Search Results (354)

C-C motif chemokine ligand 2 (CCL2) interacts with cytokines, adipokines, miRNAs, and multiple synovial cell populations. Experimental studies indicate that these interactions can form a CCL2-associated inflammatory amplification network across cell types. In cellular and animal models, increased CCL2 is associated with monocyte recruitment, synovial fibroblast activation, osteoclast-related bone remodelling, and vascular responses. Therapeutic strategies targeting the CCL2-centered inflammatory network include antagonists of the CCL2/CCR2 axis, natural products, synthetic compounds, conventional antirheumatic drugs, and emerging delivery-based approaches. Notably, direct CCL2/CCR2 inhibition has shown biological activity in experimental models but has not produced consistent clinical benefit in established rheumatoid arthritis (RA). Although these findings do not establish CCL2 as a dominant causal driver of RA, human observational studies suggest that circulating CCL2 may complement established markers in preclinical RA risk assessment, disease activity and remission classification, estimation of treatment response, and evaluation of RA-related complications such as interstitial lung disease. Of note, no validated concentration cut-off or standardized assay currently supports its routine clinical use. This review examines the CCL2-related inflammatory network in RA and evaluates its cellular mechanisms, therapeutic implications, and potential clinical applications. Full article

Background: Non-proliferative diabetic retinopathy (NPDR) is a common microvascular complication of type 2 diabetes mellitus (T2DM) associated with chronic inflammation, metabolic dysregulation, and multiple interacting systemic factors. This study evaluated the associations of inflammatory biomarkers, serum 25-hydroxyvitamin D [25(OH)D], electrolyte homeostasis, and lipid-derived indices with NPDR. Methods: In this cross-sectional study with prospective recruitment, 98 patients with T2DM were classified into NPDR (n = 55) and non-DR (n = 43) groups. Clinical characteristics, hematological inflammatory indices, serum interleukin-6 (IL-6), C-reactive protein (CRP), 25(OH)D, electrolyte concentrations, lipid profile, and derived biomarkers—including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune–inflammation index (SII), LDL-C/HDL-C ratio, and calculated serum osmolarity—were compared. Receiver operating characteristic (ROC) analysis and multivariable logistic regression were performed to assess discriminatory performance and independent associations with NPDR. Results: Patients with NPDR had significantly lower serum 25(OH)D concentrations than the non-DR group (16.6 ± 7.5 vs. 21.0 ± 5.2 ng/mL, p < 0.001). Serum IL-6 levels (4.2 ± 3.1 vs. 2.8 ± 1.4 pg/mL, p = 0.047), NLR (p = 0.043), LDL-C/HDL-C ratio (p = 0.031), and calculated serum osmolarity (p = 0.033) were significantly higher, whereas lymphocyte count and the lymphocyte-to-monocyte ratio were significantly lower. Among individual biomarkers, serum 25(OH)D showed the best discriminatory performance (AUC = 0.712). A multivariable model including insulin therapy, IL-6, serum 25(OH)D, and the LDL-C/HDL-C ratio demonstrated good discrimination (AUC = 0.813), with 81.8% sensitivity and 81.4% specificity. Bootstrap validation supported the stability of the model. Conclusions: NPDR was associated with lower serum 25(OH)D concentrations, systemic inflammation, and a less favorable LDL-C/HDL-C ratio. A multivariable model integrating inflammatory, metabolic, and nutritional biomarkers showed better discriminatory performance than individual biomarkers. The association between insulin therapy and NPDR likely reflects greater diabetes severity rather than a direct effect of insulin. These findings are exploratory, and prospective studies in larger independent cohorts are needed to determine whether these biomarkers improve risk stratification beyond established clinical factors. Full article

Serotonin (5-hydroxytryptamine, 5-HT) is traditionally considered a neurotransmitter, but most of the body’s serotonin is peripheral and participates in vascular, hemostatic, inflammatory, and immune processes. This review summarizes current evidence on the role of peripheral serotonin in innate and adaptive immunity and evaluates its clinical relevance in inflammatory and immune-mediated diseases. The article synthesizes experimental and clinical data on serotonin sources, 5-HT receptors, SERT, serotonylation, and 5-HT-dependent regulation of neutrophils, monocytes/macrophages, mast cells, dendritic cells, T cells, and B cells. The reviewed data indicate that serotonin modulates leukocyte recruitment, platelet–immune interactions, NETosis, macrophage polarization, dendritic cell–T-cell communication, lymphocyte activation, vascular permeability, and tissue remodeling. Clinically, serotonergic mechanisms are implicated in sepsis, inflammatory bowel disease, autoimmune disorders, cardiovascular inflammation, thromboinflammation, and the tumor microenvironment. However, the direction of 5-HT effects is not uniform and depends on receptor subtype, cell type, local mediator concentration, disease stage, and tissue context. Serotonin should therefore be regarded as a context-dependent immunoregulatory mediator rather than an exclusively pro- or anti-inflammatory factor. Further studies are needed to standardize clinical measurements of serotonin and its metabolites and to define therapeutically relevant serotonergic targets. Full article

Elevated plasma lipoprotein(a) [Lp(a)] levels represent a predominantly genetically determined risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease (CAVD). Mechanistically, Lp(a) transports oxidized phospholipids, lysophosphatidylcholine, and autotaxin, components capable of promoting inflammation, oxidative stress, and valvular fibrocalcific remodeling. This review synthesizes the molecular, cellular, and clinical evidence linking Lp(a) to CAVD progression. Retention of Lp(a) and other apolipoprotein B-containing lipoproteins in the valvular matrix promotes endothelial activation, recruitment of cells of the monocytic lineage, and the release of proinflammatory mediators. Oxidized phospholipids and the autotaxin–lysophosphatidic acid axis activate redox-dependent pathways and promote the transition of valvular interstitial cells toward myofibroblastic and/or osteogenic phenotypes. These processes converge in alterations in cholesterol metabolism, the release of procalcifying extracellular vesicles, and hydroxyapatite nucleation. Genetic and imaging evidence supports an association between elevated Lp(a), microcalcifying activity, and accelerated hemodynamic progression. Although anti-Lp(a) therapies substantially reduce plasma Lp(a) concentrations, their effect on valvular outcomes has not yet been demonstrated. Full article

Fine particulate matter (PM2.5) is an air pollutant that significantly impacts environmental and health outcomes. In Chiang Mai province, Thailand, residents face recurring PM2.5 pollution from November to May each year, primarily due to open biomass burning and transboundary emissions. The long-term health impacts of PM2.5 in Chiang Mai remain inadequately documented. This study aims to investigate leukocyte distribution and IgE level in response to long-term PM2.5 exposure. Participants residing in San Patong district, Chiang Mai, were recruited. Leukocyte distribution was investigated by the complete blood count and flow cytometry. IgE levels were measured by sandwich enzyme-linked immunosorbent assay. Long-term PM2.5 exposure is associated with significant changes in leukocyte distribution, including WBC count, neutrophil, monocyte, and basophil absolute count, while lymphocyte and eosinophil counts were not significantly affected. In the present study, flow cytometric immunophenotyping was performed during the late PM2.5 season to evaluate the distributions of major leukocyte populations and the expression of activation and inhibitory markers on lymphocyte subsets. Interestingly, IgE levels showed a decreasing trend. These findings highlight the immunological effects of repeated PM2.5 exposure and underscore the need for further research to clarify its mechanisms and health implications. Full article

Chronic inflammation and immune remodeling are key features of colorectal cancer (CRC) development and progression, particularly because of the high level of microbiome presence. Among inflammatory mediators, CCL2 has been implicated in the recruitment of monocytes and tumor-associated macrophages, supporting its potential role as a marker of CRC-associated inflammatory remodeling. Therefore, we evaluated nine circulating inflammatory mediators, including CCL2, to assess their potential diagnostic value in patients with CRC. The study included 96 individuals, comprising 52 CRC patients and 44 healthy controls. Plasma cytokine levels were measured using the ProteinSimple Ella microfluidic immunoassay platform, and analyses were also stratified according to sex and BMI category (BMI < 25 vs. ≥25 kg/m²). Patients with CRC had significantly higher levels of CCL2 and IL-6 than healthy controls (p-value < 0.001), regardless of gender or overweight or obesity, confirming a chronic pro-tumor inflammatory profile. Among all markers, CCL2 showed strong exploratory diagnostic performance with an AUC of 0.918, 90.4% sensitivity, and 90.9% specificity (cut-off 436.5 pg/mL). This study highlights the central role of CCL2 as a candidate marker of systemic chronic inflammation associated with colorectal cancer. Full article

The evolving understanding of the regulation of allergic airway inflammation has offered new approaches for asthma therapy. For example, our understanding of the role of alarmins, Th2 cytokines and eosinophils has allowed the development of biologics that have revolutionized therapy for severe asthma. However, many questions remain and several of our patients are still not controlled with the current available therapies. Many immune cells have been implicated in asthma pathophysiology, but one cell that is missing from these studies is the monocyte. Monocytes (Mos) are bone marrow-derived cells that circulate in the blood and develop into macrophages and/or dendritic cells following migration to peripheral tissues. Macrophages (Møs) and dendritic cells have been implicated in the development and progression, of allergic airway inflammation, but also in tissue repair after inflammation. Recent studies in animal models suggest a major role for Mos in allergic airway inflammation, primarily through their ability to mediate recruitment of eosinophils and/or neutrophils to the airways. However, there is little information regarding the role of monocytes in human asthma. Here we review the literature regarding the presence and functions of peripheral blood and airway Mos in human asthma and suggest further work that needs to be done to consolidate the information on Mo functions. Studies show changes in Mo numbers and activation status in the peripheral blood of patients with asthma, changes that in many cases correlate with disease severity and/or activity. Studies also show altered phenotype of Mos present in the airways of patients with asthma. Detailed human studies need to be performed, if possible, studies that include therapeutic interventions, to allow for a full understanding of the role of Mos in asthma. Full article

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neuroinflammatory disorder often leading to demyelination of the spinal cord. Progression to HAM/TSP is closely associated with the high proviral load and the presence of virally infected CD4+ T cells that release extracellular vesicles (EVs). Exosomes, an EV subtype released by many cell types, transport proteins and nucleic acids that regulate intercellular communication and have been implicated in the progression of cancer and neuroinflammatory diseases. Herein, we have studied the effect of exosomes from HTLV-1 infected cells on the Peripheral Blood Mononuclear Cells (PBMCs) of HAM/TSP patients by single-cell sequencing utilizing innovative Honeycomb technology. We observed a distinct transcriptional response in monocyte populations compared with other immune cell types. Given that monocytes remain understudied in HTLV-1 pathogenesis, these findings highlight a potential role for infection-derived exosomes in shaping monocyte-driven immune dysregulation in HAM/TSP. A total of 41 genes were identified to be differentially expressed in HAM/TSP monocytes treated with exosomes; 28 were upregulated and 13 were downregulated. The most significantly altered genes are involved in chemokine activity and signaling, macrophage differentiation, lipid metabolism, and lysosomal function. Overall, our data suggests that exosome-treated HAM/TSP monocytes undergo immune remodeling that favors cell recruitment, activation, and a shift toward a mixed M1/M2-like phenotype. Such a shift may support viral persistence and chronic inflammation. These findings highlight a potential therapeutic pathway for addressing HTLV-1-induced neuroinflammation by modulating exosome-mediated signaling. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate in cancer and represent one of the major drivers of tumor-associated immunosuppression. MDSCs actively contribute to tumor progression by inhibiting both innate and adaptive immune responses, promoting angiogenesis, metastatic dissemination, and resistance to immunotherapy. Two major subsets have been identified, polymorphonuclear (PMN-) and monocytic (Mo-) MDSCs, each characterized by distinct phenotypic, metabolic, and suppressive properties. Within the tumor microenvironment (TME), MDSCs establish a complex network of interactions with T-, B-, NK-cells, dendritic cells, and macrophages, thereby orchestrating immune escape and tumor persistence. Recent evidence highlights the pivotal role of metabolic rewiring in regulating MDSC survival and suppressive activity. Enhanced aerobic glycolysis, fatty acid oxidation, amino acid depletion, reactive oxygen species (ROS) production, and adenosine metabolism collectively sustain MDSC-mediated immune dysfunction and shape the immunosuppressive TME. In particular, the crosstalk between PMN-MDSCs and NK cells has emerged as a critical mechanism of tumor immune evasion, leading to impaired NK cell cytotoxicity, altered activating receptor expression, and defective cytokine production. In this review, we summarize the current knowledge on the phenotypic and functional heterogeneity of MDSCs, their metabolic adaptations, and their interactions with immune effector populations in cancer. Furthermore, we discuss emerging therapeutic strategies aimed at targeting MDSC recruitment, differentiation, metabolic pathways, and suppressive functions. Understanding the molecular and metabolic mechanisms governing MDSC biology may provide novel opportunities to overcome tumor-induced immunosuppression and improve the efficacy of current cancer immunotherapies. Full article

Objective: To evaluate the association of routine complete blood count (CBC)-derived inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI), with disease activity and exploratory neuropsychiatric risk stratification in patients with systemic lupus erythematosus (SLE). Methods: In this multi-center retrospective study, 579 SLE patients and 282 healthy controls (HCs) were recruited from five clinical centers between 2018 and 2025. NLR, MLR, PLR, and SIRI were calculated from routine CBC parameters. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K), with high activity defined as SLEDAI-2K ≥ 10. The comparison between SLE patients and HCs was performed as an exploratory descriptive analysis to characterize systemic inflammatory profiles, whereas the primary analyses focused on associations with disease activity and NPSLE-related risk stratification. Results: SLE patients exhibited significantly higher levels of SIRI, NLR, PLR, and MLR compared to HCs (all p < 0.001). In this exploratory comparison, MLR showed the largest area under the curve for distinguishing SLE patients from HCs (AUC: 0.849, Cut-off: 0.263). In regression analyses, MLR, NLR, PLR, and SIRI were positively associated with SLEDAI-2K score. In multivariable linear regression analysis, MLR was associated with a higher SLEDAI-2K score (B = 4.600, 95% CI: 2.039–7.160, p < 0.001). In patients with available neuropsychiatric data, MLR, NLR, and SIRI were higher in patients with NPSLE than in those with non-NPSLE, whereas PLR showed no significant difference. SIRI showed modest exploratory discriminatory ability for NPSLE and may provide auxiliary information for NPSLE risk stratification (AUC: 0.710, p < 0.001, Cut-off: 1.438). Conclusions: Routine CBC-derived inflammatory biomarkers, particularly MLR, NLR, and SIRI, are associated with SLE disease activity and may serve as accessible, low-cost adjunctive tools for rapid clinical assessment. SIRI may provide additional auxiliary information for identifying patients at higher risk of neuropsychiatric involvement. However, these biomarkers should be interpreted as complementary screening or risk-stratification tools rather than substitutes for established disease activity indices or organ-specific evaluations. Further prospective studies are warranted to validate their clinical utility. Full article

Autoimmune myocarditis frequently progresses to inflammatory cardiomyopathy through dysregulated immune–stromal interactions. This study employs single-nuclei RNA-sequencing (snRNA-seq) to profile 46,233 cardiac nuclei from the experimental autoimmune myocarditis (EAM) mouse model at four timepoints: day 0 (healthy), day 14 (inflammation), day 21 (acute inflammation), and day 40 (late cardiac remodelling). Single-nuclei RNA profiling identified 18 transcriptionally distinct cell populations. Global cell–cell communication analysis revealed a dramatic peak of intercellular signalling at day 14 (5907 interactions), with fibroblast subpopulations and macrophages as dominant hubs, followed by partial resolution at day 21 (2264 interactions) and renewed remodelling at day 40 (4862 interactions). Subclustering of the macrophage compartment identified five subpopulations: Mac-TLF, Mac-MHCII, Mac-rMHCII, Mac-ResL, and Classical Monocytes. Tissue-resident macrophages (Mac-TLF, CCR2-) dominated at healthy state (~55%) but were rapidly depleted at day 14, coinciding with a dramatic influx of recruited CCR2⁺ macrophages (Mac-rMHCII), which expanded to over 70% of the compartment and maintained dominance through day 40. At inflammation (day 14), the expanded Mac-rMHCII subpopulation displayed a strongly pro-inflammatory signature (Il1b, Stat2, Parp14, Apoe), and the overall macrophage compartment was enriched for cytokine response, Fc-gamma receptor, and Notch signalling pathways, while downregulating homeostatic and mitochondrial metabolic programmes, potentially contributing to impaired efferocytosis and cardiomyocyte dysfunction. Macrophage-centred communication networks expanded markedly at day 14 (1047 interactions), with resting fibroblasts (FB-R) as the primary signalling partner, driving pro-inflammatory stromal activation marked by upregulation of Ccl2, Ccl7, and Csf2. Intra-macrophage subcluster communication also intensified at this timepoint (447 interactions). These findings delineate the temporal and functional heterogeneity of cardiac macrophages during EAM progression and identify key immune–stromal interactions driving pathological cardiac remodelling. The coexistence of pro-inflammatory and transitional reparative macrophage subsets highlights the limitations of broad immunosuppression and supports precision strategies targeting CCR2-mediated recruitment, the SPP1 signalling axis, and macrophage–fibroblast crosstalk as therapeutic avenues in myocarditis and its progression. Full article

Leukocyte recruitment from blood into tissues involves sequential adhesive steps, including rolling and integrin-dependent arrest. VLA-4 can support firm adhesion and, in some settings, rolling interactions, whereas CD44–hyaluronan interactions have also been implicated in leukocyte rolling. Here, we used adhesion assays and parallel-plate flow chamber experiments to analyze CD44–hyaluronan-dependent monocyte interactions on ECV304 monolayers and to compare them with α4-integrin-sensitive adhesion on endothelial monolayers. WEHI 78/24 monocytoid cells interacted with ECV304 monolayers in a CD44- and hyaluronan-dependent manner, whereas adhesion to HMEC-1 and bEnd.3 monolayers was sensitive to α4-integrin blockade. Blocking CD44, adding soluble hyaluronan, or treating ECV304 monolayers with hyaluronidase reduced adhesion and rolling. Mixed primary human monocyte preparations also showed CD44-dependent adhesion and rolling on ECV304 monolayers. ECV304 cells are interpreted here not as endothelial cells, but as T24-derived, hyaluronidase-sensitive cellular monolayers useful for functional analysis of CD44–hyaluronan-dependent interactions. These findings support a substrate-dependent functional hierarchy in which CD44–hyaluronan-dependent monocyte rolling becomes detectable when α4-integrin-dependent adhesion is not dominant, while emphasizing the cell-model-based nature of the assay. Full article

Developing potent adjuvants is critical for enhancing vaccine efficacy, particularly for subunit antigens. Background/Objectives: This study evaluates a novel composite adjuvant system combining liposomal QS-21 and CpG ODNs to enhance vaccine-induced immunogenicity, particularly Th1-type cellular immunity. Methods: To mitigate QS-21’s hemolytic toxicity and ensure precision delivery, a stable liposomal formulation was developed. Mice models were established using varicella-zoster virus (VZV) glycoprotein E (gE) or ovalbumin (OVA) as antigens to evaluate humoral and cellular immune responses. Results: Immunization with gE protein formulated with this novel adjuvant synergistically triggered robust immune responses, outperforming single adjuvants and the combination of QS-21/MPL. Across broad dose ranges, it induced higher Th1-type cellular immunity and comparable humoral immunity relative to AS01_B. Mechanistic studies revealed that the adjuvant significantly enhances the recruitment of dendritic cells (DCs), monocytes, and neutrophils to draining lymph nodes (dLNs) while upregulating co-stimulatory molecules CD40 and CD86 on DCs. Furthermore, the formulation triggered robust, transient increases in Th1-associated cytokines (IFN-γ, IL-12) and chemokines (CXCL9, CXCL10) across the injection site, serum, and dLNs. Conclusions: These findings indicate that the liposomal QS-21 and CpG ODNs system is a highly effective platform for promoting robust Th1-biased immunity, offering a promising adjuvant candidate and a solid experimental foundation for developing next-generation vaccines requiring potent cellular immunity. Full article

Background: Resveratrol is a plant-derived polyphenol with reported anti-inflammatory activity, and the MCP-1/CCL2 axis is a key mediator of monocyte recruitment and inflammatory tissue remodeling. Although individual preclinical studies have examined resveratrol effects on MCP-1/CCL2-related outcomes, the overall in vivo evidence has not been quantitatively synthesized. This systematic review and meta-analysis evaluated whether resveratrol treatment is associated with reduced MCP-1/CCL2-related inflammatory readouts in animal models. Methods: The protocol was registered in PROSPERO (CRD420261339126), and reporting followed the PRISMA 2020 statement. PubMed was searched from inception to 12 March 2026, with additional reference-list screening. Eligible studies were in vivo animal experiments comparing resveratrol-treated and control groups with extractable quantitative MCP-1/CCL2-related outcomes. Effect sizes were calculated as Hedges’ g with 95% confidence intervals and pooled using random-effects models fitted by restricted maximum likelihood. Subgroup, sensitivity, cumulative, influence, funnel-plot, dose meta-regression, and SYRCLE-based risk-of-bias analyses were conducted. Results: Twenty-seven studies contributing 29 analyzable datasets were included. The overall pooled effect was −3.74 (95% confidence interval, −4.50 to −2.98), indicating lower MCP-1/CCL2-related readouts in resveratrol-treated groups than in controls, with substantial heterogeneity (I2 = 78.9%). The negative association was driven mainly by rat and mouse datasets, whereas the piglet estimate was directionally opposite and the rabbit estimate came from a single dataset. Funnel-plot inspection suggested asymmetry, and dose meta-regression did not significantly explain between-study variation (slope = −0.17, p = 0.482). Leave-one-out and cumulative analyses indicated directional stability but did not resolve the underlying heterogeneity. Conclusions: These preclinical data indicate lower MCP-1/CCL2-related readouts after resveratrol treatment, but high heterogeneity, PubMed-only retrieval, and pharmacokinetic limitations limit direct clinical inference. 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