Search Results (1,776)

Activation of macrophages plays a key role in both inflammation and oxidative stress, key features of many chronic diseases. Pro-inflammatory M1-like macrophages, in particular, contribute to pro-oxidative environments and are a frequent focus of immunological research. This research examined the effects of kiwifruit allergen Act d 1, in comparison to LPS, on THP-1 macrophages in vitro differentiated under optimized conditions, both in the presence and in the absence of selected vanilloids. THP-1 monocyte differentiation was optimized by varying PMA exposure and resting time. Act d 1 induced M1-like phenotypic changes comparable to LPS, including upregulation of CD80, IL-1β and IL-6 secretion, gene expression of iNOS and NF-κB activation, in addition to increased reactive oxygen species (ROS) and catalase activity. Treatment with specific vanilloids mitigated these responses, primarily through reduced oxidative stress and NF-κB activation. Notably, vanillin (VN) was the most effective, also reducing CD80 expression and IL-1β levels. These results suggest that vanilloids can affect pro-inflammatory signaling and oxidative stress in THP-1 macrophages and highlight their potential to alter inflammatory conditions characterized by similar immune responses. Full article

Myxoma virus (MYXV), a rabbit-specific poxvirus and non-pathogenic in humans and mice, is an excellent candidate oncolytic virus for cancer therapy. MYXV also has immunotherapeutic benefits. In ovarian cancer (OC), immunosuppressive tumor-associated macrophages (TAMs) are key to inhibiting antitumor immunity while hindering therapeutic benefit by chemotherapy and dendritic cell (DC) vaccine. Because MYXV favors binding/entry of macrophages/monocytes, we examined the therapeutic potential of MYXV against TAMs. We found previously that a replication-defective MYXV with targeted deletion of an essential gene, M062R, designated ΔM062R MYXV, activated both the host DNA sensing pathway and the SAMD9 pathway. Treatment with ΔM062R confers therapeutic benefit comparable to that of wild-type replicating MYXV in preclinical models. Here we found that ΔM062R MYXV, when integrated with cisplatin and DC immunotherapy, further improved treatment benefit, likely through promoting tumor antigen-specific T cell function. Moreover, we also tested ΔM062R MYXV in targeting human immunosuppressive TAMs from OC patient ascites in a co-culture system. We found that ΔM062R treatment subverted the immunosuppressive properties of TAMs and elevated the avidity of cytokine production in tumor antigen-specific CD4⁺ T cells. Overall, ΔM062R presents a promising immunotherapeutic platform as a beneficial adjuvant to chemotherapy and DC vaccine. Full article

Crohn’s disease is a chronic inflammation affecting the gastrointestinal tract. To date, patients are commonly treated with corticosteroids or more aggressive biologics for high-risk subjects. Stem Cell Educator therapy has been successfully utilized to treat patients with type 1 diabetes and other autoimmune conditions. A 78-year-old patient with long-standing Crohn’s disease received one treatment with the Stem Cell Educator therapy, followed by clinical, radiographic, pathological examinations and immune marker testing by flow cytometry. After the treatment with Stem Cell Educator therapy, the patient’s clinical symptoms were quickly improved with normal bowel movements, without abdominal pain or rectal bleeding. Flow cytometry analysis revealed a marked decline in inflammatory markers, such as the percentage of monocyte/macrophage-associated cytokine interleukin-1 beta (IL-1β)⁺ cells, which reduced from 94.98% at the baseline to 18.21%, and down-regulation of the percentage of chemokine CXCL16⁺ cells from 91.92% at baseline to 42.58% at 2-month follow-up. Pathologic examination of the biopsy specimens from colonoscopy five weeks and six months post-treatment showed ileal mucosa with no specific abnormality and no significant inflammation or villous atrophy; no granulomas were identified. A follow-up CT scan four and one-half months post-treatment showed no evidence of the previously seen stenosis of the ilio-colonic anastomosis with proximal dilatation. Stem Cell Educator therapy markedly reduced inflammation in the subject with Crohn’s disease, leading to durable clinical, immunological, radiographic, and pathological improvements. Full article

Crotoxin (CTX), the main toxin in Crotalus durissus terrificus venom, is a heterodimeric complex known for its antitumoral, anti-inflammatory, and immunomodulatory properties. In macrophages, CTX stimulates energy metabolism, pro-inflammatory cytokines, superoxide production, and lipoxin A₄ secretion while inhibiting macrophage spreading and phagocytosis. These effects are completely blocked by Boc-2, a selective formyl peptide receptors (FPRs) antagonist. Despite the correlation between FPRs and CTX-mediated effects, their involvement in mediating CTX entry into macrophages remains unclear. This study aimed to investigate the involvement of FPRs in CTX entry into monocytes and macrophages. For this, THP-1 cells were silenced for FPRs or treated with Boc-2. Results demonstrated that FPR-related signaling pathways, which influence macrophage functions such as ROS release, phagocytosis, and spreading, were reduced in FPR-silenced cells. However, even in the absence of FPRs, CTX was efficiently internalized by macrophages. These findings suggest that FPRs are essential for the immunomodulatory effects of CTX, but are not involved in CTX internalization. Full article

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

Tissue-resident macrophages are essential for skin homeostasis. This study investigated whether lipopolysaccharide (LPS)-activated macrophages affect senescence and rejuvenation in human dermal fibroblasts. Human monocytic THP-1 cells were stimulated with Pantoea agglomerans–derived LPS (1–1000 ng/mL), and culture supernatants were collected. These were applied to two NB1RGB fibroblast populations: young, actively dividing cells (Young cells) and senescent cells with high population doubling levels and reduced proliferation (Old cells). Senescence markers P16, P21, and Ki-67 were analyzed at gene and protein levels. Conditioned medium from Old cells induced senescence in Young cells, increasing P16 and P21 expression levels. This effect was suppressed by cotreatment with LPS-activated THP-1 supernatant. Old cells treated with the LPS-activated supernatant exhibited decreased P16 and P21 levels as well as increased Ki-67 expression, indicating partial rejuvenation. These effects were not observed following treatment with unstimulated THP-1 supernatants or LPS alone. Overall, these findings suggest that secretory factors from LPS-activated macrophages can suppress cellular senescence and promote human dermal fibroblast rejuvenation, highlighting the potential role of macrophage activation in regulating cellular aging and offering a promising strategy for skin aging intervention. Full article

Background: Psoriasis, an inflammatory skin disorder, involves pyroptosis—a pro-inflammatory cell death process. However, cell-specific pyroptosis dynamics and immune microenvironment interactions remain unclear. Objective: To investigate cell-type-specific pyroptosis patterns in psoriasis and their immunoregulatory mechanisms. Methods: We integrated 21 transcriptomic datasets (from 2007 to 2020) obtained from the GEO database and two single-cell RNA sequencing datasets to quantify pyroptotic activity using Gene Set Variation Analysis and AUCell algorithms. Immune cell infiltration profiles were evaluated via CIBERSORT, while cell-cell communication networks were analyzed by CellChat. In vitro and in vivo experiments were performed to validate key findings. Results: Our analysis revealed that psoriasis patients exhibited significantly elevated levels of pyroptosis compared to healthy controls, with pyroptotic activity reflecting treatment responses. Notably, monocyte-derived macrophages (MDMs) in psoriatic lesions displayed markedly heightened pyroptotic activity. In vitro experiments confirmed that MDMs derived from psoriasis patients overexpressed pyroptosis-related molecules (Caspase 1 and Caspase 4) as well as pro-inflammatory cytokines (TNFα, IL6, IL1β) when compared to healthy controls. Furthermore, these cells showed increased expression of CXCL16, which might potentially activate Th17 cells through CXCR6 signaling, thereby driving skin inflammation. Inhibition of monocyte migration in an imiquimod-induced psoriasiform dermatitis model significantly alleviated skin inflammation and reduced the proportion of M1 macrophages and Th17 cells in lesional skin. Conclusions: This study revealed that MDMs in psoriatic lesions exhibited a hyperactive pyroptotic state, which contributed to disease progression through CXCL16-mediated remodeling of the immune microenvironment. These findings highlight pyroptosis as a potential therapeutic target for psoriasis. Full article

Macrophages are a heterogenous population of cells that adopt specific phenotypes in response to signals from their dynamic microenvironment. Apart from being key players in innate immunity and in the maintenance of tissue homeostasis, macrophages are also important drivers of low-grade inflammation, which is associated with different chronic conditions including stress and cancer. The activation of macrophages during chronic stress and cancer results in their multifaceted pathogenic roles. Macrophages residing in the tumor microenvironment are commonly known as tumor-associated macrophages and favor or inhibit tumor growth depending on the microenvironmental cues and their activation state. Activated macrophages display a continuum of properties rather than a distinct proinflammatory or anti-inflammatory dichotomy. Emerging evidence suggests that prolonged tissue residency restricts the plasticity of macrophages, while recruited monocytes are more plastic and their differentiation into tumor-associated macrophages during stress can result in a dual imprinting from both the existing stress-induced inflammation and the tumor microenvironment. In addition, the immunomodulation of the tumor microenvironment and reprogramming of tumor-associated macrophages toward the anti-tumor phenotypes have emerged as promising therapeutic approaches. In this review, we will focus on how the persistent inflammatory state underlying chronic stress affects macrophages as well as the macrophages’ contribution to various aspects of tumor growth and progression, highlighting a therapeutic potential of modulation of the macrophage-mediated immunosuppressive tumor microenvironment. Full article

Macrophages are a principal pulmonary source of type I and III interferons (IFNs), initiating and coordinating the early antiviral response to respiratory viral infections. Yet the contribution of macrophage-derived IFNs to host defense during human metapneumovirus (HMPV) infection remains poorly defined. Here, we use human primary monocyte-derived macrophages (MDMs) and THP-1-derived macrophages to analyze the IFN responses induced by HMPV compared to its closely related human pneumovirus, respiratory syncytial virus (RSV). We show that HMPV induced a robust response of type I and type III IFNs and ISGs, whereas RSV elicited only a modest, delayed IFN response despite strong IRF activation; instead, RSV preferentially activates NF-κB and exhibits a pronounced proinflammatory cytokine output. Our results highlight the role of macrophages as key modulators of the IFN and proinflammatory responses during HMPV and RSV infection. Full article

Multiple sclerosis (MS) is a complex autoimmune disease with both genetic and environmental influences, yet its underlying mechanisms remain only partially understood. In this review, we compile evidence suggesting that trained immunity—a form of innate immune memory—may play a crucial role in the autoimmune component of MS. By examining key findings from immunology, neuroinflammation, and MS pathophysiology, we explore how innate immune cells, particularly monocytes and macrophages, could contribute to disease onset and progression through persistent pro-inflammatory responses. Understanding the impact of trained immunity in MS could open new avenues for therapeutic strategies targeting the innate immune system. Full article

Neuroinflammation is a key process in Alzheimer’s disease (AD). We aimed to examine the development and evaluation of a comprehensive in vitro model that captures the complex interplay between neurons and immune cell types. Retinoic acid-differentiated SH-SY5Y neuroblastoma cells exposed to LPS-conditioned media (CM) from RAW264.7 macrophages, BV2 microglia, and HL60 promyelocytic cells differentiated into neutrophil- or monocyte-like phenotypes were analyzed. The effects of CM containing inflammatory factors on neuronal viability and function were systematically evaluated. Neuronal oxidative stress, mitochondrial function, autophagy and protein aggregates were analyzed. The involvement of insulin resistance was studied by assaying glucose uptake and determining its IC₅₀ values for cell viability improvement and GSK3β phosphorylation. After short-term exposure (3 h), most inflammatory CMs induced peroxide production in neurons, with the strongest effect observed in media from DMSO- or RA-differentiated HL60 cells. Mitochondrial membrane potential was markedly reduced by LPS-stimulated BV2 and HL60-derived CMs. Prolonged exposure (72 h) revealed partial normalization of oxidative stress and mitochondrial membrane potential. Glucose uptake was significantly impaired in cells treated with LPS-activated RAW264.7, BV2, and DMSO-differentiated HL60 cell media, while insulin partially rescued this effect, except for the CM of BV2 cells. Notably, insulin IC₅₀ increased dramatically under LPS-treated BV2 cells induced inflammation (35 vs. 198 pM), confirming the development of insulin resistance. Immune cell-specific inflammation causes distinct effects on neuronal oxidative stress, mitochondrial function, protein aggregation, insulin signaling and viability. LPS-activated BV2-derived CM best recapitulates AD-related pathology, offering a relevant in vitro model for further studies. Full article

The NADPH oxidase 2 (NOX2) complex is a critical regulator of immune homeostasis. It is utilized by phagocytic leukocytes including neutrophils, monocytes, and macrophages to generate reactive oxygen species (ROS) that drive microbe clearance and modulate inflammatory responses. Within NOX2, the essential scaffold protein p47phox plays a pivotal role in orchestrating enzyme activation and facilitating the assembly and membrane translocation of cytosolic components of the complex. Tight regulation of p47phox activity is crucial, and its disruption is linked to a number of pathological conditions. Conversely, its hyperactivity contributes to oxidative stress, tissue damage, the progression of cardiovascular diseases, neurodegenerative disorders, inflammatory conditions, metabolic syndromes, and cancer. In this review, we detail the structural and functional roles of p47phox, mechanisms of its regulation, and its multifaceted contributions to disease pathogenesis. We explore the latest advances in p47phox-targeted therapeutic strategies, discuss current challenges in the field, highlight p47phox’s potential as a transformative target in redox biology and propose future directions to unlock its clinical utility. Full article

Type 2 diabetes mellitus (T2DM) is a major public health concern that significantly increases the risk of diabetic retinopathy (DR), a leading cause of visual impairment worldwide. This study aimed to identify molecular markers of inflammation (INF) and angiogenesis (ANG) in the aqueous humor (AH) of patients with non-proliferative diabetic retinopathy (NPDR). We conducted an observational, multicenter, case–control study including 116 participants classified into T2DM with NPDR, T2DM without DR, and non-diabetic controls (SCG) undergoing cataract surgery. AH samples were collected intraoperatively and analyzed for 27 cytokines using multiplex immunoassay. Eighteen immune mediators were detected in AH samples, and several were significantly elevated in the NPDR group, including the interleukins (IL) -1β, -6, -8, -15, -17, as well as the granulocyte–macrophage colony stimulating factor (GM-CSF), basic fibroblast growth factor (bFGF), interferon gamma-induced protein (IP-10), macrophage inflammatory protein 1 beta (MIP-1b), monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell-expressed and -secreted protein (RANTES), and the vascular endothelial growth factor (VEGF). These molecules are involved in retinal INF, blood–retinal barrier breakdown, and pathological neovascularization. Our findings reveal a distinct pro-INF and pro-ANG profile in the AH of NPDR patients, suggesting that these cytokines may serve as early diagnostic/prognostic biomarkers for DR. Targeting these molecules could provide novel therapeutic strategies to mitigate retinal damage and vision loss in diabetic patients. Full article

Chickpeas are used as alternative protein sources in healthy snacks due to their bioactive compounds beneficial for gut health. Combining chickpeas with dark chocolate improves palatability and may enhance biological functionality, although mechanistic evidence is still limited. In this explorative research, we evaluate the nutrigenomic, antioxidant and anti-inflammatory properties of a chickpea and chocolate snack using in vitro Caco-2 (colon adenocarcinoma cells) and THP-1 (monocyte-derived macrophages) models. The total polyphenol content and antioxidant activity were measured after in vitro digestion (30.30 mg/mL to 1.9 mg/mL). Caco-2 epithelia and THP-1 were pre-treated for 4 days (2 h/day) with high (15.1 mg/mL) or low (3.8 mg/mL) concentrations of digests. Inflammation was induced for 3 h by LPS (Lipopolysaccharides) and IL-1β (Interleukin-1β). Transepithelial electrical resistance (TEER) was measured to assess barrier integrity. Gene expression related to tight junctions and inflammation was analysed using qPCR (quantitative polymerase chain reaction). Chocolate and snack digests showed the highest total polyphenol content and 2,2-diphenyl-1-picrylhydrazyl activity. Barrier integrity improved with all treatments. Chickpea upregulated tight junction gene expression. Chickpea and chocolate reduced IL-1β expression in both cell types. In THP-1, the chocolate and the snack upregulated CD206 (mannose receptor C-type 1) expression. IL-10 increased with all treatments. These results pave the way for future research that may support the potential use of this snack as a functional food with antioxidant, gut-protective and anti-inflammatory effects. Full article

Background: Metabolic-associated fatty liver disease (MAFLD) is characterized by metabolic syndrome and immune infiltration, with glycolysis pathway activation emerging as a pivotal contributor. This study aims to identify glycolysis-associated key genes driving MAFLD progression and elucidate their crosstalk with immune infiltration through bioinformatics analysis and experimental validation. Methods: Integrative multi-omics analysis was performed on bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomic datasets from MAFLD patients and controls. Differential expression analysis and WGCNA were employed to pinpoint glycolysis-correlated key genes. The relationship with immune infiltration was analyzed using single-cell and spatial transcriptomics technologies. Machine learning was applied to identify feature genes for matching shared TFs and miRNAs. External cohort validation and in vivo experiments (methionine choline-deficient diet murine models) were conducted for biological confirmation. Results: Five glycolysis-associated key genes (ALDH3A1, CDK1, DEPDC1, HKDC1, SOX9) were identified and validated as MAFLD discriminators. Single-cell analysis revealed that the hepatocyte–fibroblast–macrophage axis constitutes the predominant glycolysis-active niche. Spatial transcriptomics showed that CDK1, SOX9, and HKDC1 were colocalized with the monocyte-derived macrophage marker CCR2. Using four machine learning models, four feature genes were identified, along with their common transcription factors YY1 and FOXC1, and the miRNA “hsa-miR-590-3p”. External datasets and experimental validation confirmed that the key genes were upregulated in MAFLD samples. Conclusions: In this study, we identified five glycolysis-related key genes in MAFLD and explored their relationship with immune infiltration, providing new insights for diagnosis and metabolism-directed immunomodulation strategies in MAFLD. Full article