCG1/SR-B1 pathway and suppressing lipid raft-driven TLR9/MyD88 inflammation. Full article
(This article belongs to the Section Lipids)
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20 pages, 3249 KiB  
Article
Granulocyte-Macrophage Colony-Stimulating Factor Inhibition Ameliorates Innate Immune Cell Activation, Inflammation, and Salt-Sensitive Hypertension
by Hannah L. Smith, Bethany L. Goodlett, Gabriella C. Peterson, Emily N. Zamora, Ava R. Gostomski and Brett M. Mitchell
Cells 2025, 14(15), 1144; https://doi.org/10.3390/cells14151144 - 24 Jul 2025
Viewed by 333
Abstract
Hypertension (HTN) is a major contributor to global morbidity and manifests in several variants, including salt-sensitive hypertension (SSHTN). SSHTN is defined by an increase in blood pressure (BP) in response to high dietary salt, and is associated with heightened cardiovascular risk, renal damage, [...] Read more.
Hypertension (HTN) is a major contributor to global morbidity and manifests in several variants, including salt-sensitive hypertension (SSHTN). SSHTN is defined by an increase in blood pressure (BP) in response to high dietary salt, and is associated with heightened cardiovascular risk, renal damage, and immune system activation. However, the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) has not yet been explored in the context of SSHTN. Previously, we reported that GM-CSF is critical in priming bone marrow-derived (BMD)-macrophages (BMD-Macs) and BMD-dendritic cells (BMD-DCs) to become activated (CD38+) in response to salt. Further exploration revealed these cells differentiated into BMD-M1 Macs, CD38+ BMD-M1 Macs, BMD-type-2 conventional DCs (cDC2s), and CD38+ BMD-cDC2s. Additionally, BMD-monocytes (BMDMs) grown with GM-CSF and injected into SSHTN mice traffic to the kidneys and differentiate into Macs, CD38+ Macs, DCs, and CD38+ DCs. In the current study, we treated SSHTN mice with an anti-GM-CSF antibody (aGM) and found that preventive aGM treatment mitigated BP, prevented renal inflammation, and altered renal immune cells. In mice with established SSHTN, aGM treatment attenuated BP, reduced renal inflammation, and differentially affected renal immune cells. Adoptive transfer of aGM-treated BMDMs into SSHTN mice resulted in decreased renal trafficking. Additionally, aGM treatment of BMD-Macs, CD38+ BMD-M1 Macs, BMD-DCs, and CD38+ BMD-cDC2s led to decreased pro-inflammatory gene expression. These findings suggest that GM-CSF plays a role in SSHTN and may serve as a potential therapeutic target. Full article
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22 pages, 3921 KiB  
Article
Quantitative Proteomics Reveals Fh15 as an Antagonist of TLR4 Downregulating the Activation of NF-κB, Inducible Nitric Oxide, Phagosome Signaling Pathways, and Oxidative Stress of LPS-Stimulated Macrophages
by Albersy Armina-Rodriguez, Bianca N. Valdés Fernandez, Carlimar Ocasio-Malavé, Yadira M. Cantres Rosario, Kelvin Carrasquillo Carrión, Loyda M. Meléndez, Abiel Roche Lima, Eduardo L. Tosado Rodriguez and Ana M. Espino
Int. J. Mol. Sci. 2025, 26(14), 6914; https://doi.org/10.3390/ijms26146914 - 18 Jul 2025
Viewed by 304
Abstract
There is a present need to develop alternative biotherapeutic drugs to mitigate the exacerbated inflammatory immune responses characteristic of sepsis. The potent endotoxin lipopolysaccharide (LPS), a major component of Gram-negative bacterial outer membrane, activates the immune system via Toll-like receptor 4 (TLR4), triggering [...] Read more.
There is a present need to develop alternative biotherapeutic drugs to mitigate the exacerbated inflammatory immune responses characteristic of sepsis. The potent endotoxin lipopolysaccharide (LPS), a major component of Gram-negative bacterial outer membrane, activates the immune system via Toll-like receptor 4 (TLR4), triggering macrophages and a persistent cascade of inflammatory mediators. Our previous studies have demonstrated that Fh15, a recombinant member of the Fasciola hepatica fatty acid binding protein family, can significantly increase the survival rate by suppressing many inflammatory mediators induced by LPS in a septic shock mouse model. Although Fh15 has been proposed as a TLR4 antagonist, the specific mechanisms underlying its immunomodulatory effect remained unclear. In the present study, we employed a quantitative proteomics approach using tandem mass tag (TMT) followed by LC-MS/MS analysis to identify and quantify differentially expressed proteins that participate in signaling pathways downstream TLR4 of macrophages, which can be dysregulated by Fh15. Data are available via ProteomeXchange with identifier PXD065520. Based on significant fold change (FC) cut-off of 1.5 and p-value ≤ 0.05 criteria, we focused our attention to 114 proteins that were upregulated by LPS and downregulated by Fh15. From these proteins, TNFα, IL-1α, Lck, NOS2, SOD2 and CD36 were selected for validation by Western blot on murine bone marrow-derived macrophages due to their relevant roles in the NF-κB, iNOS, oxidative stress, and phagosome signaling pathways, which are closely associated with sepsis pathogenesis. These results suggest that Fh15 exerts a broad spectrum of action by simultaneously targeting multiple downstream pathways activated by TLR4, thereby modulating various aspects of the inflammatory responses during sepsis. Full article
(This article belongs to the Special Issue From Macrophage Biology to Cell and EV-Based Immunotherapies)
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14 pages, 6653 KiB  
Article
Targeting Triple-Negative Breast Cancer with Momordicine-I for Therapeutic Gain in Preclinical Models
by Kousik Kesh, Ellen T. Tran, Ruchi A. Patel, Cynthia X. Ma and Ratna B. Ray
Cancers 2025, 17(14), 2342; https://doi.org/10.3390/cancers17142342 - 15 Jul 2025
Viewed by 362
Abstract
Background: TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms. Methods: Signaling pathways were analyzed to study the effect [...] Read more.
Background: TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms. Methods: Signaling pathways were analyzed to study the effect of M-I on TNBC cells (human MDA-MB-231 and mouse 4T1). We used orthotopic mouse models to examine the anti-tumor efficacy of M-I. Tumor volume and the status of tumor-associated macrophages (TAMs) were assessed by qRT-PCR or FACS analysis. Results: We found a significant dose- and time-dependent inhibition of TNBC cell proliferation following treatment with M-I. Cell cycle analysis revealed a shortened S phase in M-I-treated cells and downregulation of AURKA, PLK1, CDC25c, CDK1, and cyclinB1. Furthermore, M-I treatment reduced the expression of pSTAT3, cyclinD1, and c-Myc in TNBC cells. To evaluate the anti-tumor efficacy of M-I, we employed orthotopic TNBC mouse models and observed a significant reduction in tumor growth without measurable toxicity. Next, we analyzed RNA from control and M-I-treated tumors to further assess the status of TAMs and observed a significant decrease in M2-like macrophages in the M-I-treated group. Immortalized bone marrow-derived mouse macrophages (iMacs) exposed to conditioned media (CM) of TNBC cells with or without M-I treatment indicated that the M-I treated CM of TNBC cells significantly reduce the M2phenotype in iMacs. Mechanistically, we found that M-I specifically targets the IL-4/MAPK signaling axis to reduce immunosuppressive M2 macrophage polarization. Conclusions: Our study reveals a novel mechanism by which M-I inhibits TNBC cell proliferation by regulating intracellular signaling and altering TAMs in the tumor microenvironment and highlights its potential as a promising candidate for TNBC therapy. Full article
(This article belongs to the Section Cancer Therapy)
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10 pages, 1764 KiB  
Brief Report
Cathelicidins Limit Intracellular Neospora caninum-Infection in Macrophages
by Franco Fiorani, Priyoshi Lahiri, Rodrigo Puentes, Peter John Bradley, Dadin Prando Moore and Eduardo Ruben Cobo
Pathogens 2025, 14(7), 663; https://doi.org/10.3390/pathogens14070663 - 5 Jul 2025
Viewed by 556
Abstract
Infections with the protozoan Neospora caninum cause abortion in cattle, likely due to the parasite’s replication and excessive inflammation in the placenta. Cathelicidins are host defense peptides known for their antimicrobial and immunomodulatory functions, but their role in N. caninum infections remains elusive. [...] Read more.
Infections with the protozoan Neospora caninum cause abortion in cattle, likely due to the parasite’s replication and excessive inflammation in the placenta. Cathelicidins are host defense peptides known for their antimicrobial and immunomodulatory functions, but their role in N. caninum infections remains elusive. Using bone marrow-derived macrophages (BMDMs) isolated from mice expressing (wild-type, Camp+/+) and lacking (Camp/−) cathelicidins, we investigated the role of endogenous cathelicidin in infections with N. caninum. We show that Camp/− macrophages primed with lipopolysaccharide (LPS) had an increased number of intracellular N. caninum tachyzoites, and these macrophages released higher amounts of IL-1β and lactate dehydrogenase (LDH), a marker of cytotoxicity. These findings indicate that cathelicidins contribute to intracellular N. caninum control and inflammation by limiting the activation of the inflammasome, particularly under LPS-induced conditions. This insight reveals the immunomodulatory role of cathelicidins in controlling N. caninum-associated pathologies. Full article
(This article belongs to the Special Issue Genetics and Molecular Evolution of Parasitic Protozoa)
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15 pages, 2550 KiB  
Article
Anti-Inflammatory Secondary Metabolites from Penicillium sp. NX-S-6
by Hanyang Peng, Jiawen Sun, Rui Zhang, Yuxuan Qiu, Yu Hong, Fengjuan Zhou, Chang Wang, Yang Hu and Xiachang Wang
Mar. Drugs 2025, 23(7), 280; https://doi.org/10.3390/md23070280 - 4 Jul 2025
Viewed by 525
Abstract
Five new natural products, including two sorbicillinoids (12), one indolinone alkaloid (10), one tetracyclic steroid (11), and one α-pyrone derivative (14), were identified from the endophytic Penicillium sp. NX-S-6, together with thirteen known [...] Read more.
Five new natural products, including two sorbicillinoids (12), one indolinone alkaloid (10), one tetracyclic steroid (11), and one α-pyrone derivative (14), were identified from the endophytic Penicillium sp. NX-S-6, together with thirteen known natural products. The structures of new compounds were unambiguously elucidated by comprehensive spectroscopic analyses (NMR, MS), as well as electronic circular dichroism (ECD) calculation. Notably, quinosorbicillinol (1) was identified as a rare hybrid sorbicillinoid incorporating a quinolone moiety, representing a unique structural scaffold in this natural product class. Biological evaluation revealed that Compounds 1, 4 and 8 potently inhibited the production of nitric oxide and interleukin 6 in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Mechanistic studies furthermore demonstrated that Compounds 4 and 8 effectively suppressed interleukin-1β secretion in LPS-induced immortalized mouse bone marrow-derived macrophages (iBMDMs) by blocking NLRP3 inflammasome activation. This inhibition was attributed to their ability to disrupt the assembly of the NLRP3-caspase-1 complex, a key event in the pathogenesis of inflammatory disorders. These findings not only expand the structural diversity of endophyte-derived natural products but also highlight their potential as lead compounds for developing anti-inflammatory therapeutics targeting the NLRP3 pathway. Full article
(This article belongs to the Special Issue Structural Diversity in Marine Natural Products)
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21 pages, 4035 KiB  
Article
Exploring the Role of Peripheral Macrophages in Glioma Progression: The Metabolic Significance of Cyclooxygenase-2 (COX-2)
by Jens Pietzsch, Magali Toussaint, Cornelius Kurt Donat, Alina Doctor, Sebastian Meister, Johanna Wodtke, Markus Laube, Frank Hofheinz, Jan Rix, Winnie Deuther-Conrad and Cathleen Haase-Kohn
Int. J. Mol. Sci. 2025, 26(13), 6198; https://doi.org/10.3390/ijms26136198 - 27 Jun 2025
Viewed by 505
Abstract
Glioblastoma (GBM) is the most aggressive form of malignant gliomas, with the eicosanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) playing a pivotal role in its progression via the COX-2/prostaglandin E2/4 axis. COX-2 upregulations in tumor cells induces a pro-inflammatory tumor microenvironment (TME), affecting the behavior of [...] Read more.
Glioblastoma (GBM) is the most aggressive form of malignant gliomas, with the eicosanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) playing a pivotal role in its progression via the COX-2/prostaglandin E2/4 axis. COX-2 upregulations in tumor cells induces a pro-inflammatory tumor microenvironment (TME), affecting the behavior of invading bone marrow-derived macrophages (Mϕ) and brain-resident microglia (MG) through unclear autocrine and paracrine mechanisms. Using CRISPR/Cas9 technology, we generated COX-2 knockout U87 glioblastoma cells. In spheroids and in vivo xenografts, this resulted in a significant inhibition of tumorigenic properties, while not observed in standard adherent monolayer culture. Here, the knockout induced a G1 cell cycle arrest in adherent cells, accompanied by increased ROS, mitochondrial activity, and cytochrome c-mediated apoptosis. In spheroids and xenograft models, COX-2 knockout led to notable growth delays and increased cell death, characterized by features of both apoptosis and autophagy. Interestingly, these effects were partially reversed in subcutaneous xenografts after co-culture with Mϕ, while co-culture with MG enhanced the growth-suppressive effects. In an orthotopic model, COX-2 knockout tumors displayed reduced proliferation (fewer Ki-67 positive cells), increased numbers of GFAP-positive astrocytes, and signs of membrane blebbing. These findings highlight the potential of COX-2 knockout and suppression as a therapeutic strategy in GBM, particularly when combined with suppression of infiltrating macrophages and stabilization of resident microglia populations to enhance anti-tumor effects. Full article
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18 pages, 6105 KiB  
Article
Zirconium-89-Oxine Cell Tracking by PET Reveals Preferential Monocyte Recruitment to Cancer and Inflammation over Macrophages
by Sho Koyasu, Hannah A. Minor, Kingsley O. Asiedu, Peter L. Choyke and Noriko Sato
Pharmaceuticals 2025, 18(6), 897; https://doi.org/10.3390/ph18060897 - 15 Jun 2025
Viewed by 564
Abstract
Background/Objectives: Cell-based therapies have become increasingly important in the treatment of cancers and inflammatory diseases; however, therapies utilizing monocyte–macrophage lineage cells remain relatively underexplored. Non-invasive cell tracking allows a better understanding of the fate of such cells, which is essential for leveraging their [...] Read more.
Background/Objectives: Cell-based therapies have become increasingly important in the treatment of cancers and inflammatory diseases; however, therapies utilizing monocyte–macrophage lineage cells remain relatively underexplored. Non-invasive cell tracking allows a better understanding of the fate of such cells, which is essential for leveraging their therapeutic potential. Here, we employed a Zirconium-89 (89Zr)-oxine cell labeling method to compare the trafficking of monocytes and macrophages in vivo. Methods: Mouse bone marrow-derived monocytes and macrophages were each labeled with 89Zr-oxine and evaluated for their viability, radioactivity retention, chemotaxis, and phagocytic function in vitro. Labeled cells were intravenously administered to healthy mice and to murine models of granuloma and syngeneic tumors. Cell migration was monitored using microPET/CT, while cell recruitment to the lesions was further assessed via ex vivo biodistribution and flow cytometry. Results: Labeled cells exhibited similar survival and proliferation to unlabeled cells for up to 7 days in culture. While both maintained phagocytic function, monocytes showed higher CCL2-driven chemotaxis compared to macrophages. 89Zr-oxine PET revealed initial cell accumulation in the lungs, followed by their homing to the liver and spleen within 2–24 h, persisting through the 5-day observation period. Notably, monocytes trafficked to the liver and spleen more rapidly than macrophages. In both inflammation and cancer models, monocytes demonstrated higher accumulation at the lesion sites compared to macrophages. Conclusions: This study demonstrates the usefulness of 89Zr-oxine PET in tracking monocyte–macrophage lineage cells, highlighting their distinct migration patterns and providing insights that could advance monocyte-centered cell therapies. Full article
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19 pages, 880 KiB  
Review
Unraveling the Roles of Macrophages in Vascularized Composite Allotransplantation
by Hui-Yun Cheng, Madonna Rica Anggelia and Cheng-Hung Lin
Biomedicines 2025, 13(6), 1425; https://doi.org/10.3390/biomedicines13061425 - 10 Jun 2025
Viewed by 468
Abstract
The phenotypic heterogeneity and functional diversity of macrophages have been increasingly appreciated, particularly regarding their roles as innate immune cells in shaping transplantation outcomes. However, their functions in vascularized composite allotransplantation (VCA) remain underexplored. In this review, we first describe the development of [...] Read more.
The phenotypic heterogeneity and functional diversity of macrophages have been increasingly appreciated, particularly regarding their roles as innate immune cells in shaping transplantation outcomes. However, their functions in vascularized composite allotransplantation (VCA) remain underexplored. In this review, we first describe the development of macrophages and the heterogeneity of macrophage differentiation, then present current insights into macrophages’ involvement across key stages of VCA, including ischemia–reperfusion injury at the peri-transplantation stage, and the outcomes following transplantation, including acute rejection, chronic rejection, and development of transplantation tolerance. The existing evidence supports that macrophages significantly influence both short- and long-term VCA graft survival. The presence of vascularized bone marrow within some VCA grafts further suggests the involvement of donor bone marrow-derived macrophage population and adds another layer of complexity to immune dynamics. Collectively, current understanding highlights the macrophage as a promising target for therapeutic intervention and warrants continued investigation into their diverse functions and potential for improving VCA outcomes. Full article
(This article belongs to the Special Issue An Update on Transplantation Immunology)
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15 pages, 3326 KiB  
Article
Structural and Functional Insights into a Novel Aspergillus ochraceus Polysaccharide from the Weddell Sea: Implications for Melanoma Immunotherapy In Vitro
by Jiale Hao, Kouame kra Wilfred Armel, Pengcheng Gao, Jinglei Wang, Weibin Zhang, Kexin Du, Qi Li, Huishu Gao, Guangli Yu and Guoyun Li
Mar. Drugs 2025, 23(6), 246; https://doi.org/10.3390/md23060246 - 10 Jun 2025
Viewed by 575
Abstract
Immunotherapy is a transformative strategy in oncology, yet the development of novel immunomodulatory agents remains essential. This study explores the anti-tumor potential of a structurally unique polysaccharide isolated from an Aspergillus ochraceus (AOP), sourced from the Antarctic Weddell Sea. Using alkaline-assisted extraction and [...] Read more.
Immunotherapy is a transformative strategy in oncology, yet the development of novel immunomodulatory agents remains essential. This study explores the anti-tumor potential of a structurally unique polysaccharide isolated from an Aspergillus ochraceus (AOP), sourced from the Antarctic Weddell Sea. Using alkaline-assisted extraction and chromatographic purification, we obtained a homogeneous polysaccharide predominantly composed of galactose and mannose, with an average molecular weight of 39.67 kDa. The structure was characterized by an integrated nuclear magnetic resonance spectroscopy and mass spectrometry analysis, revealing that the AOP is composed of β (1→5)-linked galactofuranose units, with a minor substitution by α-D-mannopyranose residues via (1→2) glycosidic bonds at the C2 of the galactofuranose. Functional assays, including CCK8 and wound-healing tests, demonstrated that this polysaccharide, referred to as AOP, inhibited melanoma cell proliferation and migration in a dose-dependent manner. Additionally, the AOP activated RAW264.7 and bone marrow-derived macrophage (BMDM) cells without exhibiting significant cytotoxicity, leading to the release of inflammatory factors such as TNF-α, IL-1β, and IL-6. Mechanistically, the AOP was found to upregulate the expression of CD86 and IFN-γ, while downregulating genes like IL-4 and Arg1. These findings position the AOP as the first documented Antarctic fungal polysaccharide with macrophage-reprogramming capabilities against melanoma, offering novel molecular insights for marine-derived immunotherapeutics. Full article
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23 pages, 4349 KiB  
Article
The RXR Agonist MSU-42011 Reduces Tumor Burden in a Murine Preclinical NF1-Deficient Model
by Pei-Yu Hung, Jessica A. Moerland, Ana S. Leal, Bilal Aleiwi, Edmund Ellsworth, D. Wade Clapp, Verena Staedtke, Renyuan Bai and Karen T. Liby
Cancers 2025, 17(12), 1920; https://doi.org/10.3390/cancers17121920 - 9 Jun 2025
Viewed by 671
Abstract
Background/Objectives: Neurofibromatosis type 1 (NF1) is a prevalent inherited disorder, with approximately 50% of affected individuals developing plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is [...] Read more.
Background/Objectives: Neurofibromatosis type 1 (NF1) is a prevalent inherited disorder, with approximately 50% of affected individuals developing plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is limited and associated with dose-limiting toxicities. NF1 deficiency drives tumorigenesis and alters immune dynamics via RAS hyperactivation. Given the substantial macrophage infiltration in NF1 lesions and its association with disease progression, we hypothesized that targeting tumor-promoting immune cells with the retinoid X receptor (RXR) agonist MSU-42011 could be an alternative therapeutic strategy, as it has shown promise in KRAS-driven cancers by decreasing pERK levels and reducing tumor-promoting immune cells. Methods: We examined the effects of MSU-42011 and selumetinib, alone and in combination, on NF1-deficient cells and in a syngeneic MPNST model. Results: In vivo, the combination of MSU-42011 and selumetinib significantly reduced tumor growth, pERK levels, and tumor-promoting macrophages and increased activated CD8+ T cells in syngeneic MPNST models. In NF1-deficient cells, MSU-42011 or selumetinib reduced pERK levels, with combination treatment achieving greater reductions. Conditioned media (CM) from NF1-deficient cells increased the protein and mRNA levels of several cytokines and chemokines in human THP1 cells and bone marrow-derived macrophages (BMDMs). MSU-42011 and selumetinib, alone or in combination, partially reversed this induction. Conclusions: These findings suggest RXR agonists may have therapeutic potential against NF1, and their combination with MEK inhibitors could represent a promising strategy for NF1-associated tumors. Further studies are needed to validate these results and assess their translational relevance. Full article
(This article belongs to the Special Issue Neurofibromatosis)
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22 pages, 8752 KiB  
Article
B10 Promotes Polarization and Pro-Resolving Functions of Bone Marrow Derived Macrophages (BMDM) Through PD-1 Activation
by Takumi Memida, Guoqin Cao, Elaheh Dalir Abdolahinia, Sunniva Ruiz, Shengyuan Huang, Sahar Hassantash, Satoru Shindo, Motoki Okamoto, Shohei Yamashita, Shin Nakamura, Maiko Suzuki, Toshihisa Kawai and Xiaozhe Han
Cells 2025, 14(12), 860; https://doi.org/10.3390/cells14120860 - 7 Jun 2025
Viewed by 827
Abstract
Regulatory B cells (B regs) are immune cells that help suppress excessive inflammatory responses by interacting with other immune components. Among them, B-10 cells are known for their strong immunoregulatory function. This study focused on how B-10 cells influence macrophage phenotype and function [...] Read more.
Regulatory B cells (B regs) are immune cells that help suppress excessive inflammatory responses by interacting with other immune components. Among them, B-10 cells are known for their strong immunoregulatory function. This study focused on how B-10 cells influence macrophage phenotype and function through the PD-1 signaling pathway. To investigate this, B-10 cells derived from mouse spleens were co-cultured with bone marrow-derived macrophages (BMDMs) from either wild-type (WT) or PD-1 knockout (PD-1 KO) mice, using both direct contact and Transwell setups. The findings indicated that direct co-culture with B-10 cells significantly promoted the polarization of macrophages towards the anti-inflammatory M2 type, characterized by increased expression of surface markers (F4/80+, CD206+, CD163+), higher levels of PD-1, and upregulation of M2-related genes (IL-1ra, IL-10, Arg-1, IL-6, and CCL1). These macrophages also exhibited enhanced phagocytic activity and greater secretion of specialized pro-resolving mediator (SPMs) like RvD2 and 15-epi LXA4. In contrast, these effects were reduced when B-10 cells were cultured indirectly or when PD-1 was absent. These findings suggest that B-10 cells promote anti-inflammatory macrophage activity primarily through PD-1 signaling, offering insights into potential therapeutic approaches for controlling inflammation. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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16 pages, 3005 KiB  
Article
Pro-Resolving Macrophage-Induced IL-35+ but Not TGF-β1+ Regulatory B Cell Activation Requires the PD-L1/PD-1 Pathway
by Guoqin Cao, Takumi Memida, Shengyuan Huang, Elaheh Dalir Abdolahinia, Sunniva Ruiz, Sahar Hassantash, Jayant Ari, Satoru Shindo, Jiang Lin, Toshihisa Kawai and Xiaozhe Han
Int. J. Mol. Sci. 2025, 26(11), 5332; https://doi.org/10.3390/ijms26115332 - 1 Jun 2025
Cited by 1 | Viewed by 565
Abstract
The interaction between immune regulatory cells, such as regulatory B cells (Breg) and pro-resolving macrophages (M2 macrophages), plays an important role in the restoration of immune homeostasis during inflammation. PD-L1 is one of the effector molecules that mediates the immune regulation function of [...] Read more.
The interaction between immune regulatory cells, such as regulatory B cells (Breg) and pro-resolving macrophages (M2 macrophages), plays an important role in the restoration of immune homeostasis during inflammation. PD-L1 is one of the effector molecules that mediates the immune regulation function of M2 macrophages. The activation of PD-L1/PD-1 signaling promotes the differentiation of Breg. Previous studies have shown that Breg promoted M2 macrophage polarization and enhanced their function, but little is known about the regulatory function of M2 macrophages on Breg differentiation. This study aims to determine the effect of M2 macrophages on Breg induction and the potential mechanism in vitro. Bone-marrow-derived macrophages were isolated from wild-type (WT) mice and polarized into M2 using IL-4/IL-13. To investigate the role of PD-L1/PD-1 in M2 macrophage-induced Breg differentiation, spleen B cells were isolated from WT or PD-1 knockout (KO) mice and co-cultured with either naïve (M0) or M2 macrophages for 48 h with or without trans-well inserts. The expression of IL-10, IL-35, and TGF-β1 in B cells was evaluated by flow cytometry and immunofluorescence staining. Recombinant PD-L1 was used to stimulate activated B cells, followed by the detection of IL-35 and TGF-β1. The results show that there was no significant difference in IL-10 expression among all groups. However, IL-35 and TGF-β1 expression in B cells was significantly increased in the M2+B, but not in M0+B, compared to B cells alone. Notably, such increases were diminished when M2 and B cells were separated by trans-well inserts. IL-35 expression was not significantly changed when B cells from PD-1 KO mice were co-cultured with M2 compared to the control. However, TGF-β1 expression was significantly increased when PD-1 KO B cells were co-cultured with M2 compared to the control. IL-35 expression in activated B cells was increased upon stimulation with PD-L1. However, TGF-β1 expression in activated B cells was increased regardless of the PD-L1 availability. This study demonstrates that pro-resolving macrophage-induced IL-35+ but not TGF-β1+ regulatory B cell activation requires the PD-L1/PD-1 pathway. Full article
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23 pages, 7919 KiB  
Article
Bone Marrow-Derived Inducible Microglia-like Cells Promote Recovery of Chronic Ischemic Stroke Through Modulating Neuroinflammation in Mice
by Bach Ngoc Nguyen, Tomoaki Kitamura, Shuhei Kobashi, Makoto Urushitani and Tomoya Terashima
Biomedicines 2025, 13(6), 1347; https://doi.org/10.3390/biomedicines13061347 - 30 May 2025
Viewed by 598
Abstract
Background: Chronic ischemic stroke presents a significant challenge in neurology, with limited therapeutic options available for long-term recovery. During cerebral infarction, anti-inflammatory phenotype microglia/macrophages produce anti-inflammatory cytokines and neurotrophic factors that facilitate the process of brain repair. However, obtaining sufficient anti-inflammatory microglia/macrophages from [...] Read more.
Background: Chronic ischemic stroke presents a significant challenge in neurology, with limited therapeutic options available for long-term recovery. During cerebral infarction, anti-inflammatory phenotype microglia/macrophages produce anti-inflammatory cytokines and neurotrophic factors that facilitate the process of brain repair. However, obtaining sufficient anti-inflammatory microglia/macrophages from the human central nervous system is challenging. Bone marrow-derived inducible microglia-like cells (BM-iMGs) with an anti-inflammatory microglial phenotype were explored to induce neuroprotective properties. Here, we transplanted BM-iMGs into the brain of middle cerebral artery occlusion (MCAO) model male mice to explore their potential for treating chronic ischemic stroke. Methods: Bone marrow-derived mononuclear cells (BM-MNCs) were isolated from green fluorescent protein mice and incubated with granulocyte–macrophage colony-stimulating factor (GM-CSF) and IL-4 to induce BM-iMGs with an anti-inflammatory phenotype. BM-iMGs were transplanted into the brains of mice on day 14 after MCAO, and behavioral tests, histology, cerebral blood flow, and gene expression were evaluated. Results: An intracranial injection of BM-iMGs promoted neurobehavioral recovery, reduced neuronal cell loss, suppressed neuroinflammatory astrocytic and microglial responses in the brain, and increased cortical surface cerebral blood flow in MCAO mice. Furthermore, neuroprotective genes were upregulated, whereas proinflammatory genes were downregulated. Conclusions: The intracranial injection of BM-iMG cells shows significant potential as a novel therapy for chronic ischemic stroke. Full article
(This article belongs to the Section Gene and Cell Therapy)
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