Search Results (28)

The article presents the results of a structured literature review of the past decade and focuses on the crucial role of platelets in the pathogenesis of pulmonary arterial hypertension (PAH). It explores how endothelial dysfunction initiates early prothrombotic signals that activate platelets, which, in response, adopt a pro-inflammatory phenotype, release cytokines and chemokines, and form aggregates with leukocytes, thereby modulating their migration and activity. A key feature of PAH is the “platelet paradox,” in which chronic in vivo activation coexists with reduced ex vivo reactivity due to functional exhaustion. Prolonged stimulation and disease progression lead to complex hemostatic dysregulation, characterized by heterogeneity in platelet phenotypes. At the same time, platelets undergo immunometabolic reprogramming, with a predominance of glycolysis, over oxidative phosphorylation, mitochondrial dysfunction, altered fatty acid oxidation (FAO), increased lactate production, and enhanced vesicle release. These phenomena sustain inflammation and promote pulmonary vascular remodeling. This study aims to review the current mechanisms of immunometabolic platelet activation in pulmonary arterial hypertension. It primarily focuses on platelet aspects as key elements in disease progression and as potential sources of new biomarkers and therapeutic targets. Full article

Sepsis, which affects 49 million people yearly, killing 11 million of them, is known to induce severe liver dysfunction. It is characterized by extensive metabolic reprogramming, resulting in acute metabolic loss of function and maladaptive repair that can prime the organ for fibrosis rather than functional regeneration. To understand how intercellular communication dictates these outcomes, we performed cell type-specific bulk RNA-sequencing on hepatocytes (HEP), hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), and CD45⁺ leukocytes (CD45) from mice following polymicrobial sepsis. Cell-cell communication analyses using CellChat and NicheNet revealed a clear reorganization of the hepatic environment. While HSCs remain largely quiescent during homeostasis, after sepsis, they become the liver’s central signaling hub and broadcast potent fibrogenic and chemotactic signals (e.g., Ccl7) to surrounding cells. This actively suppresses hepatocyte metabolic functions, promotes leukocyte infiltration, and may further initiate early fibrogenic priming. Our findings highlight HSCs as regulators during septic acute liver injury, revealing communication nodes that could be targeted to constrain fibrosis responses and promote normal functions and repair. Full article

Poor bone quality in osteoporotic patients remains a major challenge for achieving predictable osseointegration. This study serves as a mechanistic complement to previously reported structural data, aiming to investigate the molecular pathways underlying the synergy between nanostructured surfaces and autologous blood concentrates in compromised bone. Ninety-six Wistar rats were divided into healthy (SHAM) and osteoporotic (OVX) groups. Implants with nanostructured hydroxyapatite (NanoHA) or dual acid-etched (DAE) surfaces were installed in the tibiae, associated or not with leukocyte- and platelet-rich fibrin (L-PRF). Gene expression (RT-qPCR) for Runx2, Alpl, Bglap, Spp1, Tnfrsf11, and Tnfrsf11b was assessed at 7 and 30 days. In compromised systemic conditions (OVX), the NanoHA + L-PRF association promoted a robust “molecular rescue” of bone metabolism. At 30 days, this synergistic group exhibited a significant upregulation of Alpl (mean: 11.69 ± 1.65) and Runx2 (mean: 4.49 ± 0.82) compared to DAE controls (p < 0.05). Crucially, the therapy orchestrated a protective remodeling environment by significantly inducing Tnfrsf11b expression (5.50 ± 0.88), effectively balancing the Tnfrsf11/Tnfrsf11b ratio. Late-stage maturation markers (Bglap and Spp1) were also significantly elevated, effectively mimicking healthy physiological levels observed in the SHAM group. NanoHA biofunctionalization, synergistically with L-PRF, triggers a transcriptional reprogramming of the peri-implant microenvironment, mitigating the catabolic effects of estrogen deficiency. These findings provide a biological foundation for enhanced clinical predictability in high-risk patients, suggesting that local interfacial modifications can overcome systemic bone compromise. Full article

Trained immunity refers to the enduring functional reprogramming of innate immune cells after particular stimuli, driven by epigenetic and metabolic alterations that augment non-specific responses upon subsequent exposure. Neutrophils and monocytes/macrophages, as essential innate effectors, are crucial for the induction and control of trained immunity, which is the primary emphasis of this review. Neutrophils, the predominant circulating leukocytes, were historically considered incapable of memory owing to their brief lifespan. Emerging evidence indicates that trained immunity functions at the bone marrow progenitor level, influencing granulopoiesis to produce neutrophils with lasting functional modifications. This research offers new insights into neutrophil functions in infection, cancer, and inflammation. Monocytes and macrophages, characterized by phenotypic plasticity and tissue residence, function as conventional models of trained immunity. They experience direct peripheral reprogramming or emerge as primed descendants of trained bone marrow precursors, performing pro-inflammatory or reparative roles in malignancies, infections, and ischemia lesions. This study comprehensively outlines the regulatory mechanisms of trained immunity in these cells, clarifies their functions in various clinical situations, and examines therapeutic applications. Comprehending these pathways is crucial for elucidating the cellular foundation of innate immunological memory, uncovering its multiple functions in disease, and guiding innovative therapeutics aimed at granulopoiesis and monocyte-macrophage polarization. Full article

Kupffer cells (KCs) make up the predominant population of resident innate immune cells in the liver, serving as key immune sentinels that maintain local immune surveillance and immunoregulatory homeostasis. However, their functional involvement and phenotypic dynamics during radiation-induced liver damage (RILD) remain insufficiently explored. Therefore, we established a mouse model of RILD and, through systematic single-cell-level profiling of hepatic immune cell populations, found that KCs play a critical role in hepatic immune responses and undergo a pronounced radiation-induced shift toward a pro-inflammatory M1 phenotype. Further KC depletion/reconstitution, molecular assays, and coculture experiments consistently demonstrated that M1-polarized KCs exacerbate liver damage, with secretory leukocyte protease inhibitor (SLPI) being identified as a key molecular mediator driving this polarization and its pathogenic effects. To further substantiate these findings, we designed a liposome-based delivery strategy to selectively inhibit SLPI in KCs, which effectively suppressed M1 polarization and alleviated radiation-induced liver damage, underscoring the therapeutic relevance and translational potential of this approach in RILD. Overall, these findings demonstrate that radiation drives KCs toward an SLPI-dependent pro-inflammatory M1 state, thereby exacerbating liver injury. Moreover, targeted liposomal suppression of SLPI effectively reverses this polarization and protects against RILD, highlighting SLPI-modulated KC reprogramming as a promising therapeutic approach. Full article

Platelets have traditionally been viewed as passive cellular elements involved in hemostasis and vascular integrity. However, growing evidence over the last decade has radically changed this paradigm, revealing platelets as dynamic immune and inflammatory effectors that actively participate in host–pathogen interactions. In viral infections, platelets are not merely innocent bystanders but represent key players in a bidirectional and tightly regulated platelet–virus axis that influences viral dissemination, immune activation, endothelial dysfunction, and the development of thrombotic and hemorrhagic complications. Several clinically relevant viruses, including SARS-CoV-2, influenza virus, HIV, dengue virus, and viral hemorrhagic fever-associated pathogens, have been shown to directly or indirectly interact with platelets through surface receptors, immune complexes, and inflammatory mediators, leading to platelet activation, phenotypic reprogramming, and accelerated clearance. These processes contribute to the paradoxical coexistence of thrombocytopenia and hypercoagulability that characterizes many severe viral diseases. Moreover, platelets can act as immune sentinels by sensing viral components, releasing cytokines and chemokines, forming platelet–leukocyte aggregates, and modulating both innate and adaptive immune responses, thereby shaping the clinical course of infection. In this review, we synthesize current evidence on the molecular and cellular mechanisms governing virus–platelet interactions, with particular emphasis on their role in immune-thrombosis, endothelial injury, and organ dysfunction. We further discuss the clinical implications of platelet dysregulation in viral infections, including its potential value as a biomarker of disease severity and as a therapeutic target. Understanding the platelet–virus axis provides a unifying framework to explain the thrombo-inflammatory phenotype of viral diseases and may open new avenues for risk stratification and targeted interventions in affected patients. Full article

Soft tissue manipulation (STM) is widely used by physical therapists, massage therapists, athletic trainers, and osteopathic physicians to manage musculoskeletal pain, yet its biological mechanisms remain poorly understood. Preclinical studies indicate that STM can alter immune cell behavior in animal models, increasing anti-inflammatory cytokines (IL-4, IL-10) and reducing chemokines such as RANTES/CCL5. Single-cell transcriptomic analyses suggest mechanical treatment may reprogram stromal cells and shift immune cell recruitment in aged or inflamed tissues. However, many of these mechanistic findings have yet to be confirmed in human studies. Early clinical trials show massage therapy can modify circulating leukocytes and reduce cytokine responses, but direct tissue-level evidence in human subjects remains limited. This narrative review summarizes existing insights and emphasizes the need for future clinical investigations targeting populations with chronic inflammation, repetitive-use injuries, post-surgical fibrosis, or age-related muscle decline. We advocate for studies incorporating tissue or fluid sampling, cytokine profiling, and molecular assays such as flow cytometry or transcriptomics to characterize STM’s immunological effects in people. Rather than simply easing symptoms, STM may act as a precision mechanical stimulus that recalibrates immune tone and promotes tissue repair. Bridging basic science with clinical research will be essential to establish STM as a biologically informed, mechanobiology-based therapeutic strategy. Full article

Background: The global health burden of mosquito-borne viruses, including dengue, yellow fever, Zika, and chikungunya, is rising due to climate change and globalisation, which favour mosquito habitat expansion. The genetic diversity of these viruses complicates the development of virus-specific vaccines or antivirals, highlighting the need for pan-viral strategies. As the common vector for these pathogens, mosquitoes and specifically their salivary proteins represent a promising target for such interventions. Mosquito saliva, secreted into the skin during biting, has immunomodulatory effects that can enhance host susceptibility to infection, but these mechanisms are not well defined in humans. Methods: The objective of this study was to determine whether AGS-v PLUS, a vaccine targeting mosquito salivary antigens, could modulate the human skin immune response to mosquito biting and potentially promote antiviral bystander immunity. In a Phase I trial, healthy volunteers were vaccinated with AGS-v PLUS (with or without adjuvant) or placebo, and three weeks later, they were exposed to bites from Aedes albopictus and Aedes aegypti mosquitoes. Skin biopsies from bitten and unbitten sites were analysed by transcriptomic profiling. Results: In placebo recipients, mosquito biting elicited a marked adaptive immune response at 48 h, characterised by CD4⁺ Th1 and CD8⁺ T cell signatures and leukocyte recruitment. While responses to Ae. aegypti and Ae. albopictus bites were broadly similar, those to Ae. albopictus were stronger. Vaccination with AGS-v PLUS, particularly with adjuvant, enhanced Th1 and CD8⁺ T cell-associated gene expression while suppressing pathways linked to neutrophilic inflammation and epithelial stress, which together may provide enhanced antiviral capacity. Conclusions: These findings demonstrate that targeting the host response to mosquito saliva via vaccination can reprogram the skin’s immune response to mosquito bites, supporting a novel and broadly applicable pan-viral strategy to mitigate the impact of arboviral diseases. Full article

High-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy characterized by intraperitoneal spread and chemotherapy resistance. Chemotherapies have demonstrated limited effectiveness in HGSOC, underscoring the urgent need to evaluate how the tumor microenvironment (TME) was reshaped by chemotherapy in different sites of tumor foci. In this study, we performed single-cell transcriptomic analysis to explore the TME in samples obtained from various sites of tumor foci, with or without the history of Neoadjuvant chemotherapy (NACT). We discovered that chemotherapy reshaped the tumor immune microenvironment, evident through the reduction in human leukocyte antigen (HLA) diversity and the increase in PDCD1/CD274 in CD8_ANXA1, LAMP3+ dendritic cell (DC_LAMP3), and EREG+ monocytes (mono_EREG). Moreover, cancer.cell.2, cancer-associated C3+ fibroblasts (CAF_C3), and Fibrocyte_CD34, which are prone to accumulate in the metastatic site and post-NACT group, harbored poor clinical outcome, reflected in the immune exclusion and tumor progression signaling. Cell–cell communication identified a stronger interaction between cancer.cell.2 and CAF_C3, as well as Fibrocyte_CD34, in post-NACT samples, indicating that chemotherapy reshapes pre-existing cell clusters in a site-dependent manner. Our findings suggest that chemotherapy and sites of foci were critical for the transcriptional reprogramming of pre-existed cell clusters. Our study offers a single-cell phenotype data substrate from which to develop a personalized combination of chemotherapy and immunotherapy. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy characterized by a complex tumor microenvironment (TME) that plays a critical role in disease progression and therapeutic resistance. Tumor-infiltrating immune cells, including T lymphocytes, macrophages, dendritic cells, and myeloid-derived suppressor cells, exhibit dual functions, either promoting or suppressing tumor growth depending on their phenotype and interactions within the TME. The presence of immune evasion mechanisms, such as the loss of human leukocyte antigen (HLA) expression, upregulation of immune checkpoint molecules, and metabolic reprogramming (hypoxia-induced glycolysis and lactate accumulation), further contributes to immune suppression and poor treatment responses. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent/metastatic HNSCC, response rates remain highly variable, underscoring the need for biomarker-driven patient selection and combinatorial therapeutic strategies. This review provides a comprehensive analysis of the role of immune cells in the TME of HNSCC, discusses the mechanisms underlying immune escape, and explores emerging immunotherapeutic and epigenetic-targeting approaches aimed at enhancing antitumor immune responses and improving clinical outcomes. Full article

Exposure to endocrine-disrupting chemicals (EDCs) has been linked to several pathologies in human health, especially those involving the immune system. The vast majority of studies have focused on cells and functions of the adaptive immune system with little investigation of the impact of EDCs on innate immunity. While EDC exposure remains a threat throughout the lifetime of an individual, the most detrimental effects on human health occur during critical stages of development, such as in utero. Fetal development is not only associated with growth and tissue remodeling but also with the establishment of key processes, including those of the immune system. Unfortunately, due to fetal plasticity, developmental exposure to certain EDCs, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), can affect mammalian health well into adulthood by altering fetal programming. Herein, we hypothesize that in utero exposure to TCDD induces developmental reprogramming of the innate immune system that subsequently impacts the adult response to infection. To interrogate our hypothesis, we challenged adult mice with and without a history of in utero TCDD exposure with 1 × 10⁸ CFU Pseudomonas aeruginosa via intraperitoneal injection. Results revealed a significant decrease in the number of innate leukocytes at the site of infection six hours after inoculation in toxicant-exposed mice compared to unexposed mice. The reduction in the number of phagocytes correlated with a reduction in bacterial clearance in toxicant-exposed mice. We also noted a decreased ability of peritoneal immune cells from toxicant-exposed mice to produce chemokines necessary for immune cell recruitment. Taken together, our results indicate that in utero EDC exposure impairs the innate immune response to a bacterial infection in adult offspring, particularly in males. Full article

Conventional cancer treatments include surgical resection, chemotherapy, hyperthermia, immunotherapy, hormone therapy, and locally targeted therapies such as radiation therapy. Standard cancer therapies often require the use of multiple agents, which can activate nuclear factor kappa B (NF-κB) in tumor cells, leading to reduced cell death and increased drug resistance. Moreover, the use of multiple agents also contributes to added toxicity, resulting in poor treatment outcomes. Cancer cells gradually develop resistance to almost all chemotherapeutics through various mechanisms, such as drug efflux, alterations in drug metabolism and transport, changes in signal transduction pathways, enhanced DNA repair capacity, evasion of apoptosis, increased mutations, reactivation of drug targets, interaction with the cancer microenvironment, cancer cell-stroma interactions, epithelial–mesenchymal transition (EMT)-mediated chemoresistance, epigenetic modifications, metabolic alterations, and the effect of cancer stem cells (CSCs). Developing new strategies to improve chemotherapy sensitivity while minimizing side effects is essential for achieving better therapeutic outcomes and enhancing patients’ quality of life. One promising approach involves combining conventional cancer treatments with propolis and its flavonoids. These natural compounds may enhance tumor response to treatment while reducing toxicity. Propolis and its components can sensitize cancer cells to chemotherapeutic agents, likely by inhibiting NF-κB activation, reprogramming tumor-associated macrophages (TAMs; an M2-like phenotype), and thereby reducing the release of matrix metalloproteinase (MMP)-9, cytokines, chemokines, and the vascular endothelial growth factor (VEGF). By reducing TAMs, propolis and its components may also overcome EMT-mediated chemoresistance, disrupt the crosstalk between macrophages and CSCs, inhibit the maintenance of stemness, and reverse acquired immunosuppression, thus promoting an antitumor response mediated by cytotoxic T-cells. This review highlights the potential of flavonoids to modulate the responsiveness of cancer to conventional treatment modalities. The evidence suggests that novel therapeutic strategies incorporating flavonoids could be developed to improve treatment outcomes. The positive effects of combining propolis with chemotherapeutics include reduced cytotoxicity to peripheral blood leukocytes, liver, and kidney cells. Therefore, polyphenolic/flavonoid components may hold potential for use in combination with chemotherapeutic agents in the clinical treatment of various types of cancers. Full article

Background: Cell-based therapies for drug-resistant epilepsy using induced pluripotent stem cell-derived inhibitory interneurons are now in early-phase clinical trials, building on findings from trials in Parkinson’s disease (PD) and Huntington’s disease (HD). Graft rejection and the need for immunosuppressive therapy post-transplantation pose potential barriers to more epilepsy patients becoming potential candidates for inhibitory interneurons transplantation surgery. Objectives: The present literature review weighs the evidence for and against human leukocyte antigen (HLA)-mediated graft rejection in PD and HD and examines the potential advantages and drawbacks to five broad approaches to cell-based therapies, including autologous cell culture and transplantation, in vivo reprogramming of glial cells using viral vectors, allogeneic transplantation using off-the-shelf cell lines, transplantation using inhibitory interneurons cultured from HLA-matched cell lines, and the use of hypoimmunogenic-induced pluripotent stem cell-derived inhibitory interneurons. The impact of surgical technique and associated needle trauma on graft rejection is also discussed. Methods: Non-systematic literature review. Results: While cell-based therapies have enjoyed early successes in treating a host of central nervous system disorders, the immunologic reaction against surgical procedures and implanted materials has remained a major obstacle. Conclusions: Adapting cell-based therapies using iPSC-derived inhibitory interneurons for epilepsy surgery will similarly require surmounting the challenge of immunogenicity. Full article

Immune alterations in end-stage renal patients receiving hemodialysis are complex and predispose patients to infections. Anticoagulation may also play an immunomodulatory role in addition to the accumulation of uremic toxins and the effects of the dialysis procedure. Accordingly, it has been recently shown that the infection rate increases in patients under regional citrate anticoagulation (RCA) compared with systemic heparin anticoagulation (SHA). We hypothesized that RCA affects the immune status of hemodialysis patients by targeting monocytes. In a cohort of 38 end-stage renal patients undergoing hemodialysis, we demonstrated that whole blood monocytes of patients receiving RCA—but not SHA—failed to upregulate surface activation markers, like human leukocyte antigen class II (HLA-DR), after stressful insults, indicating a state of deactivation during and immediately after dialysis. Additionally, RNA sequencing (RNA-seq) data and gene set enrichment analysis of pre-dialysis monocytes evidenced a great and complex difference between the groups given that, in the RCA group, monocytes displayed a dramatic transcriptional change with increased expression of genes related to the cell cycle regulation, cellular metabolism, and cytokine signaling, compatible with the reprogramming of the immune response. Transcriptomic changes in pre-dialysis monocytes signalize the lasting nature of the RCA-related effects, suggesting that monocytes are affected even beyond the dialysis session. Furthermore, these findings demonstrate that RCA—but not SHA—impairs the response of monocytes to activation stimuli and alters the immune status of these patients with potential clinical implications. Full article

The immune response to infectious diseases is directly influenced by metabolic activities. COVID-19 is a disease that affects the entire body and can significantly impact cellular metabolism. Recent studies have focused their analysis on the potential connections between post-infection stages of SARS-CoV2 and different metabolic pathways. The spike S1 antigen was found to have in vitro IgG antibody memory for PBMCs when obtaining PBMC cultures 60–90 days post infection, and a significant increase in S-adenosyl homocysteine, sarcosine, and arginine was detected by mass spectrometric analysis. The involvement of these metabolites in physiological recovery from viral infections and immune activity is well documented, and they may provide a new and simple method to better comprehend the impact of SARS-CoV2 on leukocytes. Moreover, there was a significant change in the metabolism of the tryptophan and urea cycle pathways in leukocytes with IgG memory. With these data, together with results from the literature, it seems that leukocyte metabolism is reprogrammed after viral pathogenesis by activating certain amino acid pathways, which may be related to protective immunity against SARS-CoV2. Full article