Search Results (1,959)

Macrophages are highly plastic innate immune cells that adopt context-dependent phenotypes along a continuum, integrating developmental origin with local microenvironmental cues rather than conforming to discrete M1/M2 states. This review delineates the molecular circuits shaping macrophage identity—TLR/cytokine signaling, microRNA networks, metabolic rewiring, and epigenetic mechanisms including histone lactylation—and traces how circulating monocyte subsets contribute to tissue macrophage diversity. We examine macrophage plasticity across a broad disease spectrum—oncology, autoimmune and rheumatic diseases, inflammatory bowel disease, infectious diseases, metabolic disorders, and neurological conditions—showing that the pathogenic phenotype is strikingly context-dependent: for instance, M2-like tumor-associated macrophages promote immune evasion in solid tumors, whereas M1-skewed programs drive tissue damage in autoimmunity. Soluble markers (sCD163, sCD14, soluble mannose receptor) are emerging biomarkers of disease activity and prognosis. High-dimensional flow cytometry and mass cytometry (CyTOF) bridge molecular biology and clinical phenotyping, enabling integrated readouts of surface phenotype, intracellular signaling, and metabolic state. Therapeutic strategies discussed include selective tumor-associated macrophage (TAM) reprogramming, chimeric antigen receptor (CAR)-M cell therapies, and biomaterial-based platforms. Future priorities encompass spatially resolved multi-omics, epigenetic and metabolic targeting, and macrophage-centered vaccine approaches. Standardized cytometry panels will be essential for biomarker-guided stratification and context-specific interventions. Full article

Mayaro virus (MAYV) is an emerging arbovirus from the Togaviridae family where inflammation plays a central role in disease development. As the cause of Mayaro fever, MAYV triggers strong production of pro-inflammatory cytokines, which can result in long-lasting arthralgia in affected individuals. Macrophages are both targets for viral infection and key regulators of inflammatory responses. Human monocyte-derived macrophages (MDMs) are susceptible to MAYV infection in vitro and support productive viral replication. With no approved antivirals or vaccines, finding host-directed therapies is an urgent priority. Cannabinoids are compounds with antiviral and immunomodulatory properties, suggesting potential against MAYV infection. Here, we examined the effects of cannabidiol (CBD) and the synthetic cannabinoid WIN 55,212-2 on MAYV-infected MDMs in pre- and post-treatment conditions. Cells and supernatants were collected at 6 and 24 h post-infection (h.p.i). To understand the mechanisms involved, transcriptomic and functional analyses were performed at 24 h.p.i in the post-treatment setting, focusing on inflammatory, antiviral, and endoplasmic reticulum (ER) stress pathways. WIN 55,212-2 post-treatment significantly decreased viral replication at 24 h.p.i without any direct virucidal activity and was independent of type I interferon activation or interferon-stimulated gene induction, instead being linked to the modulation of ER stress signaling. Specifically, WIN 55,212-2 increased IRE-1α RNase activity, promoting the alternative splicing of sXBP1, while the integrated stress response appeared central to its antiviral effect. Additionally, WIN 55,212-2 downregulated inflammation-related genes and altered cytokine and chemokine production, counteracting the strong inflammatory response caused by MAYV. Remarkably, it also exerted broader immunomodulatory effects independent of infection. Full article

Background: Matrix-bound nanovesicles (MBV) are extracellular vesicles (EVs) that are embedded within the extracellular matrix (ECM), and they have shown immunomodulatory effects in various cell types. The THP-1 cell line is often used to study monocyte and macrophage functions due to its easy culture potential and relatively simple conditioning into different macrophage phenotypes, but the optimal culturing conditions that allow MBV immunomodulation have not been established. Methods: In this study, we evaluated different culturing and differentiation conditions of THP-1 cells in which MBVs showed immunomodulatory effects. We also studied the effect of MBVs on relevant inflammation pathways (NF-κB and ERK 1/2). Results: Quantification of inflammatory cytokine IL-6 indicated modulation effects by MBVs in the majority of the conditions, but TNF-α showed very limited modulation. ERK1/p44 phosphorylation was significantly increased in MBV groups, but NF-κB protein p65 expression was unaffected. When compared to serum EVs, vesicle uptake by THP-1 cells remained low after 24 h. Multispectral flow cytometry analysis of THP-1 cells exposed to MBV and serum EVs showed internalization of lipids, proteins and RNA within the cells in higher cell proportions, but colocalization of the different vesicle components was not observed. Conclusions: Overall, this study provided insights into MBV immunomodulatory effects on THP-1 cells and compared the effects of MBV and serum EVs. Slight differences in modulation were observed between both EV sources, pointing to cargo differences that need further investigation. Full article

In recent years, the study of interleukins (ILs), crucial cytokines involved in inflammation, has garnered significant attention within coronary artery disease including atherosclerosis. This review provides a detailed overview of anti-inflammatory ILs, elucidating their functions within the pathogenesis of atherosclerosis. We examine aspects of all the known anti-inflammatory ILs role in atherosclerosis, the direct impact of these ILs on the inflammation; endothelial, smooth vascular cells and macrophage’s function; and their interactions with signaling pathways and molecules. The potential for diagnostic possibilities and targeted drug therapy to modulate anti-inflammatory ILs activity in atherosclerosis was explored. Taken together, findings from recent studies suggest that the main pathways through which ILs exerts its anti-inflammatory effects are: (1) taking part in the regulation of cholesterol transport or oxidised low-density lipoprotein (oxLDL) phagocytosis (IL-1Ra and IL-36Ra—indirectly); (2) affecting different blood cells’ participation in the inflammation (monocytes, lymphocytes, macrophages); (3) taking place in the remodelation of the arterial wall (affecting smooth muscle and endothelium cells). Overall, IL-35, IL-37, and IL-38 appear to be the most promising for modulation of signaling pathways in experimental works and could be investigated as treatment targets. Recombinant IL-10 is investigated in experimental models as therapeutic tool. IL-1Ra is started being translated into clinical practice already. IL-13 and IL-19 are the least studied. It turns out that anti-inflammatory ILs are unlikely to serve as diagnostic markers for atherosclerosis due to their limited specificity and inconsistent associations with disease progression, as well as insufficient validation in large human cohorts. Moreover, key challenges related to delivery, dosing, and safety remain unresolved. Full article

Background: Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, frequently involves impaired macrophage efferocytosis that leads to apoptotic cell accumulation, secondary necrosis, and persistent inflammation. Early prognostic stratification remains challenging, as current biomarkers lack sufficient specificity and sensitivity, underscoring the urgent need for novel prognosis-related indicators. Methods: We integrated bulk transcriptomic data from a discovery cohort (GSE205672) and an independent validation cohort (GSE133822) with single-cell RNA-seq profiles of early- and late-stage sepsis (GSE167363, GSE175453). WGCNA and five consensus machine-learning algorithms were combined to screen core efferocytosis-associated genes, and expression was validated via qPCR in PBMCs from sepsis patients and CLP-induced septic mice. Results: ADAP2 was identified as the core gene achieving strict consensus across all five algorithms, with early upregulation and late depletion in sepsis, predominant expression in monocytes/macrophages—particularly M1-like and IFN-responsive subsets—and a significant correlation with efferocytosis scores and immune cell infiltration. Its expression was negatively correlated with sepsis severity (SOFA score) and showed a trend toward worse survival in patients with low ADAP2 levels. Conclusions: This multi-dimensional transcriptomic study establishes ADAP2 as a candidate biomarker with potential prognostic value in sepsis, closely linked to macrophage efferocytosis. These findings may aid early risk stratification and inform macrophage-directed immunotherapies, although prospective validation and functional studies are required. Full article

Inactive rhomboid protein 2 (iRhom2) regulates ADAM17-mediated shedding of tumor necrosis factor-α (TNF-α) from immune cells. We previously showed that iRhom2 deficiency attenuates early atherosclerosis in mice. This study aimed to characterize the impact of iRhom2 deficiency on macrophage phenotype and function. Bone marrow-derived macrophages (BMDMs) from iRhom2^−/− and iRhom2^+/+ mice were analyzed for proliferation, phagocytosis, survival of cytotoxic stress, and polarization. Cytokine secretion after LPS stimulation was quantified, and iRhom2 expression under atherogenic stimuli was assessed. Conditioned media from BMDMs (BMDMcM) were applied to human aortic endothelial cells (HAoECs) to evaluate adhesion molecule expression and monocyte adhesion. iRhom2 deficiency did not affect BMDM proliferation, phagocytosis, survival, or polarization marker expression. iRhom2 expression was upregulated in iRhom2^+/+ BMDMs by atherogenic stimulation. Following LPS stimulation, TNF-α secretion was decreased and IL-10 secretion was increased in iRhom2^−/− compared with iRhom2^+/+ BMDMs. HAoEC expression of adhesion molecules—ICAM-1, VCAM-1, and E-selectin—was attenuated after exposure to iRhom2^−/− compared with iRhom2^+/+ BMDMcM. Monocyte adhesion to HAoECs was reduced following treatment with iRhom2^−/− BMDMcM; TNF-α neutralization abolished this effect, indicating TNF-α dependency. iRhom2 deficiency in BMDMs selectively alters macrophage inflammatory cytokine secretion without affecting basal macrophage functions, thereby reducing endothelial activation and monocyte adhesion. These findings identify iRhom2 as a regulator of macrophage–endothelial crosstalk and a potential target to modulate inflammation in atherogenesis. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disorder driven by genetic predisposition, epigenetic programming, metabolic rewiring, and immune dysregulation. Although population genetics and single-cell transcriptomics have advanced our understanding, the multi-omic causal architecture of MASLD at cellular resolution remains poorly defined. This study aimed to establish an integrative framework linking genetic causality to cell-type-specific tissue dysfunction. Methods: Multi-layered Mendelian randomization (MR) and summary-data-based MR (SMR) across large-scale eQTL and pQTL datasets were applied to prioritize causal genes. Single-cell eQTL-based MR across 14 immune lineages generated cell-type-specific causal hypotheses, which were validated using human hepatic single-cell RNA-sequencing data (GSE136103). Two-step mediation MR quantified upstream epigenetic and downstream metabolic mechanisms. A high-fat diet (HFD)-induced murine model provided organismal validation. Results: Multi-layered MR nominated PLXND1 as a robust causal driver of MASLD. Single-cell eQTL-based MR revealed a functional dichotomy: PLXND1 upregulation in CD8⁺ effector memory T-cells decreased MASLD risk (OR = 0.486, 95% CI: 0.290–0.813, p = 0.006), whereas upregulation in natural killer cells (OR = 1.567, 95% CI: 1.337–1.837, p < 0.001), non-classical monocytes, and dendritic cells increased risk. Human hepatic single-cell transcriptomics confirmed that PLXND1 marks an anti-fibrotic, IFNG-high CD8⁺ T subset and a pro-inflammatory lipid-associated macrophage (LAM) population. Mediation MR identified DNA methylation at cg26767922 and cg08471739 as protective mediators acting predominantly via PLXND1 downregulation (92.39% and 64.50% mediation, respectively), and linked PLXND1 to six circulating metabolites. HFD mice showed significant hepatic PLXND1 upregulation. Conclusions:PLXND1 functions as a lineage-dependent molecular switch in MASLD, validated across genetic, epigenetic, metabolic, and single-cell dimensions. These findings caution against systemic PLXND1 blockade and support precision therapeutic strategies targeting hepatic innate immune cells. Full article

Burn injury induces profound immune dysregulation that extends beyond the acute phase of wound healing, contributing to complications such as delayed repair, infection, and long-term immune dysfunction. Importantly, these effects are not restricted to severe trauma, as similar immune alterations occur following small- to moderate-sized burns. Despite increasing recognition of post-burn immune dysregulation, targeted immunomodulatory therapies remain limited. In this review, we synthesize current insights into the mechanisms driving immune dysfunction after burn injury and outline therapeutic strategies aimed at restoring immune homeostasis. We examine approaches targeting inflammatory triggers and mediators, including acute clinical interventions, reduction in microbial burden, and inhibition of immune cell activation through systemic and local delivery. We also explore strategies to modulate dysregulated innate immune responses by targeting cell-specific functions, such as neutrophil activity and monocyte/macrophage polarization. Persistent activation and exhaustion of the adaptive immune system may be alleviated through interventions such as β-adrenergic blockade, while metabolic, endocrine, and oxidative stress pathways represent additional therapeutic targets. Finally, we highlight key challenges, including the need for improved diagnostics, early prognostic stratification, and personalized treatment approaches to improve outcomes following burn injury. Full article

FcγRIII (CD16) is expressed by several leukocyte populations, including monocytes, macrophages, and natural killer cells, and plays an important role in IgG-mediated immune responses. Altered CD16 expression has been reported in inflammatory and autoimmune conditions, including thyroid-associated immune alterations. This preliminary in vitro study investigated whether the indole-derived compounds melatonin and indole-3-propionic acid (IPA) affect surface FcγRIII/CD16-related parameters in porcine peripheral blood mononuclear cells (PBMCs) cultured alone or with autologous thyroid follicular cells. PBMCs were left untreated or treated with melatonin or IPA, both at 50 µM, and analysed by flow cytometry at baseline and after 24 and 48 h of culture. The percentage of CD45⁺CD16⁺ cells and the CD16 mean fluorescence intensity were assessed as surface CD16-related parameters. Untreated PBMC cultures showed a time-dependent decrease in both the percentage of CD45⁺CD16⁺ cells and CD16 mean fluorescence intensity. Melatonin and IPA further enhanced this decrease compared with untreated cultures. Co-culture with thyroid follicular cells did not significantly modify CD16-related parameters under the tested conditions. These findings suggest that melatonin and IPA may modulate the surface CD16-related phenotype of porcine CD45⁺ leukocytes in vitro. The results provide preliminary evidence for the potential immunomodulatory activity of indole-derived compounds within the CD16-expressing leukocyte compartment and warrant further investigation in extended experimental models. Full article

The micro-immunotherapy medicine (MIM) 2LEID-N^® was developed to sustain immune response, notably in the framework of respiratory infections. This pilot study investigated the potential effects of one capsule of this MIM, referred to as 2LEID-N-9 throughout the manuscript, containing IL-12 (5 CH), IFN-γ (6 CH), and TNF-α (5 CH). Phagocytosis and surface marker expression were assessed using flow cytometry, and cytokine secretion was assessed by ELISA. Cellular models included human monocyte-derived macrophages, peripheral blood mononuclear cells (PBMCs) from healthy donors, and THP-1 cells. Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS/MS) was used to detect the actives. Compared with vehicle control, 2LEID-N-9 showed a trend towards the enhanced phagocytic activity of macrophages. In PBMCs, 2LEID-N-9 upregulated the secretion of several cytokines, including IL-2, IL-4, IL-13, IFN-γ, and TNF-α in both basal and CD3/CD28-stimulated conditions. Notably, a tendency towards increased secretion of TNF-α was found in LPS-stimulated THP-1 cells. The presence of the three actives, as assessed by LC-HRMS/MS, combined with the functional data, provide promising exploratory evidence of immunomodulatory effects and tendencies towards the stimulation of innate and adaptive immune cells, warranting further investigation. Full article

Background: Recruitment and activation of monocyte-derived macrophages (MoMFs) sustain cholangitis in primary biliary cholangitis (PBC), but whether MoMFs amplify inflammation through ferroptosis remains unclear. We defined ferroptotic programs in MoMFs and evaluated the calpain/ACSL4 axis as a regulatory and therapeutic node. Methods: We analysed a public human liver single-cell RNA sequencing (scRNA-seq) dataset and examined MoMF-associated ACSL4 and 4-hydroxynonenal (4-HNE) signals in CD11b⁺CD68⁺ cells by multiplex immunofluorescence. We used a 2OA–BSA-induced PBC-like mouse model to assess liver injury, inflammation and ferroptosis-related markers and tested Liproxstatin-1 (Lip-1), rosiglitazone (ROSI) or the calpain inhibitor PD150606. Bone marrow-derived macrophages (BMDMs) from control and PBC mice were profiled and challenged with RSL3, with or without Ferrostatin-1 (Fer-1), ROSI or PD150606. Results: MoMFs were expanded in PBC livers and showed the strongest induction of ferroptosis signatures, centered on ACSL4, with enhanced inflammatory crosstalk with cholangiocytes. Human PBC tissues showed increased CD11b⁺CD68⁺ cells positive for ACSL4 or 4-HNE. In PBC-like mice, malondialdehyde (MDA) increased and glutathione (GSH) decreased, and macrophages showed greater colocalization with ferroptosis markers; Lip-1, ROSI or PD150606 improved liver biochemistry, reduced inflammation scores and limited macrophage infiltration. PBC-derived BMDMs upregulated ACSL4 and CAPN1/2 and were more sensitive to RSL3; Fer-1, ROSI or PD150606 attenuated ferroptosis-associated molecular changes. Conclusions: MoMF ferroptosis is prominently engaged in PBC, and our findings implicate a pharmacologically tractable calpain/ACSL4 axis that may contribute to macrophage ferroptotic susceptibility and inflammatory liver injury. Full article

Kidney transplantation remains the optimal treatment for end-stage renal disease, yet long-term allograft survival has plateaued due to persistent rejection. This review provides a comprehensive overview of the inflammatory and immune pathways implicated in kidney allograft rejection, integrating current evidence from basic and translational research. Ischemia–reperfusion injury initiates an inflammatory cascade through the release of damage-associated molecular patterns, activating Toll-like receptors and the complement system, thereby priming the alloimmune response. Innate immune cells, including macrophages, dendritic cells, and natural killer cells, bridge sterile tissue injury to adaptive alloimmunity, while the emerging concept of trained immunity reveals long-lasting epigenetic reprogramming of monocytes with direct implications for graft longevity. The adaptive response encompasses T cell-mediated rejection, driven by Th1, Th17, and CD8⁺ cytotoxic lymphocytes, and antibody-mediated rejection, mediated by donor-specific antibodies through complement activation and antibody-dependent cellular cytotoxicity. Key signalling pathways, including JAK-STAT, NF-κB, NLRP3 inflammasome, and mTOR, amplify allograft inflammation and promote progression toward chronic injury. Macrophage polarisation and macrophage-to-myofibroblast transition have been identified as major drivers of interstitial fibrosis and late graft failure. Recent advances in non-invasive biomarkers, such as donor-derived cell-free DNA and molecular phenotyping, are transforming rejection diagnostics. Emerging therapies, including costimulation blockade, anti-CD38 antibodies, complement inhibitors, and regulatory T cell-based approaches, offer the potential to shift transplant medicine toward precision-guided, tolerance-inducing strategies. This review synthesises these developments and discusses future perspectives for improving long-term allograft outcomes. Full article

Chamaecrista nomame (Siebold) H. Ohashi (C. nomame), a leguminous plant traditionally consumed in East Asia, contains diverse bioactive phytochemicals, but whether its activities act convergently under obesity-related pathological conditions remains unclear. This study investigated the anti-inflammatory, anti-obesity, and insulin-sensitizing effects of a 40% ethanol extract of C. nomame (ECNE) and its marker compound luteolin in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, differentiating and mature 3T3-L1 adipocytes, and tumor necrosis factor-α (TNF-α)-induced insulin-resistant adipocytes. In LPS-stimulated macrophages, ECNE and luteolin reduced nitric oxide and pro-inflammatory cytokine (TNF-α, interleukin (IL)-6, IL-1β) production, accompanied by suppression of nuclear factor-κB and mitogen-activated protein kinase signaling. In differentiating adipocytes, both reduced lipid accumulation and downregulated peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, and adipocyte protein 2. In mature adipocytes, they enhanced insulin-stimulated glucose uptake and Akt phosphorylation. In TNF-α-challenged adipocytes, pretreatment partially restored glucose uptake and Akt phosphorylation while attenuating IL-6 and monocyte chemoattractant protein-1 production. ECNE exerted effects equal to or greater than those of luteolin at equivalent luteolin-based concentrations, indicating contributions from additional phenolic constituents. These findings support ECNE as a multifunctional natural resource against obesity-associated inflammation and insulin resistance. Full article

Surface hardness is a fundamental parameter influencing wear resistance, durability, and the interaction of occlusal ramps with opposing enamel during orthodontic treatment. Five commercially available materials (Harmonize, Leone F3172-01, Transbond™ XT, Band and Build LC, and Ultra Band-Lok) and one experimental material (Composite RK-F10) were evaluated for bite ramps. Twelve standardized specimens (n = 2 per material) were prepared using EVA molds and polymerized according to manufacturers’ instructions or internal protocols. Vickers microhardness (HV) was measured following ASTM E384-16 using a 500 g load, 20 s dwell time, and ten indentations per specimen. Load dependence was assessed (25–2000 g). Surface morphology was analyzed by SEM, and cytotoxicity of eluates was evaluated on dental pulp stem cells (DPSCs) and monocyte/macrophage cell lines using CCK-8 assays (ISO 7405, ISO 10993). Significant differences in hardness were observed among materials (p < 0.05). Harmonize (64.5 ± 1.6 HV), Band and Build LC (64.4 ± 1.9 HV), and Ultra Band-Lok (64.1 ± 2.0 HV) showed the highest values, whereas Transbond™ XT exhibited the lowest value (53.7 ± 6.0 HV). Composite RK-F10 demonstrated intermediate hardness and good cytocompatibility. SEM analysis revealed differences in surface homogeneity and filler distribution. Overall, the materials exhibited distinct mechanical and biological profiles. The combined Vickers microhardness, short-term (24 h) cytotoxicity, and SEM data provide an integrated preliminary in vitro characterization of materials for bite ramps. The observed differences contribute to a comparative description of their physico-biological behavior. Full article

Background: We previously reported that knocking down the ubiquitin E3 ligase LNX2 in bone marrow monocytes by shRNAs attenuated osteoclastogenesis in vitro. However, the role of LNX2 in the regulation of osteoclasts and bone homeostasis in vivo remains unknown. Methods: In this study, we generated myeloid Lnx2 conditional knockout mice by crossing Lnx2-flox mice with LysM-Cre mice. The role of LNX2 was verified through in vitro osteoclast induction experiments using mononuclear macrophages and experiments on estrogen-deficient osteoporosis models. Results: Micro-CT and histological analysis unveiled that loss of Lnx2 in osteoclast precursor cells decreased osteoclast numbers and increased trabecular bone mass in mice. Moreover, Lnx2 deficiency prevented bone loss in an ovariectomized mouse model of postmenopausal osteoporosis. In vitro mechanistic studies identified that the loss of Lnx2 had little effect on cell proliferation but significantly inhibited the formation of osteoclasts and bone resorption. Furthermore, the deletion of Lnx2 decreased the expression of NOTCH2 and its downstream HES1 via enhancing the level of the NOTCH2 inhibitor, NUMB. Conclusions: Our findings elucidate an important role of Lnx2 in the regulation of osteoclasts and bone metabolism and indicate that Lnx2 is a potential therapeutic target for the treatment of osteoporosis. Full article