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High-throughput glycan array screening reveals rhamnogalacturonan-I as a ligand for Arabidopsis leucine-rich repeat receptor kinases involved in plant immunity.

The plant cell wall not only serves as a physical barrier against pathogens but, when damaged, also functions as a source of cell wall-derived molecules that play crucial roles in plant immunity as damage-associated molecular patterns. While oligogalacturonides from homogalacturonan are well-studied damage-associated molecular patterns, the immune-signaling potential of other cell wall components remains largely unexplored. Conventional genetic and biochemical approaches aimed at identifying ligand-receptor pairs in plant immunity have been limited by the vast diversity of potential ligand molecules and functional redundancy of putative receptors. In this study, we developed a high-throughput screening pipeline that simultaneously examines multiple interactions between plant cell wall-derived glycans and >350 extracellular domains of receptor kinases and receptor-like proteins in Arabidopsis, resulting in the screening of >40 000 interactions. We discovered a group of leucine-rich repeat receptor kinases named ARMs (AWARENESS of RG-I MAINTENANCES) that interact with rhamnogalacturonan-I (RG-I), a major component of pectin. RG-I treatment induced pattern-triggered immunity responses with distinct kinetics compared to oligogalacturonide responses. We identified RG-I oligosaccharide structures required for interaction with ARM receptors and immune activation and found that ARM receptors function redundantly in plant immunity. Collectively, our work provides a powerful platform for discovering glycan-receptor pairs in plants, facilitating a more comprehensive understanding of cell wall surveillance mechanisms in plant immunity.

Arabidopsis

Glutathione reductase deficiency potentiates the immunogenicity of ferroptosis and cuproptosis via amplified reactive oxygen species accumulation and cGAS-STING pathway activation.

BACKGROUND: Cancer remains a major therapeutic challenge due to drug resistance and metastasis, processes driven by oxidative stress and redox imbalance. Targeting this vulnerability through ferroptosis (iron-dependent lipid peroxidation) and cuproptosis (copper-driven mitochondrial dysfunction), two ROS-mediated cell death pathways, offers a promising therapeutic strategy. However, clinical translation is hindered by incomplete understanding of their redox regulation and limited immunogenicity. METHODS: A genome-wide CRISPR knockout screen was performed to identify key regulators of ferroptosis. Genetic depletion or pharmacological inhibition of candidate genes was evaluated across multiple cancer cell lines for sensitivity to ferroptosis inducer RSL3 and the cuproptosis inducer elesclomol (Es). Antitumor efficacy was assessed in xenograft, orthotopic, metastatic, and syngeneic mouse models, alone or combined with immune checkpoint inhibitors. Mechanistic studies also examined ROS production, mitochondrial stress, mitochondrial DNA release, cGAS-STING activation, and immune responses within the tumor microenvironment. RESULTS: Glutathione reductase (GSR), a central enzyme maintaining reduced glutathione (GSH) homeostasis, was identified as the top suppressor of ferroptosis. GSR knockout or pharmacological inhibition markedly sensitized diverse cancer cell lines to RSL3-induced ferroptosis, while GSR overexpression conferred resistance. Strikingly, GSR depletion also enhanced sensitivity to cuproptosis triggered by the copper ionophore Es. In multiple in vivo tumor models, GSR inhibition synergizes with RSL3 or Es to suppress tumor growth, inhibit lung metastasis, and prolong survival. Mechanistically, GSR deficiency amplified ROS production, induced mitochondrial stress, and triggered the cytosolic mitochondrial DNA release under ferroptotic or cuproptotic stress, activating the cGAS-STING pathway in vitro and in vivo. This increased inflammatory cytokine production, promoted immunogenic cell death, and enhanced the release of damage-associated molecular patterns (DAMPs), including HMGB1. Together, GSR inhibition combined with a ferroptosis or cuproptosis inducer transformed the tumor microenvironment into a highly immune stimulatory state, thereby enhancing the efficacy of immune checkpoint blockade through increased dendritic cell activation and T-cell infiltration and activation. CONCLUSIONS: GSR represents a key molecular node connecting and modulating ferroptosis and cuproptosis through redox regulation. Targeting GSR amplifies ROS-mediated immunogenic cell death, triggers cGAS-STING activation in cancer cells, and enhances the efficacy of cancer immunotherapy, providing a promising redox-based therapeutic strategy.

Ferroptosis

HMGB1 as a convergent host factor in virus-induced carcinogenesis.

High-mobility group box 1 (HMGB1) is a chromatin-associated protein and a prototypical damage-associated molecular pattern whose dual intracellular and extracellular functions are increasingly implicated in cancer progression. Because viral proteins can harness HMGB1 to facilitate their own replication and remodel the microenvironment of transformed cells, human oncogenic viruses provide an instructive model for examining this duality. In this conceptual review, we organized the available evidence around two functional nodes. At the first node, intracellular HMGB1 supports viral replication, acting on viral chromatin in Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus, and on structured viral RNA in hepatitis C virus. At the second node, viral infection or specific viral oncoproteins induce HMGB1 secretion, which promotes infected-cell survival and remodels the tumor microenvironment, as reported for KSHV, hepatitis B virus, and human T-cell leukemia virus type 1. Human papillomavirus engage a receptor-level variant of this node through the HMGB1-TLR4 axis. Only KSHV currently supports both nodes in matched experimental systems. Therefore, we present a sequential two-node arrangement as a hypothesis, instead of an established property of oncogenic viruses. We further considered how viruses reverse the tumor-suppressive, genome-stabilizing functions of nuclear HMGB1, with conserved and divergent strategies apparent across viral families; why the absence of HMGB1 data for Merkel cell polyomavirus is a tractable and informative gap; and which HMGB1- and RAGE-directed agents are realistically positioned for evaluation in virus-associated cancers.

Damage-associated molecular pattern

miRNA-mediated control of TLR-NLR interplay in the uterus: A hidden corner of recurrent pregnancy loss.

Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are crucial pattern recognition receptors that initiate inflammatory responses and immunological activation upon detecting pathogen- or damage-associated molecular patterns (PAMPs/DAMPS) in the female reproductive tract, thereby maintaining homeostasis and supporting pregnancy success. Their signaling pathways play a significant role in reproductive disorders by mediating the immune response to various pathogenic stimuli. Recurrent pregnancy loss (RPL), defined as the natural ending of two or more pregnancies before 24 weeks of gestation, approximately half of these patients remain idiopathic without precise prognostic, diagnostic, and therapeutic plans. Emerging data point that microRNAs are essential for immunological control in the female reproductive tract. MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression by binding to mRNA and preventing translation into protein. miRNAs play a role in many biological processes, including the development and differentiation of trophoblasts, the activation and implantation of embryos, immune tolerance, and the receptivity of the endometrium during implantation. Given their capacity to regulate up to 30 % of the human genome, miRNAs offer a promising avenue for understanding the immunopathogenesis of pregnancy complications. Recent research has detected differential expression of specific miRNAs in reproductive system pathologies. This review focuses on microRNAs and their association with idiopathic recurrent miscarriage, a condition characterized by considerable heterogeneity. Future studies identifying the precise mechanisms linking miRNA-mediated immune dysregulation in RPL immunopathogenesis could open the way for novel personalized therapeutic and diagnostic strategies.

Female

Participation of the purinergic P2X7 receptor in molecular complexes in the nucleus of human chondrocytes.

In addition to the purinergic receptor P2X7R's known activity as a sensor of damage-associated molecular patterns (DAMPs), evidences support its role in maintaining tissue homeostasis. Its presence in cellular compartments other than its usual transmembrane localization suggests its involvement in specific signaling pathways. This study aimed to analyze P2X7R in the nucleus of human chondrocytes and search for potential interacting partners. Through co-immunoprecipitation and proximity ligation assay we discovered that, independent of extracellular ATP levels, P2X7R is abundantly present in both the nuclear membrane and in the nucleoplasm, where it is found in close proximity to lamin A/C (a component of the nuclear lamina), emerin (a protein involved in the assembly and disassembly of the nuclear envelope), and SUN2 (an inner nuclear membrane protein that facilitates the transmission of mechanical forces). Furthermore, chromatin immunoprecipitation revealed the participation of P2X7R in molecular complexes located in the promoter of specific genes including Sox9, TRPS1, FOXO3a, integrin β2 and connective tissue growth factor. Overall, this evidence reveals for the first time novel partners of P2X7R that place it in an intricate network that influences nuclear structure, mechanosensitivity, chromatin organization, and gene expression. Specifically, on the one hand, a close association between P2X7R and nuclear proteins participating in the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex (lamin A/C, emerin, and SUN2) places it among the factors involved in mechanosignaling and the maintenance of nuclear integrity; on the other, its recruitment to specific gene promoters suggests that it may act as a transcription regulator.

Humans

Exploring the proteomic landscape of THP-1 monocytes through two-challenge LPS induction.

Proteome remodelling is central to the regulation of innate immune activation, yet the temporal organisation of protein networks engaged during repeated lipopolysaccharide (LPS) stimulation remains incompletely defined. In the present study, label-free quantitative mass spectrometry-based proteomics was used to characterise protein abundance changes in THP-1 monocytes at early (30 min) and later (2 h) time points following a second LPS challenge. This analysis was complemented by an independent co-immunoprecipitation proteomics experiment designed to identify candidate proteins associated with the regulatory pseudo-kinase IRAK3 during early TLR4 signalling. At 30 min, differentially abundant proteins were enriched in pathways associated with pattern-recognition receptor signalling, NF-κB activity, RNA processing, phosphorylation, and ribonucleoprotein complex organisation. By 2 h, the proteomic response broadened to include oxidative phosphorylation, antigen processing and presentation, vesicle-mediated transport, protein folding, and cytokine-regulatory pathways. These findings indicate that repeated LPS stimulation is accompanied by progressive remodelling of inflammatory, metabolic, translational, and proteostatic programmes rather than major changes in protein identity. Co-immunoprecipitation identified established TLR/IRAK3-associated components together with candidate IRAK3-associated proteins linked to RNA regulation, kinase signalling, ubiquitin-mediated processes, redox control, cytoskeletal remodelling, and damage-associated molecular pattern responses. Collectively, these findings define a temporal framework of proteomic adaptation during repeated inflammatory stimulation and expand the range of candidate proteins potentially contributing to IRAK3-centred regulation of innate immune signalling.

Humans

KEAP1 loss-of-function suppresses immunogenic ferroptosis and limits PD-1 blockade efficacy through an NRF2-FSP1 pathway.

Loss-of-function mutations in Kelch-like ECH-associated protein 1 (KEAP1) frequently occur in lung adenocarcinoma and are associated with poor prognosis and limited benefit from immunotherapy. However, the mechanisms linking KEAP1 deficiency to immune evasion remain elusive. We combined clinical data analysis, in vivo tumor models, and in vitro co-culture systems to investigate how KEAP1 deficiency shapes dendritic cell (DC) biology and response to PD-1 blockade. Ferroptosis induction assays, damage-associated molecular patterns (DAMPs) quantification, cytokine profiling, and mechanistic interrogation of the FSP1-CoQ10 axis were performed to delineate pathways.KEAP1 mutations correlated with poor response to PD-1 blockade and reduced DC infiltration. In mice, KEAP1-deficient tumors exhibited accelerated growth and reduced DC and CD8+ T-cell infiltration, consistent with an immune-cold phenotype. Mechanistically, KEAP1 loss impaired DC function in vitro, as evidenced by reduced maturation, phagocytosis, and naïve CD8+ T-cell priming capacity. This defect was linked to two mechanisms. First, KEAP1-deficient tumor cells resisted ferroptosis and failed to release immunogenic DAMPs, including extracellular ATP, HMGB1, and calreticulin. Second, KEAP1 deficiency reprogrammed the cytokine secretion profile, with downregulation of CCL2, IL-6, CXCL1, and CXCL2, thereby diminishing DC recruitment and inflammatory signaling. Notably, inhibition of the FSP1-CoQ10 antioxidant axis restored ferroptosis-associated immunogenic cell death. Our study identifies KEAP1 deficiency as a driver of immune-cold tumor microenvironments and resistance to PD-1 blockade, acting through impaired ferroptosis-induced immunogenic cell death and disrupted DC function. Genetic FSP1 deletion restored ferroptosis-associated immunogenicity and DC activation in KEAP1-deficient cells, supporting FSP1 as a potential therapeutic target for further in vivo evaluation.

DAMPs

Genome-wide characterization of NOD-like receptor genes links NLR repertoire evolution to spleen immune responses after Aeromonas hydrophila challenge in the Chinese spiny frog (Quasipaa spinosa).

NOD-like receptors (NLRs) are cytosolic pattern-recognition receptors that detect pathogen-associated and damage-associated molecular patterns and mediate innate immune signaling in vertebrates. However, the genomic repertoire, evolutionary diversification, and infection-associated expression of NLR genes remain poorly defined in non-model amphibians. In this study, 66 NLR genes were identified from the Chinese spiny frog (Quasipaa spinosa) genome and designated as QsNLR1-QsNLR66. These genes were unevenly distributed across chromosomes and were classified into three phylogenetic groups, with most members exhibiting conserved motif architectures. Gene duplication analysis indicated that dispersed duplication was the main contributor to QsNLR expansion. Synteny analysis detected five conserved orthologous gene pairs between Q. spinosa and Pelophylax nigromaculatus, suggesting partial conservation of NLR genomic organization between the two amphibians. Ka/Ks analysis showed that several duplicated gene pairs, including NLRC3-like/QsNLR36 and NLRC3-like/QsNLR50, exhibited Ka/Ks ratios greater than one, suggesting potential sequence divergence after duplication. Spleen RNA sequencing (RNA-seq) after Aeromonas hydrophila challenge revealed enrichment of immune-related Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Weighted gene co-expression network analysis linked several QsNLRs to infection-associated modules, among which QsNLR57 was co-expressed with CYBB, ADAM17, SPI1, and HK2. RT-qPCR using time-matched phosphate-buffered saline (PBS) controls showed distinct temporal patterns, with stronger induction of QsNLR29, QsNLR57, and QsNLR66 and weaker or delayed responses of QsNLR50 and QsNLR56. These results characterize the NLR repertoire of Q. spinosa and identify infection-associated QsNLR candidates for future studies of antibacterial immunity in amphibians.

Animals

Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.

UNLABELLED: Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in patients with recurrent high-grade glioma treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAM), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the TME. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2-M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62, and autophagosome accumulation and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and damage-associated molecular patterns (DAMP), such as IL1β, HMGB1, and extracellular ATP. Coculturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and proinflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the antitumor therapeutic efficacy of OD-0J1. SIGNIFICANCE: Leveraging JAG1 antagonism in the context of oncolytic virotherapy rewires macrophage polarization within the tumor microenvironment, which has wide implications for sensitizing tumors to antibodies, senolytic agents, and BiTE therapies.

Humans

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Humans

Hypertensive disorders of pregnancy and the risk for hypertension and cardiovascular and kidney disease. International Society of Hypertension position paper, endorsed by the World Hypertension League and European Society of Hypertension.

Hypertensive disorders of pregnancy (HDP) remain a leading cause of maternal and perinatal morbidity and mortality worldwide, especially in low- and middle-income countries. Moreover, HDP are directly linked to an increased risk of long-term cardiometabolic and kidney disease in mothers and offspring. Since prevention, diagnosis, and treatment of HDP remain suboptimal globally, enhanced understanding and implementation of current guidelines on HDP present a substantial opportunity to significantly reduce maternal and fetal morbidity and mortality. This position paper by the International Society of Hypertension reviews current knowledge in the field, identifies knowledge gaps and provides recommendations on the care of women with HDP and lifelong care, thereafter.

AT1R-Aas