Search Results (771)

Microglial cells, the resident immune cells of the central nervous system (CNS), are essential for maintaining CNS homeostasis. Dysregulation of microglial function is implicated in the pathogenesis of various neurodegenerative diseases. Vasoactive intestinal polypeptide receptors 1 and 2 (VPAC1 and VPAC2) are G-protein-coupled receptors (GPCRs) expressed by microglia, with their primary ligands being pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). However, the specific roles of VPAC-type receptors in microglial regulation remain poorly understood. In this study, we generated VPAC1^+/− and VPAC2^+/− BV2 microglial cell lines using CRISPR-Cas9 gene editing and conducted a series of biological and molecular assays to elucidate the functions of these receptors. Our findings demonstrated that both mutant cell lines exhibited a polarized phenotype and increased migratory activity. VPAC1^+/− cells showed enhanced survivability and baseline activation of the unfolded protein response (UPR), a protective mechanism triggered by endoplasmic reticulum (ER) stress, whereas this response appeared impaired in VPAC2^+/− cells. In contrast, under lipopolysaccharide (LPS)-induced inflammatory conditions, UPR activation was impaired in VPAC1^+/− cells but restored in VPAC2^+/− cells, resulting in improved survival of VPAC2^+/− cells, whereas VPAC1^+/− cells exhibited reduced resilience. Overall, our findings suggest that VPAC1 and VPAC2 receptors play distinct yet complementary roles in BV2 microglia. VPAC2 is critical for regulating survival, ER stress responses, and polarization under basal conditions, while VPAC1 is essential for adaptive responses to inflammatory stimuli such as LPS. These insights advance our understanding of microglial receptor signaling and may inform therapeutic strategies targeting microglial dysfunction in neurodegenerative diseases. Full article

Disease progression and treatment resistance in colorectal and other cancers are driven by a subset of cells within the tumor that have stem-cell-like properties and long-term tumorigenic potential. These stem-cell-like cells express the leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) and have characteristics similar to tissue-resident stem cells in normal adult tissues such as the colon. Organoid models of murine and human colorectal and other cancers contain LGR5-expressing (LGR5+) stem-cell-like cells and can be used to investigate the underlying mechanisms of cancer development, progression, therapy vulnerability, and resistance. A large biobank of organoids derived from colorectal cancer or adjacent normal tissue was developed. We performed a large-scale unbiased functional screen to identify bispecific antibodies (BsAbs) that preferentially inhibit the growth of colon tumor-derived, as compared to normal tissue-derived, organoids. We identified the most potent BsAb in the screen as petosemtamab, a Biclonics^® BsAb targeting both LGR5 and the epidermal growth factor receptor (EGFR). Petosemtamab employs three distinct mechanisms of action: EGFR ligand blocking, EGFR receptor internalization and degradation in LGR5+ cells, and Fc-mediated activation of the innate immune system by antibody-dependent cellular phagocytosis (ADCP) and enhanced antibody-dependent cellular cytotoxicity (ADCC) (see graphical abstract). Petosemtamab has demonstrated substantial clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). The safety profile is generally favorable, with low rates of skin and gastrointestinal toxicity. Phase 3 trials are ongoing in both first-line programmed death-ligand 1-positive (PD-L1+) and second/third-line r/m HNSCC. Full article

The tumor microenvironment (TME) is a unique ecosystem that surrounds tumor tissues. The TME is composed of extracellular matrix, immune cells, blood vessels, stromal cells, and fibroblasts. These environments enhance cancer development, progression, and metastasis. Recent success in immune checkpoint blockade also supports the importance of the TME and immune cells residing in the tumor niche. Although the TME can be identified in almost all cancer types, the role of the TME may not be similar among different cancer types. Regulatory T cells (Tregs) play a pivotal role in immune homeostasis and are frequently found in the TME. Owing to their suppressive function, Tregs are often considered unfavorable factors that allow the immune escape of cancer cells. However, the presence of Tregs is not always linked to an unfavorable phenotype, which can be explained by the heterogeneity and plasticity of Tregs. In this review, the current understanding of the role of Tregs in TME is addressed for each cancer cell type. Moreover, recently a therapeutic approach targeting Tregs infiltrating in the TME has been developed including drug antibody conjugate, immunotoxin, and FOXP3 inhibiting peptide. Thus, understanding the role of Tregs in the TME may lead to the development of novel therapies that directly target the TME. Full article

Microglia, the resident immune cells of the central nervous system, play multifaceted roles in both health and disease. During development, they regulate neurogenesis and refine neural circuits through synaptic pruning. In adulthood, microglia maintain homeostasis and dynamically respond to pathological insults, where they contribute to responding to neuroinflammatory challenges. This review summarizes microglial contributions to neurodevelopment and also outlines their function across various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, highlighting both protective and detrimental effects. Finally, recent advances in microglial-targeted therapies and lifestyle-based interventions are highlighted, underscoring the translational potential of modulating microglial states. Elucidating the dual roles of microglia in development and disease could guide the design of therapeutic strategies aimed at enhancing neuroprotection while minimizing neurotoxicity. Full article

Objective: F. nucleatum, a tumor-resident bacterium colonizing breast cancer (BC), results in an immunosuppressive microenvironment and facilitates tumor growth and metastasis. This study aimed to develop a neutrophil-based liposome delivery system designed for dual-targeted elimination of tumor cells and F. nucleatum, while simultaneously upregulating pathogen-associated molecular patterns and damage-associated molecular patterns to potentiate tumor immunotherapy. Methods: The liposomes (PD/GA-LPs) loaded with the perylene diimide complex (PD) and gambogic acid (GA) were fabricated via the extrusion method. Subsequently, comprehensive evaluations including physicochemical characteristics, antibacterial activity, antitumor effect, and immunomodulatory effect evaluation were systematically conducted to validate the feasibility of this delivery system. Results: The resulting PD/GA-LPs exhibited a dynamic size (121.3 nm, zeta potential −44.1 mV) and a high encapsulation efficiency of approximately 78.1% (PD) and 91.8% (GA). In addition, the optimized PD/GA-LPs exhibited excellent photothermal performance and antibacterial efficacy. In vitro cellular experiments revealed that PD/GA-LPs exhibited enhanced internalization by neutrophils, followed by extracellular trap-mediated release, ultimately significantly inhibiting tumor cell proliferation and inducing immunogenic cell death. During in vivo treatment, PD/GA-LPs exhibited targeted tumor accumulation, where F. nucleatum-driven PD reduction activated near-infrared-responsive photothermal ablation. When combined with GA, this delivery system effectively eliminated tumor cells and F. nucleatum, while facilitating the subsequent T-cell infiltration. Conclusions: This strategy amplified the antitumor immune response, thus leading to effective treatment of BC and prevention of metastasis. In summary, this approach, grounded in the distinct microecology of tumor and normal tissues, offers novel insights into the development of precise and potent immunotherapies for BC. Full article

Background/Objectives: Liver and tumor-infiltrating T cells in hepatocellular carcinoma (HCC) are heterogeneous, comprising the CD69⁺ tissue-resident T-cell and the CD69⁻ circulating T-cell populations. However, the impact of these distinct T-cell populations on patient prognosis is unclear; hence, further studies are needed. Methods: Tumor and distant liver tissues from 57 HCC patients with various chronic liver disease etiologies were analyzed. Single-cell dissociation and flow cytometry were used to assess CD69⁺ and CD69⁻ T-cell populations and their correlation with recurrence-free survival (RFS). Results: CD69⁺/CD69⁻ subpopulations within CD4⁺ and CD8⁺ T cells varied by patient and alcohol etiology. CD69⁻ populations among CD4⁺ T cells were less frequent in both tumor and non-tumor tissues of alcohol-related HCC patients (p < 0.05). Higher frequencies of CD69⁻CD4⁺ and CD8⁺ T cells in tumors and CD69⁺CD103⁺CD8⁺ T cells in liver tissues were associated with better RFS. CD69- T cells expressed lower PD-1 levels, indicating less exhaustion, with PD-1 expression inversely correlated with CD69⁻ frequency. PD-1 expression was higher in CD69⁻CD4⁺ T cells in alcohol-related HCC. Conclusions: We provided a detailed analysis of the heterogeneous characteristics of tumor- and liver-infiltrating T cells in HCC, emphasizing the distinct roles of CD69⁺ and CD69⁻ cell populations and their impact on RFS. CD69⁺ T cells were associated with immune exhaustion and tumor aggressiveness, whereas CD69⁻ T cells appeared to significantly contribute to the influence of alcohol intake on the immune landscape of HCC in the tumor microenvironment. However, further research should validate these findings in larger cohorts to enhance our understanding. Full article

Immune cytopenias, such as autoimmune hemolytic anemia, immune thrombocytopenia, and Evans syndrome, are characterized by autoantibodies targeting various blood cells, initiating their destruction. Interactions between T cells, B cells, their ultimate maturational plasma cell descendants, dendritic cells, and macrophages result in antibody production, including the autoreactive ones. Autoimmune phenomena can be idiopathic or associated with various immune dysregulation conditions or malignancies. Interventions disrupting this complex network at different levels have been used to treat immune cytopenias with certain levels of success. Some cases are known to be refractory to many different therapeutic approaches, including the ones eliminating B cells. In some such cases, targeting plasma cells resulted in disease control. Among plasma cell compartments, unique long-lived plasma cells (LLPCs) residing primarily in the bone marrow, are specialized antibody-producing cells with an extended lifespan, capable of persistently secreting antibodies. LLPCs can evade conventional therapeutic strategies designed to target often-proliferating cells. Research focusing on the role of LLPCs in autoimmune phenomena including immune cytopenias has provided evidence for their role, characterized by the sustained production of autoantibodies. Frequent genetic mutations and progression to other immune dysregulation entities have been reported in a group of children with immune cytopenias. This might provide new insights focusing on the potential underlying genetic and epigenetic mechanisms leading to generation and maintenance of LLPCs in autoimmune disorders. We provide a brief review of LLPC biology and evidence for their role in immune cytopenias with potential future implications in this article. Full article

The aim of this study was to systematically review literature on immune responses in liver tissue pathology in diabetes, focusing on immune cell populations and related cytokines. A systematic search of relevant English full-text articles up to June 2024 from online databases, covering animal and human studies, was conducted using the PRISMA workflow. Thirteen studies met criteria. Immune cells in the liver, including monocytes/macrophages, neutrophils, and iNKT and T cells, were implicated in liver inflammation and fibrosis in diabetes. Pro-inflammatory cytokines, including interferon-ɣ, tumor necrosis factor-α, interleukin (IL)-15, IL-18, and IL-1β were upregulated in the liver, potentially contributing to liver inflammation and fibrosis progression. In contrast, the anti-inflammatory cytokine IL-4 was downregulated, possibly attributing to chronic inflammation in diabetes. Pathological immune responses via the TLR4/MyD88/NF-κB pathway and the IL-17/IL-23 axis were also linked to liver fibrosis in diabetes. In conclusion, this review highlights the putative pivotal role of immune cells in diabetes-related liver fibrosis progression through their regulation of cytokines and signaling pathways. Further research on diabetes and dysmetabolic liver pathology is needed to clarify immune cell localization in the liver and their interactions with resident cells promoting fibrosis. Targeting immune mechanisms may provide therapeutic strategies for managing liver fibrosis in diabetes. Full article

Despite the success of antiretroviral therapy (ART) in suppressing viral replication in the blood, HIV persists in the central nervous system (CNS) and causes chronic neurocognitive impairment, a hallmark of HIV-associated neurocognitive disorders (HAND). This review looks at the complex interactions among HIV, the blood–brain barrier (BBB), neuroinflammation, and the roles of viral proteins, immune cell trafficking, and pro-inflammatory mediators in establishing and maintaining latent viral reservoirs in the CNS, particularly microglia and astrocytes. Key findings show disruption of the BBB, monocyte infiltration, and activation of CNS-resident cells by HIV proteins like Tat and gp120, contributing to the neuroinflammatory environment and neuronal damage. Advances in epigenetic regulation of latency have identified targets like histone modifications and DNA methylation, and new therapeutic strategies like latency-reversing agents (LRAs), gene editing (CRISPR/Cas9), and nanoparticle-based drug delivery also offer hope. While we have made significant progress in understanding the molecular basis of HIV persistence in the CNS, overcoming the challenges of BBB penetration and neuroinflammation is key to developing effective therapies. Further research into combination therapies and novel drug delivery systems will help improve outcomes for HAND patients and bring us closer to a functional cure for HIV. Full article

The gut microbiome, a complex community of microorganisms residing in the intestinal tract, plays a dual role in colorectal cancer (CRC) development, acting both as a contributing risk factor and as a protective element. This review explores the mechanisms by which gut microbiota contribute to CRC, emphasizing inflammation, oxidative stress, immune evasion, and the production of genotoxins and microbial metabolites. Fusobacterium nucleatum, Escherichia coli (pks+), and Bacteroides fragilis promote tumorigenesis by inducing chronic inflammation, generating reactive oxygen species, and producing virulence factors that damage host DNA. These microorganisms can also evade the antitumor immune response by suppressing cytotoxic T cell activity and increasing regulatory T cell populations. Additionally, microbial-derived metabolites such as secondary bile acids and trimethylamine-N-oxide (TMAO) have been linked to carcinogenic processes. Conversely, protective microbiota, including Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii, contribute to intestinal homeostasis by producing short-chain fatty acids (SCFAs) like butyrate, which exhibit anti-inflammatory and anti-carcinogenic properties. These beneficial microbes enhance gut barrier integrity, modulate immune responses, and inhibit tumor cell proliferation. Understanding the dynamic interplay between pathogenic and protective microbiota is essential for developing microbiome-based interventions, such as probiotics, prebiotics, and fecal microbiota transplantation, to prevent or treat CRC. Future research should focus on identifying microbial biomarkers for early CRC detection and exploring personalized microbiome-targeted therapies. A deeper understanding of host–microbiota interactions may lead to innovative strategies for CRC management and improved patient outcomes. Full article

The chytrid fungus, Batrachochytrium dendrobatidis (Bd), infects amphibian skin, causing chytridiomycosis, which is a contributing cause of worldwide declines and extinctions of amphibians. Relatively little is known about the roles of amphibian skin-resident immune cells, such as macrophages, in these antifungal defenses. Across vertebrates, macrophage differentiation is controlled through the activation of colony-stimulating factor-1 (CSF1) receptor by CSF1 and interleukin-34 (IL34) cytokines. While the precise roles of these respective cytokines in macrophage development remain to be fully explored, our ongoing studies indicate that frog (Xenopus laevis) macrophages differentiated by recombinant forms of CSF1 and IL34 are functionally distinct. Accordingly, we explored the roles of X. laevis CSF1- and IL34-macrophages in anti-Bd defenses. Enriching cutaneous IL34-macrophages, but not CSF1-macrophages, resulted in significant anti-Bd protection. In vitro analysis of frog macrophage-Bd interactions indicated that both macrophage subsets phagocytosed Bd. However, IL34-macrophages cocultured with Bd exhibited greater pro-inflammatory gene expression, whereas CSF1-macrophages cocultured with Bd showed greater immunosuppressive gene expression profiles. Concurrently, Bd-cocultured with CSF1-macrophages, but not IL34-macrophages, possessed elevated expression of genes associated with immune evasion. This work marks a step forward in our understanding of the roles of frog macrophage subsets in antifungal defenses. Full article

Hypercholesterolemia causes atherosclerosis by inducing immune cell migration and chronic inflammation in arterial walls. Recent single-cell analyses reveal the presence of lipid-enriched foamy macrophages, as well as other macrophage subtypes, neutrophils, T cells, and B cells, in atherosclerotic plaques in both animal models and humans. These cells interact with each other and other cells, including non-immune cells such as endothelial cells and smooth muscle cells. They thereby regulate metabolic, inflammatory, phagocytic, and cell death processes, thus affecting the progression and stability of atherosclerotic plaques. The nuclear receptors liver X receptor (LXR)α and LXRβ are transcription factors that are activated by oxysterols and regulate lipid metabolism and immune responses. LXRs regulate cholesterol homeostasis by controlling cholesterol’s transport, absorption, synthesis, and breakdown in the liver and intestine. LXRs are also highly expressed in tissue-resident and monocyte-derived macrophages and other immune cells, including both myeloid cells and lymphocytes, and they regulate both innate and adaptive immune responses. Interestingly, LXRs have immunosuppressive and immunoregulatory functions that are cell-type-dependent. In animal models of atherosclerosis, LXRs have been shown to be involved in both progression and regression phases. The pharmacological activation of LXR enhances cholesterol efflux from macrophages and promotes atherosclerosis progression. Deleting LXR in immune cells, especially myeloid cells, accelerates atherosclerosis by increasing monocyte migration, macrophage proliferation and activation, and neutrophil extracellular traps (NETs); furthermore, the deletion of hematopoietic LXRs impairs the regression of atherosclerotic plaques. Therefore, LXRs in immune cells may be a potent therapeutic target for atherosclerosis. Full article

Background: Vitiligo is featured by the manifestation of white maculae and primarily results from inflammatory/immune-selective aggression to melanocytes. The trigger mechanism leading to the activation of resident immune cells in the skin still lacks a molecular description. There is growing evidence linking altered mitochondrial metabolism to vitiligo, suggesting that an underlying metabolic defect may enable a direct activation of the immune system. Recent evidence demonstrated the association of vitiligo with disorders related to systemic metabolism, including insulin resistance (IR) and lipid disarrangements. However, IR, defined as a cellular defect in the insulin-mediated control of glucose metabolism, and its possible role in vitiligo pathogenesis has not been proven yet. Methods: In this study, we compared the Ins/IGF-1 intracellular signaling of dermal and epidermal cells isolated from non-lesional vitiligo skin to that belonging to cells obtained from healthy donors. Results: We demonstrated that due to the intensified glucose uptake, S6, and insulin receptor substrate 1 (IRS1) chronic phosphorylation, their inducibilities were downsized, a condition that coincides with the definition of insulin resistance at the cellular level. Correspondingly, the mitogenic and metabolic activities normally provoked by Ins/IGF-1 exposure resulted in significantly compromised vitiligo cells (p ≤ 0.05). Besides all the vitiligo-derived skin cells manifesting an energetic disequilibrium consisting of a low ATP, catabolic processes activation, and chronic oxidative stress, the functional consequences of this state appear amplified in the keratinocyte lineage. Conclusion: The presented data argue for insulin and IGF-1 resistance collocating dysfunctional glucose metabolism in the mechanisms of vitiligo pathogenesis. In vitiligo keratinocytes, the intrinsic impairment of intracellular metabolic activities, particularly when associated with stimulation with Ins/IGF-1, converges into an aberrant pro-inflammatory phenotype that may initiate immune cell recruitment. Full article

Glioblastoma (GBM) is an exceedingly aggressive primary brain tumor defined by rapid growth, extensive infiltration, and resistance to standard therapies. A central factor driving these malignancies is the subpopulation of glioblastoma stem cells (GSCs), which possess self-renewal capacity, multipotency, and the ability to regenerate tumor heterogeneity. GSCs contribute to key hallmarks of GBM pathobiology, including relentless progression, resistance to chemotherapy and radiotherapy, and inevitable recurrence. GSCs exhibit distinct molecular signatures, enhanced DNA repair, and metabolic adaptations that protect them against conventional treatments. Moreover, they reside within specialized niches—such as perivascular or hypoxic microenvironments—that sustain stemness, promote immunosuppression, and facilitate angiogenesis. Recent discoveries highlight signaling pathways like Notch, Wnt/β-catenin, Hedgehog, STAT3-PARN, and factors such as TFPI2 and HML-2 as critical regulators of GSC maintenance, plasticity, and immune evasion. These findings underscore the complexity of GSC biology and their pivotal role in driving GBM heterogeneity and therapeutic failure. Emerging therapeutic strategies aim to target GSCs through multiple avenues, including surface markers, immunotherapeutics (e.g., CAR T cells), metabolic vulnerabilities, and combination regimens. Advances in patient-derived organoids, single-cell omics, and 3D co-culture models enable more accurate representation of the tumor ecosystem and personalized therapeutic approaches. Ultimately, improved understanding of GSC-specific targets and the tumor microenvironment promises more effective interventions, paving the way toward better clinical outcomes for GBM patients. Full article

Neoplastic disorders, particularly malignant carcinomas, are complex systemic diseases characterized by unregulated cellular proliferation, the invasion of adjacent tissues, and potential metastasis to distant bodily sites. Among the diverse spectrum of cancer subtypes, malignant melanoma is a highly aggressive form of cutaneous cancer originating in melanocytes, the pigment-producing cells resident in the skin. This malignancy is distinguished by its rapid and uncontrolled growth, as well as its propensity for metastasis to vital organs, thereby posing significant challenges to therapeutic intervention and prognostication. Early detection of melanoma is crucial for optimizing patient outcomes, as diagnosis at an advanced stage often yields a poor prognosis and limited treatment options. Diagnostic modalities for melanoma encompass comprehensive clinical evaluations by dermatologists; radiological imaging techniques such as ultrasonography, magnetic resonance imaging (MRI), computed tomography (CT) scans; and excisional biopsies for accurate histopathological assessment. Malignant melanoma is typically treated with surgery to remove the tumor, followed by immunotherapy to enhance the immune response, targeted therapy for tumors with specific genetic mutations, chemotherapy for advanced stages, radiation therapy to manage metastasis, and other adjunct therapies. This review presents the properties and possible adjunct therapeutic effects against malignant melanoma of quercetin found in the literature and explores, based on the observed physicochemical properties and biological activity, its potential development as a topical formulation for cutaneous application. Quercetin is a naturally occurring flavonoid compound abundant in various plant-based food sources, including apples, onions, berries, and citrus fruits, and has exhibited promising antiproliferative, antioxidant, and anticancer properties. Its distinctive biochemical structure enables quercetin to effectively neutralize reactive oxygen species and modulate key carcinogenic pathways, thereby rendering it a potential candidate for therapeutic intervention in managing malignant tumors, including melanoma. Full article