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PubMed2026

Metabolic ketosis attenuates NLRP3 inflammasome activation and is associated with improvements in hepatic steatosis and liver stiffness in MASLD: a pilot randomized controlled trial.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic metabolic-inflammatory disorder in which metabolic stress and innate immune activation, particularly through the NLRP3 inflammasome, contribute to disease progression. Metabolic ketosis, characterized by increased levels of circulating ketone bodies, especially β-hydroxybutyrate, has emerged as a promising strategy to modulate substrate utilization, inflammatory signaling, and hepatic injury. However, clinical evidence integrating molecular, metabolic, and hepatic outcomes remains limited. METHODS: In this pilot randomized controlled trial, 20 participants with newly diagnosed MASLD were randomly assigned to either a 3-month intervention with a daily C8-enriched medium-chain fatty acid formulation (m-CAP; meta-Capridin, providing approximately 20 g/day of C8) or a standardized low-carbohydrate dietary protocol. Metabolic indices, inflammatory mediators, adipokines, and hepatic enzymes were assessed. The expression of key inflammasome components (NLRP3, caspase-1, and ASC) was evaluated in peripheral blood mononuclear cells, and hepatic steatosis and liver stiffness were measured via transient elastography. RESULTS: The C8-enriched intervention was associated with increased circulating β-hydroxybutyrate levels, indicating the achievement of nutritional ketosis. Changes over time were observed in metabolic parameters, including fasting serum glucose (p < 0.05), HOMA-IR (p < 0.05), body fat percentage (p < 0.05), and BMI (p < 0.05). Alterations in inflammatory mediators and adipokine-related outcomes were also observed following the intervention. At the molecular level, changes in inflammasome-related markers were detected, including caspase-1 mRNA expression (p < 0.05) and NLRP3 expression at the transcriptional (p < 0.05) and protein levels (p < 0.01), whereas ASC expression remained unchanged. Changes in hepatic steatosis (p < 0.01) and liver stiffness measurements were observed following the intervention. Given the absence of significant Group × Time interactions for several secondary outcomes, these findings should be interpreted as exploratory and hypothesis-generating. CONCLUSIONS: Induction of metabolic ketosis was associated with changes in metabolic, inflammatory, and hepatic parameters in patients with MASLD. The observed associations between ketosis, inflammasome-related markers, and noninvasive liver outcomes warrant further investigation of ketosis-based interventions as adjunctive approaches in MASLD. Larger and longer-term clinical trials are needed to confirm these findings and to determine whether short-term changes in liver stiffness reflect sustained alterations in hepatic status rather than structural fibrosis regression. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT); Unique identifier: IRCT20170315033086N12; Registration date: 19 September 2024; Registry URL: https://www.irct.ir. IRCT is a primary registry in the WHO Registry Network (https://www.who.int/tools/clinical-trials-registry-platform/network/primary-registries).

Humans↗

PubMed2026

Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV.

People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1β, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4+ T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.

HIV↗

PubMed2026

Artificial Intelligence-Driven Multi-Omics Analysis Reveals Hydroxytyrosol Targeting of the TXNIP-NLRP3 Inflammasome Axis in Traumatic Brain Injury.

Traumatic brain injury (TBI) induces secondary neuroinflammation driven by oxidative stress, inflammasome activation, and immune remodeling, yet specific mechanism-guided pharmacological interventions remain limited. This study established an artificial intelligence (AI)-integrated network pharmacology and multi-omics framework to evaluate whether hydroxytyrosol (HT), an olive-derived natural polyphenol, may regulate TBI-related neuroinflammatory targets centered on the TXNIP/NLRP3 inflammasome axis. Starting from the SMILES structure of HT, potential targets were predicted using PharmMapper, SwissTargetPrediction, and the Similarity Ensemble Approach and were standardized to UniProt identifiers. TBI-associated genes were integrated from GeneCards, DisGeNET, OMIM, and the Therapeutic Target Database. The overlapping target set was analyzed using STRING-based protein-protein interaction (PPI) networks, MCODE, CytoHubba, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Public GEO transcriptomic datasets (GSE123831 and GSE104687) were used for cross-platform expression validation, differential expression analysis, and exploratory CIBERSORT-based immune infiltration estimation. Random forest (RF), multilayer perceptron (MLP), graph convolutional network (GCN), graph attention network (GAT), SHAP/LIME explainability analysis, LASSO inflammatory-risk scoring, and two-sample Mendelian randomization (MR) were further applied for target prioritization, immune phenotype mapping, and genetic association analysis. Seventy-three overlapping HT-TBI targets were identified. PPI and topology analyses prioritized TXNIP, NLRP3, CASP1, MAPK1, and TP53 as key hubs enriched in inflammasome activation, oxidative stress, apoptosis, and NOD-like receptor signaling. TXNIP, NLRP3, and CASP1 were consistently upregulated in both TBI transcriptomic datasets. LM22-based immune deconvolution suggested increased pro-inflammatory immune signatures and a positive TXNIP-M1 macrophage association (r = 0.63, p < 0.001), which should be interpreted as a transcriptome-derived hypothesis rather than validated murine immune-cell proportions. AI-based models consistently ranked TXNIP/NLRP3 as high-contribution features under internal validation, and removal of these targets reduced model performance. A five-gene inflammatory score achieved an internally evaluated AUC of 0.87, while two-sample MR supported positive genetic associations involving TXNIP expression, TBI risk, NLRP3 and IL-1β expression. Collectively, these findings prioritize the TXNIP/NLRP3/CASP1 module as a computationally supported candidate mechanism through which HT may influence oxidative stress-inflammasome-immune coupling in TBI. This study provides an interpretable drug-target-pathway-phenotype framework and identifies TXNIP, NLRP3, and CASP1 as priority nodes for future experimental validation.

Artificial Intelligence↗

PubMed2025

Trichomonas vaginalis extracellular vesicles activate the NLRP3 inflammasome and TLR3-mediated inflammatory cascades in host cells.

Trichomonas vaginalis (TV) is a flagellated parasite that causes trichomoniasis, the most common non-viral sexually transmitted infection (STI), with over 275 million cases annually. TV has been shown to secrete extracellular vesicles (TV-EVs) to regulate intercellular communication between parasites and host immune response; however, the mechanisms by innate immunity against TV-EVs are largely unknown. Herein, we aim to investigate the molecular mechanisms of inflammation induced by TV-EVs and identify novel proteins modulating the immune response in host cells. Firstly, the morphological characteristics of TV-EVs have been analyzed by transmission electron microscope (TEM) and nanoparticle tracking analysis, revealing that the vesicles are round-shaped bilayer membrane structures with size mostly about 100-120 nm. Additionally, the internalization of TV-EVs by host cells has been validated through immunofluorescence and TEM analysis. The multiplex immunoassay identified that TV-EVs induce the secretion of inflammatory cytokines, including CXCL1, IL-6, IL-8 and MIP-1β in THP-1 macrophages and ectocervical cells (Ect). Mechanistically, TV-EVs induce TLR3 overexpression to activate the NF-κB/NLRP3 pathway in THP-1 macrophages. Additionally, TV-EVs activate the PI3K-mediated NF-κB, p38 MAPK and ERK pathways in Ect. Moreover, TV-EV-induced TLR3 overexpression positively regulates the PI3K and NF-κB pathways, while simultaneously suppressing the p38 MAPK and ERK pathways in Ect. Proteomic analysis identified that TV-EVs upregulate MICB and TRAF3IP2, which are also positively regulated by TLR3 and involved in TV-EV-induced inflammatory cascade. Altogether, this study significantly advances our understanding of the immunomodulatory roles of TV-EVs in host cells, paving the way for future treatment of trichomoniasis and TV-associated STIs.

Humans↗

PubMed2025

Cross-talk between NLRP3 and AIM2 inflammasomes in macrophage activation by LPS and titanium ions.

BACKGROUND: Periodontitis and peri-implantitis are chronic inflammatory diseases that contribute to tissue destruction and bone loss. Periodontitis is triggered by pathogenic bacteria, while peri-implantitis also involves metallic particles, which increase the inflammatory response. Both conditions are linked to the activation of inflammasomes, such as NLRP3 and AIM2, which facilitate the release of pro-inflammatory cytokines like IL-1β and IL-18 and induce pyroptosis. This study aims to investigate the activation of NLRP3 and AIM2 inflammasomes in macrophages exposed to bacterial and metallic components, as well as to explore the potential interplay between these two signaling pathways. METHODS: Human THP-1-derived macrophages were treated with bacterial lipopolysaccharide (LPS) and titanium ions to evaluate inflammasome activation. IL-1β secretion, ROS production, mitochondrial DNA release and pyroptosis were assessed. Additionally, macrophages deficient in NLRP3 and AIM2 were used to examine the roles of these inflammasomes in inflammatory responses. RESULTS: LPS and titanium ions synergistically activated NLRP3, resulting in increased IL-1β secretion, ROS production, and pyroptosis. Under these conditions, AIM2 was indirectly activated, as indicated by elevated mitochondrial DNA release. Notably, AIM2 expression was reduced in wild-type macrophages treated with LPS and titanium ions compared to LPS alone, however, in NLRP3-deficient cells, AIM2 expression was increased following LPS and titanium ions treatment. This upregulation of AIM2 in NLRP3-deficient cells was further reduced by ROS inhibition, which decreased mitochondrial DNA release. Additionally, NLRP3 knockout had a more pronounced effect on reducing IL-1β secretion and pyroptosis compared to AIM2 knockout, indicating a greater role of NLRP3 in these inflammatory responses. CONCLUSIONS: This study demonstrates that bacterial and metallic components drive the activation of both NLRP3 and AIM2 inflammasomes in macrophages, highlighting their roles in the inflammatory responses associated with periodontitis and peri-implantitis. The findings reveal a regulatory relationship between NLRP3 and AIM2, where the absence of one inflammasome can enhance the activity of the other. These results provide new insights into the mechanisms underlying inflammasome-mediated inflammation and suggest potential therapeutic targets for managing inflammatory diseases.

NLR Family, Pyrin Domain-Containing 3 Protein↗

PubMed2026

miR-197 Targets NLRP3 3' UTR and Correlates with NLRP3/Caspase-1/IL-18 Signaling in Hyperoxia-Stimulated Neonatal BPD Mouse Model.

Reduced circulating miR-197 was previously observed in preterm infants who later developed bronchopulmonary dysplasia (BPD), but its relationship with NLRP3 inflammasome signaling remains unclear. This study examined miR-197 expression, NLRP3 inflammasome-related markers, and the interaction between miR-197 and the NLRP3 3' UTR in a neonatal hyperoxia model. Neonatal C57BL/6J mice were exposed to 60% oxygen or room air from birth, and lung tissues were collected on postnatal days 1, 7, 14, and 21. Lung injury and alveolar development were assessed by histology, radial alveolar count, mean linear intercept, and lung wet-to-dry ratio. miR-197 and NLRP3 expression and NF-κB-, caspase-1-, and IL-18-related proteins were evaluated by RT-qPCR and Western blotting. A dual-luciferase reporter assay in MLE12 cells tested the interaction between miR-197 and the NLRP3 3' UTR. Hyperoxia increased lung wet-to-dry ratios and mean linear intercept, reduced radial alveolar count, and caused progressive alveolar simplification. miR-197 expression decreased, whereas NLRP3 mRNA increased, at all examined time points; NLRP3 protein and inflammasome-related protein changes were most evident from postnatal day 7 onward. The miR-197 mimic reduced luciferase activity in the wild-type but not mutant NLRP3 3' UTR reporter. These findings show that neonatal hyperoxia is associated with reduced miR-197 and increased NLRP3/inflammasome-related signaling and support a sequence-specific interaction between miR-197 and the NLRP3 3' UTR, although causal regulation in vivo requires further investigation.

Animals↗

PubMed2026

Celery seed extract attenuates sarcopenic obesity and age-related sarcopenia by reducing intramuscular lipid accumulation in mice.

BACKGROUND & AIMS: Sarcopenia is characterized by progressive loss of skeletal muscle mass and function and is increasingly recognized to be influenced by metabolic disturbances associated with aging and obesity. Intramuscular lipid accumulation has emerged as a key pathological feature linking metabolic dysfunction to skeletal muscle deterioration. Celery seed extract (CSE) possesses anti-obesity, anti-inflammatory, and antioxidant properties; however, its potential role in skeletal muscle metabolism has not been well investigated. This study aimed to determine whether CSE attenuates skeletal muscle deterioration associated with obesity and aging through modulation of intramuscular lipid accumulation and related metabolic pathways. METHODS: Diet-induced obese mice and naturally aged mice were used to evaluate the effects of CSE supplementation. Skeletal muscle mass, grip strength, muscle morphology, intramuscular lipid content, mitochondrial metabolic signaling, inflammatory responses, and muscle protein turnover pathways were assessed using biochemical, molecular, and histological analyses. RESULTS: CSE supplementation significantly improved skeletal muscle mass, grip strength, and muscle fiber cross-sectional area in both obese and aged mice. These improvements were accompanied by reduced intramuscular triglyceride and cholesterol accumulation. Mechanistically, CSE improved mitochondrial metabolic signaling by activating the AMPK-PGC-1α pathway and increasing mitochondrial oxidative phosphorylation proteins. In addition, CSE suppressed inflammatory signaling pathways, including MAPK activation and NLRP3 inflammasome signaling, and improved muscle proteostasis by enhancing myogenic regulators while reducing the expression of proteolytic factors such as MuRF1, Atrogin-1, and myostatin. Correlation analyses further indicated that intramuscular lipid accumulation was closely associated with mitochondrial dysfunction, inflammatory activation, and muscle atrophy. CONCLUSIONS: These findings demonstrate that CSE alleviates skeletal muscle deterioration in both obesity- and aging-associated sarcopenia by reducing intramuscular lipid accumulation and improving mitochondrial metabolism, inflammatory responses, and muscle protein turnover. Targeting intramuscular lipid accumulation may therefore represent a promising nutritional strategy for preventing sarcopenia associated with metabolic and aging-related stress.

AMPK–PGC-1α↗

PubMed2025

Restraint of inflammasome-driven cytokine responses through the mRNA stability protein TTP.

Activation of the NLRP3 inflammasome causes extensive disturbance of cellular homeostasis, with Golgi disruption, mitochondrial dysfunction, and changes in intracellular ion concentration occurring rapidly upon stimulation. Given this, it would seem near certain that these changes might also globally affect cellular signaling pathways, yet few, if any, studies have explored this possibility. Here, we combine genomics and phosphoproteomics to identify inhibition of the ERK1/2 MAP kinase signaling cascade upon inflammasome stimulation. This loss of ERK1/2 activity results in rapid inactivation of the mRNA decay-promoting protein tristetraprolin (TTP), with loss of TTP promoting subsequent increased release of cytokines upon pyroptosis. Further, we observe significantly increased levels of TTP expression in patients with inflammatory bowel disease, a disease for which altered cytokine expression is a key driver of pathogenesis. Inflammasome activation thus rapidly inactivates a pathway designed to suppress cytokine release, potentially exacerbating hyperinflammatory states, including those involved in autoinflammatory disease.

Inflammasomes↗

PubMed2026

ATF4-histone 2-hydroxyisobutyrylation feedback loop drives sepsis-induced inflammation.

BACKGROUND AND PURPOSE: The role and mechanisms of lysine 2-hydroxyisobutyrylation (Khib) in the acute inflammatory phase of sepsis remain unclear. We investigated the function and underlying mechanisms of histone H4 lysine 5 2-hydroxyisobutyrylation (H4K5-hib) in sepsis-induced inflammation in vivo and in vitro. EXPERIMENTAL APPROACH: Acute sepsis was induced by caecal ligation and puncture (CLP) in mice, and inflammatory responses were modelled in lipopolysaccharide (LPS)-stimulated macrophages. CUT&Tag-seq was used to identify genomic targets associated with H4K5-hib and activating transcription factor 4 (ATF4). Immunofluorescence, Western blotting, qPCR, dual-luciferase assays, and ELISA were performed to investigate the underlying mechanisms. KEY RESULTS: H4K5-hib levels were increased in macrophages during the acute inflammatory phase of sepsis. LPS stimulation enhanced H4K5-hib enrichment at the ATF4 promoter, thereby promoting ATF4 transcription. Inhibition of EP300-mediated 2-hydroxyisobutyrylation or mutation of H4K5 abolished ATF4 activation. Increased H4K5-hib activated the ATF4/NLRP3 signalling axis, promoting inflammasome assembly and amplifying inflammatory responses. ATF4 directly bound to the EP300 promoter and enhanced its transcription, forming a positive feedback loop that further increased H4K5-hib levels. In CLP-induced sepsis, pharmacological inhibition of EP300 or ATF4 reduced H4K5-hib levels and suppressed NLRP3 inflammasome activation. CONCLUSION AND IMPLICATIONS: These findings reveal a previously unrecognized epigenetic mechanism underlying sepsis-induced inflammation and identify the EP300/ATF4/H4K5-hib positive feedback loop as a potential therapeutic target for sepsis.

Animals↗

PubMed2026

Inflammasome activation dictates the efficacy of antimycobacterial activity of frontline TB drugs.

Recent developments in tuberculosis (TB) treatment have identified an enormous potential of host-directed therapies (HDT)) in achieving better and faster control of infection. We have previously demonstrated the synergistic effect of sertraline (SRT) with frontline TB drugs in clearing infection in murine tissues. Our attempts to uncover the mechanistic basis of this enhancement, using sertraline as a probe, help identify host signalling pathways critical for controlling Mycobacterium tuberculosis (Mtb). We identify a significant role for sertraline-mediated modulation of mitochondrial physiology and consequent reactive oxygen species (ROS) generation as a secondary signal, leading to greater IL-1β release and K+ efflux from macrophages via NLRP3 inflammasome activation. We thus highlight an important relationship between mitochondrial physiology and inflammasome activation, enabling infected macrophages to better control Mtb.

Animals↗

PubMed2026

P2X7 Receptor in Rare Diseases: Shared Molecular Mechanisms and Therapeutic Implications.

Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca2+overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca2+-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.

P2X7 receptor↗

PubMed2026

Proteomics-Based Identification of the Pyroptosis-Related Biomarker PCSK9 and Its Association With the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease, and early diagnosis is critical for effective treatment. This study aims to identify potential biomarkers related to pyroptosis through serum proteomics analysis, offering new insights for the early diagnosis of RA. We enrolled 100 participants, including 50 patients with RA and 50 healthy controls. Serum samples were collected and analyzed using high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomics profiling. Differential protein expression analysis and functional annotation revealed significant upregulation of pyroptosis-related proteins in the serum of patients with RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, along with protein-protein interaction (PPI) network analysis, showed that these proteins are involved in inflammation and immune pathways, particularly the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Enzyme-linked immunosorbent assay (ELISA) validation confirmed a significant increase in PCSK9 levels in patients with RA, suggesting that PCSK9 may play a key role in the pathogenesis of RA. This study provides new directions for biomarker research in RA, particularly regarding the potential involvement of the pyroptosis pathway, with significant clinical application prospects.

Humans↗

PubMed2025

Ischemic Injury Drives Nascent Tumor Growth Via Accelerated Hematopoietic Aging.

BACKGROUND: Patients with peripheral artery disease have an increased risk of cancer development. Aging-associated changes in hematopoietic stem and progenitor cells (HSPCs), including inflammation and increased myelopoiesis, are implicated in both cardiovascular disease and cancer, but their contributions to cardiovascular disease-driven tumor progression are unclear. OBJECTIVES: This study sought to study tumor growth after peripheral ischemia and consequent changes within the HSPC bone marrow compartment to uncover mechanisms through which altered hematopoiesis promotes cancer. METHODS: Mammary cancer (E0771) growth was monitored in C57BL/6J mice after hind limb ischemia (HLI) or sham surgery. The tumor immune microenvironment, circulatory immune cells, and HSPC compartment were assessed by flow cytometry. Next-generation single-cell RNA and assay for transposase-accessible chromatin sequencing of bone marrow progenitors was performed to assess the distinct and synergistic transcriptomic and epigenetic changes of cancer and peripheral ischemia. The functional impact on tumor progression and persistence of ischemia-induced epigenetic reprogramming of HSPCs and their myeloid progeny was examined by bone marrow transplantation. RESULTS: Peripheral ischemia increased monocyte and neutrophil output at the expense of lymphocytes, driven by a shift toward CD150hi myeloid-biased hematopoietic stem cells. This was associated with accelerated cancer growth and enrichment of tumors with myeloid cells (monocytes, macrophages, neutrophils) and regulatory T cells. Increased myelopoiesis was also supported by sequencing analyses showing HLI and tumor-induced transcriptional and epigenetic enrichment for inflammatory (NLRP3 inflammasome) and aging-associated neogenin-1, thrombospondin-1) signatures in subsets of monocyte/dendritic progenitors. HLI-accelerated tumor growth and myeloid-skewing was transmissible via bone marrow transplantation, indicating long-term reprogramming of innate immune responses. CONCLUSIONS: Peripheral ischemia enhances inflammaging of hematopoietic stem cells and long-lasting alterations to antitumoral immunity, accelerating breast tumor growth.

bone marrow transplantation↗

PubMed2026

Mycobacterium tuberculosis MEM39 (Rv1977) hijacks host aldolase A (ALDOA) to subvert immunometabolism to facilitate bacterial intracellular survival.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the leading cause of infectious disease-related death. As a major intracellular pathogen, Mtb can escape clearance by the immune system, but the underlying molecular mechanisms remain incompletely elucidated. Specific genomic regions of deletion (RD)-encoded proteins in virulent Mtb H37Rv have been implicated in modulating pathogenicity and immunity. Here, we report a novel RD15-encoding protein, Rv1977 (a mycobacterial cell wall protein with a size of 39 kDa, named MEM39), which facilitates Mtb survival in macrophages. The survival of the Mtb H37Rv MEM39-deficient strain is reduced in both macrophage and murine infection models. Furthermore, the mycobacterial MEM39 protein binds fructose-diphosphate aldolase A (ALDOA), a key enzyme of glycolysis, thereby impairing ALDOA enzyme activity, disrupting macrophage metabolite flux, and reducing lactate production. The MEM39-ALDOA interaction also suppresses lysosomal acidification; reduces NLRP3 inflammasome activation and the production of proinflammatory cytokines (TNF-α, IL-6 and IL-1β); and thereby promotes bacterial survival within macrophages. Disruption of the interaction between MEM39-ALDOA and a cell-penetrating synthetic peptide (VLARYASICQ) significantly suppressed Mtb survival by restoring lactate production, lysosome acidification and proinflammatory cytokine production in both macrophage and mouse infection models. These findings revealed that mycobacterial MEM39 negatively regulates host immune defense through reprogramming ALDOA-mediated glycolysis in macrophages, thereby forming a "mycobacterial MEM39 virulence factor-glycolysis metabolism-immunity" regulatory axis. Targeting MEM39 or the MEM39-ALDOA interaction interface holds promise as a new therapeutic strategy against tuberculosis.

Mycobacterium tuberculosis↗

PubMed2026

Assessing the Frequency of VEXAS-Related Canonical UBA1 Mutations in Myelodysplastic Syndrome Patients.

OBJECTIVES: Somatic mutations in the UBA1 gene cause VEXAS syndrome, which presents with inflammatory and hematological symptoms. Case studies show a strong overlap between VEXAS and myelodysplastic syndrome (MDS). Recognizing VEXAS is important for differential diagnosis in patients with both inflammation and MDS, as accurate identification guides treatment. The study focuses on determining how often canonical UBA1 mutations linked to VEXAS occur in MDS patients. METHODS: Patients diagnosed with MDS were enrolled in the study, and genomic DNA was isolated from bone marrow FFPE samples. Molecular analysis was performed using a specifically designed ARMS-PCR approach. Additionally, protein-protein interaction (PPI) studies combined with bioinformatic analyses were carried out to explore potential links between UBA1 and pyroptosis. RESULTS: Among the 149 MDS patients analyzed, none exhibited high-Variant Allele Frequency (VAF) the canonical UBA1 point mutations linked to VEXAS syndrome. PPI analysis revealed a possible association between UBA1 and the NLRP3 inflammasome component. CONCLUSIONS: Expanding the sample size and using targeted NGS or ddPCR would improve mutation detection sensitivity and could reveal UBA1 canonical and non-canonical variants and more accurately estimate the frequency of VEXAS-related mutations in the MDS population.

Humans↗

PubMed2025

NLRP3 and AIM2 inflammasomes exacerbate the pathogenic Th17 cell response to eggs of the helminth Schistosoma mansoni.

Infection with the helminth Schistosoma mansoni can cause exacerbated morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens, with T helper (Th) 17 cells playing a major role in the development of severe granulomatous hepatic immunopathology. The role of inflammasomes in intensifying disease has been reported; however, neither the types of caspases and inflammasomes involved, nor their impact on the Th17 response are known. Here we show that enhanced egg-induced IL-1β secretion and pyroptotic cell death required both caspase-1 and caspase-8 as well as NLRP3 and AIM2 inflammasome activation. Schistosome genomic DNA activated AIM2, whereas reactive oxygen species, potassium efflux and cathepsin B, were the major activators of NLRP3. NLRP3 and AIM2 deficiency led to a significant reduction in pathogenic Th17 responses, suggesting their crucial and non-redundant role in promoting inflammation. Additionally, we show that NLRP3- and AIM2-induced IL-1β suppressed IL-4 and protective Type I IFN (IFN-I) production, which further enhanced inflammation. IFN-I signaling also curbed inflammasome- mediated IL-1β production suggesting that these two antagonistic pathways shape the severity of disease. Lastly, Gasdermin D (Gsdmd) deficiency resulted in a marked decrease in egg-induced granulomatous inflammation. Our findings establish NLRP3/AIM2-Gsdmd axis as a central inducer of pathogenic Th17 responses which is counteracted by IFN-I pathway in schistosomiasis.

Animals↗

PubMed2025

When glycobiology meets inflammasome activation: Insights and implications.

BACKGROUND: Glycobiology focuses mainly on the study of glycan structures and their biological functions. Glycans not only provide a basic energy supply through the tricarboxylic acid cycle and glycolysis but also serve as important immune regulators during pathogen invasion and homeostasis maintenance. Inflammasomes are critical multiprotein complexes of the immune system that detect both exogenous pathogenic threats and endogenous danger signals to mediate inflammatory responses. Glycobiology has revealed significant insights into the mechanisms of immune responses, particularly in the context of inflammasome activation. AIM OF REVIEW: This review summarizes the multifaceted relationships between glycobiology and inflammasome activation, highlighting how glycan structures, glycosylation patterns, and glycan-binding proteins influence inflammasome pathways. This review sheds light on novel targets for drug development aimed at modulating inflammatory pathways through the targeting of specific glycan structures. KEY SCIENTIFIC CONCEPTS OF REVIEW: Glycans directly or indirectly provide prime and activation signals for inflammasomes, glycosylation of inflammasome-related proteins by glycan structures modulates inflammasome activation and downstream inflammation, and the interaction between glycans and lectins also provides regulatory signals for inflammasome activation. This intersection of glycobiology and inflammasome activation presents a unique opportunity to elucidate the molecular mechanisms underlying inflammatory responses and their potential therapeutic implications.

Inflammasomes↗

PubMed2026

The Differential Effects of Immunosuppressants on Hepatitis E Virus Replication and the Triggered Inflammatory Responses in Macrophages.

Organ transplant recipients are at high risk of developing chronic infection when exposed to hepatitis E virus (HEV), which can rapidly progress to liver fibrosis and cirrhosis. Macrophages play a key role in the response to the infection and disease progression. However, the interactions amongst immunosuppressants, macrophages, the course of HEV infection and activation of inflammatory response remain unclear. In this study, we generated M0, M1 and M2 macrophages from the human THP-1 cell line. These macrophages were then infected with HEV and treated with different immunosuppressants. We visualised viral infection using laser confocal microscopy, and quantitatively analysed viral replication and inflammatory responses by bulk sequencing, RT-qPCR, ELISA and Western blotting. We found that the M1 inflammatory macrophages exhibited the highest, while M2 macrophages had the lowest levels of viral RNA. Genome-wide transcriptome analysis indicated that viral, inflammation and immunity-related pathways were predominantly upregulated by HEV infection. Dexamethasone exerted potent inhibitory effects on inflammatory response in macrophages. Mycophenolic acid (MPA) demonstrated inhibitory effects on viral replication, IL-1β and TNF-α expression, whereas mTOR inhibitors had the opposite effects, and tacrolimus showed no clear effect. In conclusion, immunosuppressants can differentially affect HEV replication and the subsequent inflammatory responses in macrophages.

Humans↗