Search Results (642)

Tissue repair and regeneration are highly coordinated multicellular processes that rely on the active resolution of inflammation rather than merely its passive cessation. Reciprocal orchestration among stromal, innate, and adaptive immune systems is key to maintaining or restoring tissue homeostasis from pathological perturbations. Macrophages serve as a central nexus of these responses, exhibiting dynamic functional plasticity that extends beyond dichotomous M1/M2 classification. This review explores the evolving, context-dependent roles of macrophages in restoring tissue homeostasis, with a particular focus on efferocytosis and subsequent metabolic rewiring as key drivers of inflammation resolution. Furthermore, we highlight the bi-directional crosstalk between macrophages and heterogeneous fibroblast populations. While these stromal-myeloid interactions are essential for transient matrix remodeling and physiological healing, their sustained activation under inflammatory conditions drives maladaptive repair and fibrotic remodeling. We discuss how the defects and dysregulation of these cellular circuits contribute to the pathogenesis of autoimmune disorders, as exemplified by recent findings in rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory bowel disease (IBD). Finally, we evaluate emerging “resolution therapies” that aim to harness endogenous tissue-reparative programs of macrophages therapeutically to treat autoimmune diseases, including the application of specialized pro-resolving mediators (SPMs) and macrophage reprogramming strategies. Full article

Vaccine-associated anterior uveitis (VAAU) is an uncommon ocular inflammatory phenotype reported after several vaccine platforms. It describes anterior segment inflammation occurring after vaccination when infectious, autoimmune, idiopathic, medication-related, and other possible causes have been reasonably excluded. The current literature indicates that post-vaccination uveitis is rare relative to the scale of immunization, although anterior uveitis is frequently reported among post-vaccination ocular inflammatory events. Evidence remains limited by reliance on case reports, case series, retrospective cohorts, and passive surveillance data, which restricts precise incidence estimation and causal interpretation. Accordingly, the available evidence primarily supports a temporal association rather than a confirmed causal relationship. Proposed mechanisms include innate immune activation, molecular mimicry, adjuvant- or formulation-related immune stimulation, bystander activation, delayed-type hypersensitivity, and host susceptibility related to prior uveitis, autoimmune disease, immune dysregulation, or genetic predisposition. Clinically, VAAU may present with redness, pain, photophobia, blurred vision, anterior chamber cells and flare, keratic precipitates, posterior synechiae, elevated intraocular pressure, vitritis, or cystoid macular edema. Most cases described in the literature are mild to moderate and improve with topical corticosteroids and cycloplegic therapy, whereas recurrent, severe, or treatment-intensive courses have been reported mainly in predisposed individuals. Future work should emphasize active surveillance, standardized phenotype-specific reporting, harmonized case definitions, and mechanistic studies to better define risk, recurrence patterns, and causality. Careful interpretation of suspected cases can support accurate diagnosis, patient counseling, and vaccine-safety monitoring without undermining clinically indicated immunization. Full article

Adipose tissue is now recognized as a heterogeneous endocrine and metabolic organ rather than a passive lipid reservoir. Beyond the classical white, brown, and beige adipocytes, several depot- and organ-specific lipid-storing cell populations, including pink adipocytes, bone marrow (yellow) adipocytes, and hepatic stellate cells, contribute to energy homeostasis, thermogenesis, immune regulation, bone marrow function, and hepatic retinoid storage. Most existing reviews address these populations separately or focus narrowly on classical depots. Here, we integrate classical and non-classical adipocyte populations within a single depot-specific framework, examining how anatomical location and functional specialization jointly determine their contribution to obesity-related non-communicable diseases, including type 2 diabetes mellitus, metabolic-associated fatty liver disease, hypertension, and atherosclerotic cardiovascular disease. We further highlight unresolved mechanistic questions, including macrophage phenotypic heterogeneity beyond the classical M1/M2 model, the translational limits of brown adipose tissue activation, and the paracrine role of perivascular adipose tissue, that represent priority areas for future investigation. Full article

Glioblastoma (GBM), classified as grade 4 of high-grade glioma (HGG) under the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors (WHO CNS-2021), is the most aggressive primary brain tumor in adults. However, with maximal surgical resection, concurrent radiotherapy, and temozolomide (TMZ) chemotherapy, a median patient survival is still between 14 and 16 months. The persistent failure of current treatments is not only traceable to the molecular complexity of tumor cells but is fundamentally shaped by the tumor microenvironment (TME), in which non-neoplastic cells collectively constitute up to half of the total tumor mass. Reactive astrocytes, microglia, tumor-associated macrophages (TAMs), and oligodendrocyte precursor cells (OPCs) are no longer regarded as passive bystanders but as active architects of tumor progression, immune evasion, and therapy resistance. In this comprehensive review, we systematically describe the molecular mechanisms of glial–tumor crosstalk across all three major glial cells. Reactive astrocytes sustain tumor invasion and chemoresistance through connexin-43 gap junctions, bidirectional IL-6/JAK-STAT3 paracrine signaling, and extracellular vesicle-mediated oncogenic reprogramming. Microglia and TAMs undergo profound transcriptional reprogramming via PI3K/Akt/mTOR and CSF-1R signaling, adopting immunosuppressive states that exclude cytotoxic T cells, maintain glioma stem cell (GSC) niches, and drive angiogenesis. OPCs are now underexplored, accumulate at the tumor border, and cooperate with macrophages via Notch and Wnt/β-catenin pathways to establish a therapy-resistant GSC niche at the precise site of post-surgical recurrence. We further address glial–glial interactions as an independent regulatory layer and integrate recent spatial transcriptomic (ST) results revealing a structured, multi-glial niche that governs drug penetration. Finally, we critically evaluate emerging therapeutic strategies targeting these glial–tumor interfaces, including CSF-1R inhibitors, STAT3 modulators, CD47/SIRPα blockades, and engineered extracellular vesicle-based delivery systems. Understanding and targeting the glial ecosystem is an inseparable new field to explore. Full article

Research over the last decades have demonstrated that macrophages, considered canonical players of the immune system, also perform many other important biological functions in adult organisms. These properties have stimulated extensive research, particularly given their importance in human pathologies, including cancer. However, despite significant advances in our understanding of macrophage functions in adult organisms and diseases, their roles in embryonic systems remain comparatively underexplored. Owing to their complex developmental origin and the lack of pronounced phenotypes in embryos subjected to either spontaneous or experimentally induced macrophage ablation, macrophages have often been considered as a largely passive scavenger population associated with programmed cell death during organ and tissue remodeling. Here, we highlight key findings regarding macrophage functions during vertebrate morphogenesis. We emphasize the differences in phenotypic outcomes following macrophage ablation in adult organisms, embryos, and models of organ regeneration. Currently, the remarkable plasticity of the macrophage lineage complicates the identification of specific trophic functions involved in organ morphogenesis. Developing new approaches that improve the efficiency of macrophage ablation models, along with implementing complementary gain-of-function strategies, will contribute to a deeper understanding of the role of macrophages during embryonic development. Full article

Astrocytes are increasingly recognized as key regulators of multiple sclerosis (MS) pathogenesis, known to actively influence neuroinflammation, blood–brain barrier integrity, leukocyte recruitment, glial scar formation, and tissue repair. Evidence from both MS and its animal models demonstrates substantial astrocyte heterogeneity, exerting either pathogenic or neuroprotective functions depending on the local microenvironment. In this review, we discuss the diverse roles of astrocytes in MS, with particular focus on signaling pathways that govern astrocyte responses during chronic neuroinflammation. We further explore the growing evidence that astrocytes within chronic active lesion cores are not merely passive structural cells, but instead may be involved in immune regulation, survival signaling, and tissue maintenance. Collectively, these findings support a revised view of astrocytes as regulators of lesion dynamics and CNS homeostasis during MS. A deeper understanding of astrocyte heterogeneity and the signaling networks that control astrocyte function may reveal novel therapeutic opportunities to limit neurodegeneration and disease progression. Full article

Upper gastrointestinal (GI) cancers, including esophageal, gastric, and pancreatic cancers, remain among the most lethal malignancies worldwide, mainly because they resist nearly every therapeutic modality, from platinum-based chemotherapy, and anti-HER2 and anti-VEGF agents, to immune checkpoint inhibitors. Although tumor cell-intrinsic resistance is well characterized, an increasing share of treatment failure traces to the tumor microenvironment (TME), where cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM) act not as passive stroma but as active orchestrators of resistance. Here we argue that the functional heterogeneity of CAFs, spanning myofibroblastic (myCAF), inflammatory (iCAF), and antigen-presenting (apCAF) subtypes, and the desmoplastic ECM they construct converge on a small number of shared resistance programs. Those include paracrine signaling, metabolic reprogramming, extracellular vesicle (EV) transfer, and biomechanical remodeling that together drive chemoresistance, targeted therapy evasion, and immune exclusion. Emerging spatial multi-omics now resolves these programs to define niches within upper GI tumors, reframing resistance as a spatially organized property of the tissue rather than the tumor cell alone. We bring this evidence together and evaluate strategies aimed at CAF reprogramming and ECM normalization, arguing that spatially resolved targeting of the stroma represents a tractable path to overcoming resistance in these refractory cancers. Full article

Megakaryocytes (MKs) and platelets are increasingly recognized as active regulators of the bone marrow (BM) microenvironment rather than passive effectors of thrombopoiesis and hemostasis. Recent single-cell and lineage-tracing studies have established that megakaryopoiesis generates functionally heterogeneous populations, including immune-biased and niche-supporting subsets that shape hematopoietic stem cell (HSC) behavior, inflammatory tone, and vascular homeostasis. In leukemia, these regulatory circuits are systematically rewired to establish a marrow niche that suppresses normal hematopoiesis while sustaining leukemic stem cell (LSC) fitness through cytokine gradients, stromal remodeling, and direct cell-to-cell communication. In this focused review, we propose that the immune MK (iMK)–platelet axis is a central driver of leukemic niche remodeling. We discuss how iMK states arise under leukemic pressure, how MK heterogeneity encodes distinct niche instructions, and how platelet-derived extracellular vesicles (EVs) distribute inflammatory signals across the marrow and systemic circulation. Within this framework, we position mitochondrial stress outputs—such as reactive oxygen species (mtROS), mitochondrial DNA (mtDNA) release, metabolic rewiring, and mitochondria-containing EV secretion—not as isolated phenomena, but as mechanistic amplifiers embedded within the broader inflammatory and niche-regulatory programs of MKs and platelets. We further highlight preleukemic inflammatory states as an underappreciated entry point for therapeutic intervention, and propose three clinically actionable axes: inflammatory niche interruption, mitochondrial stress modulation, and platelet–leukemia communication blockade. This framework aligns with emerging concepts in MK heterogeneity, innate immune sensing, endothelial remodeling, and preleukemic signaling, and positions the MK–platelet axis as a promising therapeutic framework in leukemia-associated niche remodeling. Full article

Respiratory syncytial virus (RSV) remains a major cause of severe lower respiratory tract infection in early infancy, a period characterized by immunological immaturity and limited capacity for effective antiviral responses. Maternal RSV vaccination has emerged as a successful strategy to protect newborns by inducing high concentrations of IgG1-dominant, prefusion F-specific antibodies, which are selectively and actively transported across the placenta. This review synthesizes current mechanistic insights into how maternally derived antibodies confer neonatal protection, focusing on (i) FcRn-mediated transplacental transport, (ii) IgG subclass-specific differences in transfer and half-life, and (iii) the role of Fc glycosylation in modulating Fcγ receptor engagement and effector functions. Beyond neutralization, vaccine-induced antibodies mediate Fc-dependent mechanisms such as antibody-dependent cellular cytotoxicity and phagocytosis, which may be preferentially enriched in the neonatal circulation. Although emerging systems serology data suggest qualitative selectivity in placental transfer, evidence remains heterogeneous and highlights the need for further clarification of glycosylation-dependent and glycosylation-independent pathways. The timing of vaccination, maternal antibody characteristics, and placental integrity critically influence neonatal antibody levels and the duration of passive immunity. Understanding these molecular determinants is essential for optimizing maternal RSV immunization strategies and improving early-life protection. Full article

The extracellular matrix (ECM) is increasingly recognized as an active regulator of breast cancer progression rather than a passive structural scaffold. This narrative review examines how ECM remodeling contributes to tumor aggressiveness through changes in matrix composition, collagen architecture, tissue stiffness, mechanotransduction, stromal permissiveness, immune and metabolic programs, invasion, metastasis and therapeutic response. A structured narrative search of literature published from 1981 to June 2026 was used to support this synthesis. Evidence from breast cancer studies indicates that collagens, fibronectin, laminins, proteoglycans, matricellular proteins, ECM-remodeling enzymes, and matrix-crosslinking pathways regulate integrin–FAK/Src, RhoA–ROCK, PI3K–AKT, MAPK, TGF-β/SMAD, Wnt/β-catenin, and YAP/TAZ signaling. Spontaneous canine mammary tumors are discussed as complementary comparative models that may preserve selected tumor–stroma–ECM interactions under naturally occurring disease conditions while requiring cautious interpretation due to species-specific biological and clinical differences. Proteomics, lipidomics, metabolomics, spatial omics, digital pathology, and artificial intelligence may support ECM-informed biomarker discovery and response prediction. However, translational application requires standardized pathology, reproducible assays, harmonized metadata, external validation, model interpretability, and clinically meaningful endpoints. Overall, ECM-informed comparative oncology is best viewed as a framework grounded in rigorous validation for identifying matrix-defined tumor phenotypes and prioritizing future biomarker and therapeutic strategies. Full article

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infection in young infants and accounts for substantial morbidity, hospitalization, and mortality worldwide, with the highest burden concentrated in the first months of life, when immunological and anatomical immaturity favors severe disease. Maternal vaccination has emerged as a strategy to bridge this window of vulnerability through the transplacental transfer of neutralizing antibodies. This integrative review synthesizes scientific articles published between 2022 and 2026, including systematic reviews, meta-analyses, narrative reviews, and position statements from national and international scientific societies, addressing the epidemiology, clinical manifestations, diagnosis, mechanism of action, efficacy, safety, and public health impact of maternal RSV immunization. The bivalent prefusion F protein vaccine (RSVpreF; Abrysvo^®), administered as a single intramuscular dose between 32 and 36 weeks of gestation, induces maternal IgG that is transferred to the fetus and confers passive protection during the first six months of life. In the phase 3 MATISSE trial, vaccination demonstrated 81.8% efficacy against severe RSV lower respiratory tract infection within 90 days of birth and 69.4% within 180 days, alongside reductions in hospitalization. The safety profile was favorable, with predominantly mild and transient adverse events; a numerical imbalance in preterm birth remains under surveillance and underlies the precautionary gestational window. Maternal vaccination and long-acting monoclonal antibodies (nirsevimab) are best regarded as complementary rather than competing strategies. Current evidence supports maternal immunization as one of the most effective measures to reduce the burden of RSV disease in early infancy. Full article

Lipid droplets (LDs) were long thought to be passive organelles merely for neutral lipid storage. Mounting evidence redefines LDs as dynamic metabolic signaling hubs orchestrating cellular stress adaptation, with multifaceted roles in organelle crosstalk, metabolic reprogramming, redox balance and immune signaling. LD function is tightly intertwined with liquid–liquid phase separation (LLPS) and epigenetic remodeling, bridging cellular metabolism to gene expression and cell fate control. LD biogenesis relies on ER lipid structures, phase-separated protein assemblies and lipid regulatory proteins. Via contacts with multiple organelles, LDs regulate lipid catabolism, ferroptosis, inflammation and chromatin accessibility, while their metabolites directly reshape epigenetic modifications and transcription. LLPS-driven biomolecular condensates further coordinate LD-linked metabolic and stress signaling. Dysregulated LD remodeling mediates metabolic flexibility, immune escape and drug resistance in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), neurodegeneration, viral infection and cancer. This review summarizes progress in LD biogenesis and metabolism, dissects mechanistic crosstalk between LDs, LLPS and epigenetic control, and outlines LD-driven pathogenic reprogramming across human disorders. We also discuss therapeutic approaches targeting LD and LLPS pathways. Despite promising translational prospects, unresolved mechanistic and clinical hurdles persist. Further research on LD biology will reshape our framework linking metabolism, chromatin regulation and stress adaptation. Full article

Background: Maternal influenza during the peripartum period poses a clinically significant risk to newborns, particularly for infants younger than 6 months. This group is especially vulnerable because of immune immaturity and the absence of an approved influenza vaccine for this age group. In light of emerging influenza virus mutations with pandemic potential, current protocols require evaluation with respect to infection prevention. Objective: To map and synthesize the available evidence and recommendations on the management of neonates born to mothers with suspected or confirmed influenza, with particular focus on delivery, skin-to-skin contact, breastfeeding, mother–infant separation, and neonatal antiviral therapy. Sources of Evidence: We performed a scoping review of the literature and professional guidance documents addressing the perinatal and postnatal management of newborns exposed to maternal influenza, using PubMed, Google Scholar, Web of Science, Embase, WHO, and CDC publications. The available evidence was synthesized narratively across the principal domains of clinical care. Conclusions: Current evidence does not support changing the mode of delivery solely because of maternal influenza. When the mother’s clinical condition permits, rooming-in, skin-to-skin contact, and breastfeeding can generally be supported with strict droplet precautions and hand hygiene. These practices provide substantial benefits for bonding, nutrition, and passive immune protection. Temporary separation may be considered in selected cases of severe maternal illness, although consistent evidence of benefit is limited. In neonates with suspected or confirmed influenza, early antiviral treatment should be considered in accordance with current pediatric guidance, whereas routine chemoprophylaxis in infants younger than 3 months remains insufficiently supported by evidence. Overall, recommendations remain heterogeneous, highlighting the need for higher-quality studies and clearer neonatal care pathways. Full article

The evolution of regenerative medicine has repositioned the extracellular matrix (ECM) from a passive structural scaffold to a dynamic signaling hub that dictates host immunity and tissue remodeling. A critical driver of this bioactivity is the matrix-bound nanovesicle (MBV), a distinct subclass of extracellular vesicles (EVs) physically embedded within collagen fibers. Unlike fluid-phase EVs, MBVs exhibit unique release kinetics triggered by matrix degradation and possess tissue-specific molecular signatures that dictate their therapeutic potential. This review evaluates the biogenesis, isolation, and cellular tropism of MBVs, highlighting the macrophage as a central mediator of their immunomodulatory effects. We propose a “precision medicine” framework for matching MBV tissue sources—ranging from pro-angiogenic small intestinal submucosa to anti-angiogenic cartilage—to the specific pathological requirements of the target injury. Furthermore, we discuss post-harvest engineering strategies, including surface functionalization via click chemistry and exogenous cargo loading, to enhance MBV targeting and potency. Finally, we address the translational hurdles of protocol standardization and pharmacokinetic characterization required to transition MBVs into a scalable, cell-free platform for regenerative therapy. Full article

The mammalian gut microbiome functions as a metabolically active immunological organ and has co-evolved with its host to maintain systemic homeostasis. This review integrates current evidence on the molecular mechanisms governing bidirectional microbiota–immune communication, emphasizing evolutionary conservation, receptor-mediated signaling, and translational implications. Microbial structural ligands and metabolites—including short-chain fatty acids, bile-acid derivatives, and tryptophan catabolites—engage host receptors such as G-protein-coupled receptors, FXR/TGR5, and the aryl hydrocarbon receptor (AhR), thereby regulating epithelial barrier integrity, regulatory T-cell differentiation, Th17 polarization, mucosal IgA production, and systemic immune tone. Riboflavin-derived metabolites presented via major histocompatibility complex class-I-related molecule (MR1) further shape mucosal-associated invariant T-cell development (MAIT), illustrating metabolite-driven immune system programming. Dysbiosis induced by antibiotics, dietary perturbation, or aging disrupts these molecular networks, promoting chronic inflammatory, metabolic, autoimmune, and neuroimmune disorders. Comparative analyses across mammalian systems underscore conserved pathways of host–microbe coadaptation and immune education. Therapeutically, microbiota-modulating strategies—including probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), postbiotics, and IgY-based passive immunotherapy—aim to restore immunometabolic signaling. Emerging in vitro and in silico platforms further provide mechanistic precision while supporting ethically aligned translational research. Collectively, these insights position microbiota-derived molecular signaling as a central determinant of adaptive immune architecture and a targetable axis in precision immunotherapy. Full article