Innate Immunity最新文献

{"title":"Retraction: The protective effect of icariin and phosphorylated icariin against LPS-induced intestinal goblet cell dysfunction.","authors":"","doi":"10.1177/17534259261427520","DOIUrl":"10.1177/17534259261427520","url":null,"abstract":"","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261427520"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12932873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The signaling adaptor insulin receptor substrate 2 (IRS2) limits lethal host responses induced by influenza infection.","authors":"Daniel Prantner, Xiulan Qi, Luz M Villaneuva, Jules Paton, Jorge C G Blanco, Stefanie N Vogel, Achsah D Keegan, Kari Ann Shirey","doi":"10.1177/17534259261469305","DOIUrl":"10.1177/17534259261469305","url":null,"abstract":"<p><p>Influenza is a highly contagious virus with most individuals showing recovery within a week after symptom onset. However, children, the elderly, and those with chronic health conditions are at high risk of developing serious complications. Extensive immune cell infiltration of the lung and massive production of pro-inflammatory cytokines can result in lung tissue damage and disruption, resulting in hypoxia and death. During the 2024-2025 influenza season in the USA, influenza caused an estimated 27,000-130,000 deaths. Our previous studies have shown that agents known to drive polarization of macrophages into the M2a phenotype mitigated inflammatory responses to influenza H1N1 A/PR/8/34 (PR8). Since IRS2 dampens the IL-4-induced differentiation to the M2a subtype, we sought to determine the impact of IRS2 on PR8 infection. Contrary to expectations, IRS2^-/- mice exhibited enhanced susceptibility to PR8 when compared to IRS2^+/+ mice, which was associated with a significant drop in blood oxygen saturation. Additionally, PR8 infection induced significantly greater inflammation in the lungs of IRS2^-/- mice than IRS2^+/+ mice. Conversely, viral replication was not significantly different. Significantly increased levels of the inflammatory mediator HMGB1 and airway epithelial cell denuding were observed in the lungs of IRS2^-/- mice, with a concomitant decrease in M2a gene expression. Mice with myeloid-specific knockout of IRS2 showed no enhanced sensitivity to PR8, supporting the hypothesis that the major impact of IRS2-deficiency on host response to PR8 infection is not myeloid cell-intrinsic. Overall, these results suggest that in the absence of IRS2, airway epithelial cells are especially sensitive to influenza-induced damage through dysregulated inflammation, resulting in increased susceptibility during infection.</p>","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261469305"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13376553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trained immunity agonists given to neonatal mice fail to protect against leptospiral infection in adulthood and may cause adverse effects.","authors":"Mégane Fernandez, Frédérique Vernel-Pauillac, Tiffany Pezier, Sonia Lacroix-Lamandé, Catherine Werts","doi":"10.1177/17534259261455983","DOIUrl":"10.1177/17534259261455983","url":null,"abstract":"<p><p>Background and ObjectivesTrained immunity (TI) refers to a non-specific, long-lasting protective immune response that occurs following initial stimulation of the immune system and thought to be largely mediated by functional reprogramming of myeloid cells. TI has been demonstrated in BCG-vaccinated infants and can be induced in human cells and adult mice via agonists of pattern recognition receptors (PRR), such as β-glucan or MDP (a muropeptide that activates NOD2). However, its induction in neonates remains poorly understood. Previously, we demonstrated that the synthetic TLR2-NOD2 dual agonist CL429 enhances antimicrobial functions in adult mice and protects against subsequent infection with <i>Leptospira interrogans</i>, a zoonotic pathogen. We also demonstrated the immediate protective benefits of NOD2 stimulation in neonates against <i>Cryptosporidium,</i> a zoonotic pathogen that affects young animals in livestock herds. However, whether NOD2 agonists can induce TI in neonates and protect them at adulthood is unknown.Methods and ResultsHere, we investigated whether exposure of neonatal mice to PRR agonists (CL429, MDP or β-glucan), administered intraperitoneally at one week interval at 7/14 or 14/21 days of age, could enhance inflammatory cytokines production after ex vivo restimulation and confer long-term protection into adulthood. Surprisingly, none of the treatments enhanced <i>ex vivo</i> cytokine responses in adulthood after restimulation, nor did they confer protection against experimental leptospirosis. Instead, MDP-treated neonates exhibited 50% mortality following adult infection, revealing an unexpected detrimental effect.ConclusionThese findings demonstrate that these PRR agonists fail to induce protective TI against <i>Leptospira</i> when administered to neonatal mice, challenging assumptions derived from adult models. Furthermore, our study reveals the risks of administering immunostimulants during the early stages of life, and highlights unanticipated and potentially harmful, PRR- and age-specific mechanisms of immune system modulation.</p>","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261455983"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13223350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune cells play a mediating role in the relationship between the gut microbiota and dementia: A Mendelian randomization study.","authors":"Jianzhun Chen, Liuhui Zhu, Jie Liu, Jieyu Chen, Chunyu Liang, Chenxi Liu, Fang Wang, Yongyun Zhu, Xinglong Yang","doi":"10.1177/17534259261426829","DOIUrl":"10.1177/17534259261426829","url":null,"abstract":"<p><p>IntroductionThe gut microbiota modulates dementia pathogenesis through immune interactions. Using Mendelian randomization, we investigate immune mediated mechanisms linking microbial dysbiosis to four dementia subtypes (Alzheimer's disease, Frontotemporal dementia, Vascular dementia, Parkinson's disease dementia . Our study tests whether gut microbiome effects on dementia are transmitted via immunoregulatory pathways.MethodsGenome wide association studies data included gut microbiota, 731 immune traits, and dementia cohorts (Alzheimer's disease, Frontotemporal dementia, Vascular dementia, Parkinson's disease dementia). Two step Mendelian randomization with Inverse Variance Weighted analyses assessed mediation effects, controlled by F-statistics >10 and Steiger filtering. Sensitivity analyses addressed pleiotropy<b>.</b>ResultsA total of 37 gut microbiome species demonstrated potential causal effects relationships with four types of dementia, and 137 immune cell subsets exhibited potential causal effects associations with these four dementia subtypes. In the Two step Mendelian randomization analysis, CD45RA + CD28- CD8+ T cells, CD19 on IgD- CD38dim B cells, and BAFF-R on CD20- B cells were shown to exert mediating effects between <i>class/order/family.Deltaproteobacteria</i> and Alzheimer's disease. CD4+ CD8+ T cells were found to exert a mediating effect between <i>genus.Roseburia</i> and Parkinson's disease dementia . CD20- CD38- B cells, CD19 on CD20- B cells, and IgD on unswitched memory B cells were found to exert a mediating effect between <i>class/order/family.Coriobacteriales,genus.Lactococcus</i> and Vascular dementia.ConclusionThis Mendelian randomization study revealed that certain immune cells serve as mediators in the pathway by which the gut microbiome contributes to the onset of dementia.</p>","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261426829"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12932898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing lupus nephritis research through multi-omics and predictive modeling.","authors":"Lisha Mou, Ying Lu, Zijing Wu, Zuhui Pu","doi":"10.1177/17534259261426818","DOIUrl":"10.1177/17534259261426818","url":null,"abstract":"<p><p>IntroductionLupus nephritis (LN) is characterized by significant heterogeneity and a complex pathophysiology, which traditional methods struggle to fully resolve. Advanced multi-omics approaches are essential to disentangle its cellular and molecular drivers.MethodsWe employed an integrative strategy combining single-cell RNA sequencing (scRNA-seq) profiling of LN biopsies with large-scale bulk RNA-seq cohorts. We applied non-negative matrix factorization (NMF) to scRNA-seq data to define robust immune meta-programs and utilized CellChat to decode cell-cell communication networks. Leveraging these insights to overcome sample size limitations, we prioritized key pathways and developed 399 machine learning predictive models using bulk transcriptomics, validated on independent cohorts.ResultsScRNA-seq analysis revealed a distinct cellular landscape, including a rare population of plasmacytoid dendritic cells (pDCs) and an expanded population of CD56dimCD16⁺ natural killer (NK) cells expressing high levels of IFN-γ and perforin, suggesting a role in inflammatory pathology. Macrophage subpopulation CM2 emerged as a central pro-inflammatory hub, potentially driving fibrosis via autocrine signaling and epithelial activation. We observed reduced Treg-B cell interactions, suggesting a regulatory collapse. Our machine learning models, based on innate immunity, circadian rhythms, apoptosis, and NF-κB signaling, achieved high diagnostic accuracy (AUC = 0.929 for innate immunity). Hub genes, including <i>CYBB</i>, <i>CSF2RB</i>, and <i>IRF8</i>, were confirmed to be upregulated in LN and correlated with clinical severity in external validation datasets. Molecular docking simulations suggested a potential structural basis for CYBB-dexamethasone interaction, providing a hypothesis for future verification.DiscussionThis study identifies CM2 macrophages and dysregulated pDC-NK axes as key drivers of LN. By bridging cellular interactomes with clinical predictive modeling, we provide a robust roadmap for precision detection and identifying potential therapeutic targets in LN.</p>","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261426818"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Periodontitis promotes gingival accumulation of cells with MDSC phenotype.","authors":"Fernando García-Arévalo, Gabriela Leija-Montoya, Dulce Martha Fuchen-Ramos, Javier González-Ramírez, Mario Isiordia-Espinoza, Nicolas Serafin-Higuera","doi":"10.1177/17534259261422539","DOIUrl":"10.1177/17534259261422539","url":null,"abstract":"<p><p>BackgroundPeriodontitis is one of the most common inflammatory diseases in humans, mostly caused by bacterial infection and with diverse populations of immune cells involved. Myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells derived from hematopoietic precursor cells, have exhibited immunomodulatory functions by production of different molecules such as inducible NO synthase (iNOS) and it is thought to be involved in periodontitis. However, reports of characterization of cells with MDSC phenotypes in gingival tissues are very scarce. This study aimed to characterize gingival cells with MDSC phenotypes in healthy gingiva and periodontitis tissues.Methods and ResultsHuman healthy gingival tissues and those with periodontitis were included to analyze cells with MDSC phenotypes by flow cytometry. Additionally, a mouse model of experimental periodontitis was used to identify cells with MDSC phenotypes and production of iNOS. Results showed an increased accumulation of CD45⁺HLA-DR^neg/lowCD11b⁺CD33⁺ cells in human gingival tissues with periodontitis. Experimental periodontitis promotes accumulation of CD45⁺CD11b⁺Gr-1⁺ and CD45⁺CD11b⁺Ly6G⁺ cells in gingival tissues. Experimental periodontitis did not promote accumulation of these subpopulations in other tissues as spleen. Additionally, gingival CD45⁺Gr-1⁺ iNOS⁺ cells were identified.Conclusionscells with MDSC phenotypes are resident in healthy gingival tissues and their accumulation is locally triggered by periodontitis. Cells with capacity of iNOS production could be implicated in generation of reactive nitrogen species, suggesting immunomodulatory properties.</p>","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261422539"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12909751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innate immune recognition of <i>Bartonella bacilliformis</i>: TLR2/TLR4 expression and cytokine modulation.","authors":"Angie K Castillo, Javier Enciso-Benavides, Ana Mayanga-Herrera, Joaquim Ruiz, Ruth García-de-la-Guarda, Maria J Pons","doi":"10.1177/17534259261446053","DOIUrl":"10.1177/17534259261446053","url":null,"abstract":"<p><p>BackgroundConsider this Carrion's disease (CD) is a biphasic illness-comprising acute and chronic phases-endemic to Peru and caused by <i>Bartonella bacilliformis</i>, a bacterium transmitted by sandflies. Despite its clinical relevance, the mechanisms underlying innate immune activation in response to <i>B. bacilliformis</i> remain poorly understood. Toll-like receptors (TLRs) play a central role in recognizing conserved molecular patterns present in pathogens, thereby initiating innate immune responses. The present study aimed to describe the expression patterns of TLR2 and TLR4, along with cytokine secretion profiles, during peripheral blood mononuclear cells (PBMCs) exposure to <i>B. bacilliformis</i>.MethodsPeripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with heat-inactivated <i>B. bacilliformis</i> (ATCC 35685 strain), zymosan (TLR2 control), or <i>E. coli</i> LPS (TLR4 control). TLR2 and TLR4 gene expression was quantified by RT-qPCR at 0, 12, 24, 36, and 48 h. Cytokines were measured using a 17-plex panel. Analyses were descriptive, using non-parametric statistics.ResultsResults elicited measurable changes in the transcriptional expression of TLR2 and TLR4 during stimulation, with peak activation typically observed at 12 h, although in one case the maximal response was delayed to 24 h. These expression changes coincided with significant modulation of multiple cytokines, including pro-inflammatory mediators (TNF-α, IL-17, IL-12p70), Th1/Th2 cytokines (IFN-γ, IL-2, IL-5, IL-13), regulatory cytokines (IL-10), and growth factors (GM-CSF, IL-7).ConclusionsThis exploratory study describes the transcriptional expression patterns of TLR2 and TLR4 and the accompanying cytokine responses in PBMCs exposed to <i>B. bacilliformis</i>. These profiles expand current knowledge of the early innate immune signature elicited by this neglected pathogen and provide a foundation for future studies using receptor-specific functional assays. Importantly, these patterns likely reflect early innate immune response signatures rather than definitive evidence of functional receptor activation.</p>","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261446053"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13342430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial progenitor cell numbers vary in newborns and adults; anti-gm-CSFα (CD116) antibody as a novel marker for EPC enumeration.","authors":"Sevil Simsek, Cagatay Karaca, Nezihe Koker, Adnan Öztürk, Mustafa Yavuz Koker","doi":"10.1177/17534259261438615","DOIUrl":"10.1177/17534259261438615","url":null,"abstract":"<p><p>ObjectiveEndothelial progenitor cells (EPCs) originate from hematopoietic stem cells and can be quantified in peripheral blood using flow cytometry. The anti-GM-CSFα antibody (CD116) may serve as a specific marker for EPC enumeration. This study aimed to quantify peripheral EPCs expressing CD116 and compare the results with other specific antibodies in newborns and adults.Materials and MethodsEPC enumeration was performed by flow cytometric analysis of peripheral blood leukocytes (PBLs) obtained from 50 individuals, including 25 newborns and 25 adults. A CD34-specific antibody was used to identify hematopoietic stem/progenitor cells, while an antibody panel consisting of CD116, CD146, CD31, and CD45 was employed for EPC identification.ResultsEnumeration of CD34⁺ hematopoietic progenitor cells (HPCs) demonstrated that the mean CD34⁺ HPC count per 10⁶ PBLs was 1643 (935-1458) in newborns and 242.7 (163-190) in adults, with a statistically significant difference between the groups (<i>p</i> < 0.001). Using CD146 staining, the mean number of circulating EPCs per 10⁶ PBLs was 94.2 (90.5-129.0) in newborns and 9.2 (7.4-12.4) in adults (<i>p</i> < 0.001). Similarly, enumeration based on CD31 staining revealed mean EPC counts of 19.0 (12.5-28.0) in newborns and 6.0 (5.0-7.0) in adults (<i>p</i> < 0.001). Enumeration using CD116 staining showed mean EPC numbers of 29.0 (23.0-34.0) in newborns and 3.0 (2.0-4.0) in adults, also indicating a significant difference between the two groups (<i>p</i> < 0.001).ConclusionEPC numbers are significantly higher in newborns than in adults, suggesting an important developmental role for these cells. The GM-CSFα-specific antibody (CD116) may serve as a novel auxiliary marker for the identification and quantification of circulating EPCsubpopulations. Furthermore, EPC numbers appear to vary across different life stages, with higher numbers in newborns potentially reflecting the presence of a highly regenerative microenvironment.</p>","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261438615"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13070191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: Effect of berberine on LPS-induced expression of NF-κB/MAPK signalling pathway and related inflammatory cytokines in porcine intestinal epithelial cells.","authors":"","doi":"10.1177/17534259261435238","DOIUrl":"10.1177/17534259261435238","url":null,"abstract":"","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261435238"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13018703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of trained immunity in chronic non-communicable inflammatory diseases.","authors":"Joseph Mucumbitsi, Jean Claude Hakizimana, Marie Gorette Kampire, Callixta Kaneza, Themistocles Bushobozi, Sophie Mukantwari, Jean Mfizi Ngaboyishema, Alex Butera, Abdullateef Isiaka Alagbonsi","doi":"10.1177/17534259261446050","DOIUrl":"10.1177/17534259261446050","url":null,"abstract":"<p><p>BackgroundTrained immunity, a form of long-term functional reprogramming of innate immune cells through epigenetic and metabolic changes, traditionally confers protection against infections. However, inappropriate activation by endogenous sterile stimuli can drive persistent maladaptive inflammation in non-communicable diseases (NCDs).ObjectiveThis systematic review synthesizes primary evidence for trained immunity in atherosclerosis, type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and neurodegenerative disorders, focusing on endogenous inducers, cellular mediators, mechanisms, and translational implications.Data Sources and MethodsFollowing PRISMA guidelines, we included original studies demonstrating trained immunity induced by sterile endogenous signals in the targeted diseases. Narrative synthesis was performed due to heterogeneity precluding meta-analysis.ResultsTwelve primary studies met the inclusion criteria. In atherosclerosis (n = 8 studies), oxLDL, aldosterone, Western diet lipids, and post-myocardial infarction signals induced trained immunity in monocytes or macrophages and hematopoietic progenitors via H3K4me3 enrichment, mTOR/NLRP3 activation, and glycolytic/fatty acid shifts, leading to persistent cytokine hyperproduction (TNF-α, IL-6), foam cell formation, and transmissible plaque progression. In T2DM/hyperglycemia (n = 3), high glucose levels triggered MLL-mediated epigenetic reprogramming and glycolysis-dependent \"metabolic memory,\" which skewed myelopoiesis and accelerated atherosclerosis despite normoglycemia. In CKD (n = 1), indoxyl sulfate induced AhR-dependent arachidonic acid pathway activation with metabolic rewiring, sustaining systemic inflammation. In neurodegeneration (n = 1), peripheral stimuli caused epigenetic reprogramming in microglia, yielding hyperresponsive or tolerized states modulating amyloid-β pathology. Convergent mechanisms (H3K4me3, glycolysis, mTOR/AhR/NLRP3) highlight trained immunity as a shared driver of chronic sterile inflammation.ConclusionsTrained immunity emerges as a unifying maladaptive mechanism perpetuating low-grade inflammation across these diseases, bridging transient endogenous insults to sustained pathology. Targeting reprogramming pathways, such as glycolysis or epigenetic inhibitors, offers promising therapeutic strategies. Expanded human studies are needed to address preclinical dominance and data gaps, particularly in CKD and neurodegeneration, where evidence is preliminary.</p>","PeriodicalId":13676,"journal":{"name":"Innate Immunity","volume":"32 ","pages":"17534259261446050"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13111844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}