bims-traimu 2026-06-28 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–06–28
sixteen papers selected by
Yantong Wan, Southern Medical University

Could Trained Immunity Impact Periapical Healing? A Biological Perspective.
Quantitative cytokine profiling of primary human macrophages reveals distinct single-cell modes of trained immunity.
[Innate immune memory - Trained immunity: Current concepts and clinical implications].
Trained immunity as a systemic bridge: the liver-gut-immune-oral axis in the comorbidity of chronic liver disease and periodontitis.
Metabolic Reprogramming-Driven Cardiovascular Immune Damage: From Glyco-Lipotoxicity and Epigenetic Memory to Multidimensional Cross-Organ Communication Networks.
Single-Nucleus Multiomic Analysis Reveals Immune-Metabolic Reprogramming Consistent With Maladaptive Trained Immunity in HIV-Associated Neurocognitive Disorders.
Trained immunity in the treatment for haematological malignancy.
Associations between population-level BCG and yellow fever vaccination and aortic mortality: A 29-year observational analysis using causal inference methods.
Two-Step Vibrio parahaemolyticus Challenge Reveals Transcriptional Reprogramming of Trained Immunity in Shrimp Hemocytes.
RNA modifications shape innate immunity and cellular adaptation during bacterial respiratory infection.
Innate immunity in allergic diseases: Novel concepts.
Immune signal-status misclassification: A theoretical framework for biological status assignment and failed status resolution.
The Gut-Immune Axis in Treated HIV Infection: From Mucosal Damage to Chronic Inflammation and Therapeutic Opportunities-A Clinician-Oriented Narrative Review.
Dissection of MAPK and NF-κB p65 signaling dynamics underlying LPS tolerance in macrophages at the single-cell level.
ZBP1-driven pyroptosis-associated alveolar macrophages exacerbate epithelial dysfunction in sepsis.
Itaconate induces noncanonical AIM2-dependent PANoptosis in sepsis.

Int Endod J. 2026 Jun 23.

Could Trained Immunity Impact Periapical Healing? A Biological Perspective.

Mohammed Turky, Paul R Cooper.

   AIM: To explore whether trained immunity, a form of innate immune memory mediated by epigenetic and metabolic reprogramming, may influence periapical healing following root canal treatment.
SUMMARY: Apical periodontitis is primarily driven by microbial infection; however, healing outcomes following root canal treatment often demonstrate substantial variability despite comparable microbial reduction and treatment quality. Trained immunity has emerged as a biological phenomenon whereby prior microbial or inflammatory exposure can induce long-term functional reprogramming of innate immune cells, resulting in altered responses to subsequent challenges. This perspective examines whether previous inflammatory episodes within periapical tissues may generate a state of immune priming capable of modifying healing trajectories. Potential mechanisms include macrophage reprogramming, altered cytokine signalling, enhanced osteoclastogenesis, and disruption of the transition from inflammation to tissue repair. Retreatment lesions and chronic periapical inflammation may represent clinically relevant models for investigating the effects of inflammatory memory within endodontic disease. Whilst microbial control remains fundamental to successful treatment, trained immunity may provide a complementary framework for understanding variability in healing outcomes.
CONCLUSIONS: Trained immunity represents a novel immunological concept whereby innate immune cells undergo long-term functional reprogramming following previous microbial or inflammatory exposure. Although currently unproven in endodontics, this phenomenon may provide a biologically plausible explanation for some of the variability observed in periapical healing following root canal treatment. Potential mechanisms include persistent macrophage activation, dysregulated cytokine signalling, and enhanced osteoclastogenic activity, all of which may influence inflammatory resolution and bone repair. Importantly, trained immunity should be viewed as a complementary biological framework rather than an alternative to the established infection-centred paradigm of apical periodontitis. Further experimental, translational, and clinical studies are required to determine whether inflammatory memory contributes to differences in healing outcomes and to clarify its potential relevance to future endodontic research and therapy.

Keywords:  apical periodontitis; epigenesis genetic; host‐pathogen interactions; immunity

DOI:  https://doi.org/10.1111/iej.70209
Cell Syst. 2026 Jun 23. pii: S2405-4712(26)00130-4. [Epub ahead of print] 101648

Quantitative cytokine profiling of primary human macrophages reveals distinct single-cell modes of trained immunity.

Aoife O'Farrell, Zijian Niu, Arjun Raj.

  Macrophages can remember prior activation and subsequently augment their response to restimulation through trained immunity. However, it remains uncertain how trained immunity phenotypes manifest in individual cells. Here, we leverage highly quantitative single-molecule RNA imaging across 90,857 individual macrophages from 26 human donors to reveal inflammatory response dynamics in trained vs. untrained populations at single-cell resolution. Different inflammatory response genes showed distinct single-cell behavior in trained populations upon restimulation. Although training increased transcription of these response genes early after restimulation, untrained populations eventually "caught up" to the transcriptional output of trained populations, highlighting the importance of sampling timescale when interpreting transcriptional assays of training. Training did not significantly alter the relationship between the transcriptional activation of different genes within the same single cell, and any single cell appeared to be capable of training. Overall, these results revealed gene-specific single-cell transcriptional changes that generate population-wide training phenotypes in macrophages.

Keywords:  RNA FISH; inflammatory response; innate immune memory; macrophages; single cell; trained immunity

DOI:  https://doi.org/10.1016/j.cels.2026.101648
Medicina (B Aires). 2026 ;86(3): 759-771

[Innate immune memory - Trained immunity: Current concepts and clinical implications].

María Cecilia Foncuberta, Olivia Gelo, Julio C Sánchez Ávalos.

Trained immunity is a phenomenon of growing understanding that redefines the classic view of the innate immune system by demonstrating its ability to develop longlasting functional memory. It is characterized by epigenetic and metabolic reprogramming that enhances the response to new homologous or heterologous stimuli, independently of the adaptive immune system. Known inducers include microbial components, live attenuated vaccines, metabolites, and inflammatory signals, although the magnitude and duration of this memory are not yet fully established. This work reviews the cellular and molecular mechanisms of trained immunity, highlighting its potential benefits in host defense and tumor surveillance, as well as its adverse effects when activation is persistent or dysregulated, leading to chronic inflammatory diseases. It emphasizes the need to identify specific biomarkers and develop accessible techniques to quantify this response, assess its persistence, and understand its interaction with immunoregulatory populations like myeloid-derived suppressor cells (MDSCs). Although trained immunity and MDSCs share common pathophysiological scenarios, such as persistent inflammation and emergency hematopoiesis, data suggest differences in their origins and induction mechanisms. While MDSCs primarily affect neutrophils and monocytes with immunosuppressive functions, trained immunity cells, myeloid and lymphoid, appears to derive from more primitive progenitors, implying a broader reprogramming of the innate immune compartment. Trained immunity holds enormous preventive and therapeutic potential. However, its clinical application requires overcoming technical limitations and gaining a deeper understanding of its induction and regulation mechanisms, its interaction with other immunoregulatory systems, and its pharmacological modulation.

Keywords: epigenetics; immunologic memory; inflammation; neoplasms; trained immunity
Front Immunol. 2026 ;17 1855561

Trained immunity as a systemic bridge: the liver-gut-immune-oral axis in the comorbidity of chronic liver disease and periodontitis.

Xiang Li, Guodong Lv, Daolang Yuan, Jun Hu, Wenrong Lou, Yulin Tu, Jing Zhou, Rong Qin.

  Trained immunity (TI) reveals that innate immune cells acquire long-term functional memory through metabolic and epigenetic reprogramming. This review examines TI in chronic liver diseases and periodontitis, proposing the "Liver-Gut-Immune-Oral Axis" as a framework where TI bridges these comorbidities. The forward pathway, currently inferred from mechanistic and associative studies, proposes that liver-gut dysfunction induces bone marrow training, generating hyper-reactive monocytes that amplify periodontal inflammation. The reverse pathway, similarly conceptual, proposes that periodontal pathogens reprogram hematopoietic progenitors, accelerating liver disease progression. Both converge on shared metabolic-epigenetic reprogramming circuits. We emphasize that this axis represents a conceptual framework synthesized from current mechanistic and associative evidence; its validity as an integrated, causally-linked biological system awaits direct experimental validation. Targeting TI with metabolic modulators, epigenetic drugs, or periodontal interventions offers strategies to disrupt this cycle and advance precision medicine for inflammatory comorbidities.

Keywords:  Chronic liver disease; comorbidity; liver-gut-immune-oral axis; periodontitis; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1855561
Int J Mol Sci. 2026 Jun 18. pii: 5526. [Epub ahead of print]27(12):

Metabolic Reprogramming-Driven Cardiovascular Immune Damage: From Glyco-Lipotoxicity and Epigenetic Memory to Multidimensional Cross-Organ Communication Networks.

Zijin Sun, Yongchao Liu, Kai Wang, Haojia Zhang, Rui Zhou, Wei Shao.

  Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, and residual inflammatory risk persists despite optimal lipid and glucose control. Emerging evidence indicates that metabolic reprogramming within immune cells constitutes a central driver of cardiovascular immune injury. In this review, we propose a unifying framework in which glyco-lipotoxicity acts as a primary metabolic trigger, inducing mitochondrial dysfunction, oxidative stress, and activation of the NLRP3 inflammasome and cGAS-STING pathways. Hyperglycaemia and dyslipidaemia reshape intracellular metabolic circuits, enhancing glycolysis and disrupting oxidative phosphorylation, thereby promoting sustained pro-inflammatory phenotypes. Crucially, metabolic intermediates function as cofactors for epigenetic remodelling. This establishes trained immunity in both circulating innate immune cells and haematopoietic stem/progenitor cells, which serves as the cellular basis for persistent metabolic memory. This persistent immunometabolic imprint amplifies sterile inflammation and accelerates vascular and myocardial remodelling. Furthermore, these processes are systemically propagated through cross-organ communication networks, including the heart-adipose, gut-heart, and cardio-hematopoietic axes, forming a multidimensional inflammatory amplification loop. We also summarise emerging therapeutic strategies targeting the metabolic-epigenetic axis, aiming to reverse maladaptive trained immunity and mitigate residual CVD risk. By integrating immunometabolism, epigenetic regulation, and organ crosstalk, this review highlights metabolic reprogramming as a pivotal mechanistic nexus and potential precision target for cardiovascular protection.

Keywords:  NLRP3 inflammasome; cross-organ communication; epigenetic remodelling; glyco-lipotoxicity; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.3390/ijms27125526
Glia. 2026 Aug;74(8): e70191

Single-Nucleus Multiomic Analysis Reveals Immune-Metabolic Reprogramming Consistent With Maladaptive Trained Immunity in HIV-Associated Neurocognitive Disorders.

Siera Martinez, Anelia Horvath, Luke Johnson, Tatiana Pushkarsky, Larisa Dubrovsky, Daria Starosyla, Ashley Bastin, Dmitri Sviridov, Michael Bukrinsky.

  HIV-associated neurocognitive disorders (HAND) remain prevalent in people with HIV (PWH) despite effective antiretroviral therapy, suggesting that persistent immune activation contributes to ongoing neurological dysfunction. Maladaptive trained immunity (TRIM), long-term innate immune reprogramming characterized by sustained inflammatory responses, metabolic rewiring, and epigenetic remodeling, has been proposed as a sustaining mechanism. We performed single-nucleus RNA-seq and ATAC-seq on post-mortem brain from PWH with HIV-associated dementia (HAD) or asymptomatic neurocognitive impairment (ANI) and compared these data with published HIV-uninfected (PWoH) datasets. In PWH versus PWoH, glia, led by microglia, showed enrichment of innate immune signaling and upregulation of inflammatory mediators including NLRP3, TLR2, and TLR4. In parallel, glia showed coordinated cholesterol remodeling, with efflux transporter and apolipoprotein upregulation alongside LDLR downregulation, and partial microglial glycolytic reprogramming (PFKFB3, HK2, PGK1 upregulation). Chromatin accessibility profiling showed concordant gains at inflammatory, cholesterol regulatory (notably RXRA and APOE), and glycolytic loci. The HAD versus ANI comparison revealed selective reorganization rather than uniform amplification, with increased lipid scavenger receptor accessibility in oligodendrocytes and reduced accessibility at cholesterol efflux and glycolytic loci. Neurons exhibited predominantly bystander epigenetic changes. Three features distinguish this pattern from chronic inflammation alone and align it with trained immunity hallmarks: concordant transcriptional and chromatin-level priming at inflammatory loci, parallel rewiring of glycolytic and cholesterol metabolism, and persistence despite long-term viral suppression. These multiomic data are consistent with maladaptive trained immunity sustaining neuroinflammation in HAND, though functional validation is required.

Keywords:  HIV; HIV‐associated neurocognitive disorders (HAND); epigenetic reprogramming; maladaptive trained immunity; microglia; neuroinflammation; neurons; single‐nucleus multiomics

DOI:  https://doi.org/10.1002/glia.70191
Ageing Res Rev. 2026 Jun 22. pii: S1568-1637(26)00202-3. [Epub ahead of print]120 103210

Trained immunity in the treatment for haematological malignancy.

Zhaoyun Liu, Xinyu Chen, Chun Yang, Hao Wang, Hui Liu, Rong Fu.

  Trained immunity, an emerging treatment strategy, confers long-term anti-tumour memory by modulating epigenetic and metabolic reprogramming of innate immune cells, offering a novel pathway for immunotherapy of haematological malignancies. This article systematically outlines the mechanisms by which inducers such as β-glucan, Bacille Calmette-Guérin (BCG) and cytokines train key effector cells including macrophages and natural killer (NK) cells. It further analyses how ageing-encompassing both organismal ageing and cellular senescence-specifically undermines the efficacy of relevant pathways at multiple levels, from haematopoietic stem cell function and intracellular signalling to the tumour microenvironment, thereby systematically impairing the induction efficiency, durability of effect, and safety of trained immunity. Building on this, the article evaluates the clinical translation prospects and associated risks, including graft-versus-host diseases (GVHDs), of strategies such as cytokine-induced memory-like (CIML) NK cells, and proposes concrete, testable translational ideas aimed at overcoming ageing-related defects. We argue that to realise the full potential of this therapy in elderly patients with haematological malignancies, future work must focus on developing individualised training protocols capable of circumventing or reversing immunosenescence.

Keywords:  Ageing; Cellular senescence; Haematological malignancy; Immunotherapy; Trained immunity

DOI:  https://doi.org/10.1016/j.arr.2026.103210
Int J Cardiol. 2026 Jun 22. pii: S0167-5273(26)00478-X. [Epub ahead of print] 134628

Associations between population-level BCG and yellow fever vaccination and aortic mortality: A 29-year observational analysis using causal inference methods.

Gabriel Kaleb Martins, Capela António Pascoal, Ester Carolina Amando Nascimento, Edoarda Carolina Bertholdi, Maikon Lucian Madeira Quarti.

   AIMS: Diseases of the aorta are driven by chronic inflammation and matrix metalloproteinase activity. Vaccines such as Yellow Fever (YF) and BCG may be associated with vascular protection through "trained immunity", epigenetic reprogramming of innate immune cells that attenuates systemic inflammatory responses. We investigated the association between population-level vaccination coverage and aortic mortality using contemporary causal inference methods.
METHODS AND RESULTS: This ecological study analyzed 27 Brazilian states over 29 years (1994-2022), encompassing 783 state-year observations and 185,429 deaths. Poisson fixed-effects models with state and year intercepts were employed to isolate within-state effects. States with high YF coverage (>80%) showed a 16% lower age-standardized aortic mortality compared to low-coverage states (IRR 0.84; 95% CI 0.76-0.93; P = 0.001). E-value analysis for this association was 1.67, indicating robustness against moderate unmeasured confounding. For BCG, associations followed a biologically plausible lag structure, peaking at 15 years post-vaccination (IRR 0.91 per 10 pp. increase; 95% CI 0.85-0.98; P = 0.009). Negative control analysis using Diphtheria-Tetanus-Pertussis (DTP) vaccine, which lacks trained immunity effects, showed no association with aortic mortality (IRR 1.02; P = 0.578), arguing against residual confounding from healthcare access. Causal mediation analysis suggested that 65% of the YF vaccine's association operated through pathways independent of infectious disease reduction.
CONCLUSION: Population-level vaccination with YF and BCG is associated with lower aortic mortality in this ecological analysis. These hypothesis-generating findings, supported by negative control validation and temporal consistency across three decades, are compatible with a trained immunity pathway but require confirmation in prospective individual-level studies before causal conclusions can be drawn.

Keywords:  Aortic diseases; Epidemiology; Trained immunity; Vaccination

DOI:  https://doi.org/10.1016/j.ijcard.2026.134628
Biology (Basel). 2026 Jun 18. pii: 956. [Epub ahead of print]15(12):

Two-Step Vibrio parahaemolyticus Challenge Reveals Transcriptional Reprogramming of Trained Immunity in Shrimp Hemocytes.

Zhongying Li, Shihao Li, Xinjia Lv, Fuhua Li.

  Invertebrates rely exclusively on innate immunity but exhibit memory-like responses termed immune priming or trained immunity. In the commercially vital whiteleg shrimp (Litopenaeus vannamei), infection by Vibrio parahaemolyticus causes severe economic losses, yet the molecular networks driving secondary immune recall remain poorly understood. In this study, we established a two-step immune challenge model in L. vannamei using formaldehyde-inactivated V. parahaemolyticus and performed transcriptomic analysis on hemocytes to compare primary and secondary immune responses. Differentially expressed gene (DEG) screening and enrichment analyses (GO, KEGG, and GSEA) suggest that shrimp hemocytes undergo a broad and coordinated transcriptional reprogramming rather than uniform upregulation of immune genes. Transcriptomic data show potential associations between secondary immune priming and the modulation of cell fate processes: genes related to cell cycle progression (e.g., CDK1, CCNB3) and spindle assembly (e.g., MPS1) were significantly upregulated alongside apoptosis inhibition (CASP6 downregulation). Concurrently, metabolic remodeling was observed through the upregulation of lipid synthesis (SREBF1, FASN) and carbohydrate uptake pathways, potentially providing anabolic support for hemocyte growth and immune activation. Furthermore, the humoral effector responses appear to be strengthened, characterized by upregulated antimicrobial peptides (PEN, ALF) and the proPO melanization cascade (PPAF3, PPO3), whereas the expression of intracellular NLR was relatively suppressed, which might help mitigate excessive immune inflammation and immunopathological damage. Collectively, these transcriptomic findings identify a putative coordinated transcriptional signature of hemocyte recall responses in L. vannamei. This study expands our understanding of innate immune memory in invertebrates and provides candidate molecular markers for further study in disease-resistant breeding research in shrimp aquaculture.

Keywords:  cell cycle; hemocyte; immune effector; innate immune memory; lipid metabolism

DOI:  https://doi.org/10.3390/biology15120956
Front Immunol. 2026 ;17 1845134

RNA modifications shape innate immunity and cellular adaptation during bacterial respiratory infection.

Martina M Ivanova, Petya A Dimitrova, Milena N Leseva.

  Gram-negative bacteria are clinically significant pathogens responsible for life-threatening infections, including respiratory infections. These can be acute or persistent and can exacerbate existing chronic diseases, such as cystic fibrosis, COPD and lung cancer. In this review, we use Pseudomonas aeruginosa as a model organism that demonstrates the molecular complexity of host-pathogen interactions during lower airway infection. Specifically, we focus on RNA modifications and show that they, on the one hand, regulate bacterial fitness and pathogenicity, and on the other control the execution of an effective host innate immune response. Furthermore, we examine the role of epigenetic and epitranscriptomic modifications in the immune dysregulation observed in sepsis, with an emphasis on sepsis-induced lung injury. Innate immune memory - a cellular adaptation mechanism to primary microbial stimulation - results in training or tolerization of host cells towards secondary immune challenges. While fundamentally grounded in epigenetic and metabolic reprogramming, we propose that it can crosstalk with epitranscriptomic regulation. To overcome limitations imposed by animal models when investigating microbe-induced epitranscriptomic dynamics, we highlight physiologically-relevant in vitro tissue models that can complement work performed in vivo. Ultimately, a detailed understanding of the RNA modification landscape regulating host-pathogen interactions will help us identify new therapeutic targets and molecular pathways to better manage the clinical symptoms of bacterial respiratory infections and address the growing challenge of antimicrobial resistance.

Keywords:  Pseudomonas aeruginosa; RNA modifications; epigenetic regulation; in vitro models; innate immune memory; innate immune response; lower airway infection

DOI:  https://doi.org/10.3389/fimmu.2026.1845134
J Allergy Clin Immunol. 2026 Jun 23. pii: S0091-6749(26)00440-9. [Epub ahead of print]

Innate immunity in allergic diseases: Novel concepts.

Angel Maldonado, Alba Angelina, Natalia Cuervo, Sofía Sirvent, Oscar Palomares.

  Dysregulation of type 2 (T2) immunity, which normally protects the host against large parasites, toxins, and venoms, leads to aberrant inflammatory responses underlying several allergic diseases. Recent advances have highlighted the important role of innate immune responses in the initiation and persistence of these disorders, identifying innate immune cells as key drivers as well as potential biomarkers and therapeutic targets. In this review, we summarize recent findings on the molecular mechanisms through which innate immune cells interact with adaptive immunity to promote the development and chronification of T2-mediated diseases, including allergic rhinitis, chronic rhinosinusitis with nasal polyps, asthma, food allergy, eosinophilic esophagitis, and atopic dermatitis. We also discuss the emerging role of trained immunity and maladaptive trained immunity in either protecting against or promoting allergic disease development. A better understanding of innate immune pathways and their interplay with adaptive immunity might be crucial for the identification of novel biomarkers and therapeutic targets, fostering precision medicine approaches aimed at improving patients' quality of life while reducing the considerable socioeconomic burden of allergic diseases.

Keywords:  Allergic diseases; innate immunity; trained immunity; type 2 inflammation

DOI:  https://doi.org/10.1016/j.jaci.2026.06.007
Biosystems. 2026 Jun 26. pii: S0303-2647(26)00171-1. [Epub ahead of print]266 105861

Immune signal-status misclassification: A theoretical framework for biological status assignment and failed status resolution.

Angelina Hintsanen.

  Biological immune regulation depends not only on detecting molecular signals, but on assigning those signals functional status. The same antigenic, inflammatory, or damage-associated input may support tolerance, activation, repair, resolution, suppression, or memory depending on tissue context, prior history, co-stimulation, regulatory state, and inflammatory load. This paper proposes immune signal-status misclassification as a conservative systems-level framework for cases in which immune systems assign inappropriate biological status to signals: harmless inputs treated as danger, self-related signals treated as threat, resolved damage treated as ongoing injury, or transient activation treated as persistent inflammatory demand. The proposal builds on established immunological concepts rather than replacing them. Pattern-recognition receptors, PAMP/DAMP signaling, danger and injury models, immune tolerance, and trained immunity already imply that immune response depends on context and history rather than signal presence alone. The contribution here is to make explicit a status-assignment layer: the operation by which a biological system assigns a signal the status of harmless, dangerous, self, damaged, repair-relevant, tolerogenic, inflammatory, or persistently threatening. A minimal toy model shows how prior danger-status assignment can maintain later danger assignment after an initiating signal declines. An illustrative public-data reanalysis of GEO accession GSE67472 shows how a documented three-gene type-2 inflammatory signature can be used to operationalize immune-status structure in airway epithelial transcriptomic data. Because the asthma subgroups in our reanalysis were reconstructed from the same signature used to define the score, this analysis is not treated as independent validation. The toy model and public-data example are used only to show how the framework can be formalized and operationalized. The central claim is narrow: some immune failures may involve wrong biological status assignment or failed status resolution, in addition to abnormal signal intensity or molecular pathway activation. Five falsifiable predictions are derived, including the context-history prediction that signal-plus-history models should outperform signal-only models near ambiguous threshold conditions, and the resolution prediction that recovery should be predicted by status-transition markers beyond raw inflammatory burden.

Keywords:  Asthma endotypes; Chronic inflammation; DAMPs; Danger signaling; Immune tolerance; Signal classification; Status assignment; Systems immunology; Trained immunity

DOI:  https://doi.org/10.1016/j.biosystems.2026.105861
Microorganisms. 2026 May 29. pii: 1229. [Epub ahead of print]14(6):

The Gut-Immune Axis in Treated HIV Infection: From Mucosal Damage to Chronic Inflammation and Therapeutic Opportunities-A Clinician-Oriented Narrative Review.

Thomas N Nitsotolis, Stelios F Assimakopoulos, Maria Lagadinou, Alexia Papalexandrou, Nikolaos Krikis, Marios Kourtidis, Eirini Christaki, Haralampos Milionis.

  Combined antiretroviral therapy (cART) has transformed HIV into a manageable chronic disease. However, people living with HIV (PLWH) experience a 16-year reduction in comorbidity-free life expectancy compared to HIV-negative individuals, driven by persistent chronic immune activation despite virological suppression. Serious non-AIDS events (SNAEs)-including cardiovascular disease, metabolic disorders, and malignancies-now represent the predominant cause of morbidity. This narrative review provides a clinician-oriented synthesis of immunopathophysiological mechanisms driving chronic inflammation in treated HIV infection, focusing on the gut-immune axis, restriction factors, trained immunity, biomarker-guided risk stratification, and therapeutic strategies. We searched PubMed/MEDLINE, Embase, and Web of Science through April 2026 using terms related to HIV chronic immune activation, gut-associated lymphoid tissue, microbial translocation, inflammaging, restriction factors, trained immunity, and biomarkers. This review followed the SANRA checklist. Irreversible destruction of gut-associated lymphoid tissue (GALT), intestinal barrier dysfunction, microbial translocation, maladaptive trained immunity, persistent myeloid activation with NLRP3 inflammasome signaling and cellular senescence, and viral reservoir persistence collectively perpetuate systemic inflammation. Biomarkers, including sCD14, IL-6, and suPAR, independently predict mortality but are not pathogen-specific. The REPRIEVE trial demonstrated a 36% reduction in cardiovascular risk with pitavastatin (HR 0.64, 95% CI 0.48-0.84), validating inflammation as a therapeutic target. Integration of early cART, statin therapy, optimal antiretroviral selection, and emerging strategies-including GLP-1 receptor agonists and gut-directed therapies-offers a practical framework for reducing inflammation-associated comorbidities in virologically suppressed PLWH.

Keywords:  HIV infection; NLRP3 inflammasome; REPRIEVE; antiretroviral therapy; biomarkers; cellular senescence; chronic immune activation; geroscience; gut microbiome; gut–immune axis; inflammaging; intrinsic restriction factors; microbial translocation; non-AIDS events; trained immunity

DOI:  https://doi.org/10.3390/microorganisms14061229
Biotechnol Rep (Amst). 2026 Sep;51 e00966

Dissection of MAPK and NF-κB p65 signaling dynamics underlying LPS tolerance in macrophages at the single-cell level.

Tuntikorn Laosuk, Patipark Kueanjinda, Hiroshi Kimura, Tanapat Palaga.

  MAPK and NF-κB pathways regulate macrophage responses to microbial stimuli. Repeated exposure to lipopolysaccharide (LPS) induces endotoxin tolerance, a state in which inflammatory cytokine production is suppressed while antimicrobial functions are preserved. Although regulatory mechanisms of LPS tolerance is well established, how prior LPS exposure reshapes signaling dynamics downstream of TLR4 remains unclear. Using biosensors and live-cell imaging, we quantified ERK and NF-κB signaling in RAW264.7 macrophages during LPS tolerance. Tolerized macrophages produced less TNF-α and IL-6 and showed reduced ERK and NF-κB activity, with lower amplitudes and areas under the curve than cells receiving a single LPS stimulation. Both pathways also displayed delayed activation, reflected by a prolonged time to first peak. Inhibition experiments revealed bidirectional crosstalk, as blocking ERK altered NF-κB signaling and NF-κB inhibition suppressed ERK dynamics. These findings show that LPS tolerance involves coordinated changes in the strength and timing of ERK and NF-κB signaling.

Keywords:  ERK; LPS tolerance; Macrophages; NF-κB; Signaling dynamics

DOI:  https://doi.org/10.1016/j.btre.2026.e00966
Cell Death Dis. 2026 Jun 26.

ZBP1-driven pyroptosis-associated alveolar macrophages exacerbate epithelial dysfunction in sepsis.

Feicheng Zhou, Haolin Tian, Haixia Wang, Hongxiang Huang, Xuwei Lin, Yuanyuan Zhao, Huaijun Chen, Ting Gong.

The lung is highly vulnerable to inflammatory injury during sepsis, and acute lung injury (ALI) is a major cause of mortality in critically ill patients. Pyroptosis amplifies immune responses by promoting the release of inflammatory cytokines, and Z-DNA binding protein 1 (ZBP1) has emerged as a key upstream regulator of programmed cell death and inflammatory signaling. Nevertheless, the contribution of ZBP1 to human sepsis-induced ALI and its associated cellular programs remains poorly defined. Here, by integrating single-cell RNA sequencing data from bronchoalveolar lavage fluid (BALF) of patients with sepsis-induced ALI and from septic mouse lungs, we identified a distinct subset of pyroptosis-associated macrophages that expands during disease progression and exhibits ZBP1-dependent inflammasome activation. ZBP1 activation promoted inflammasome assembly, induced macrophage pyroptosis, and released pro-inflammatory mediators that impaired mitochondrial function and barrier integrity of alveolar type II (AT2) epithelial cells. ZBP1 deficiency markedly attenuated macrophage-AT2 inflammatory signaling and reduced the inflammatory amplification loop. Collectively, these findings identify ZBP1-mediated macrophage pyroptosis as a critical mechanism driving epithelial dysfunction during sepsis-induced ALI and provide a rationale for developing ZBP1-targeted strategies to restore immune-epithelial homeostasis and prevent organ failure in sepsis.In sepsis-induced acute lung injury, ZBP1 drives macrophage pyroptosis and amplifies inflammatory signaling, thereby promoting mitochondrial dysfunction, inflammatory activation, and barrier integrity loss in AT2 epithelial cells. Zbp1 deficiency suppresses macrophage pyroptosis, weakens macrophage-epithelial inflammatory crosstalk, and mitigates epithelial injury.

DOI: https://doi.org/10.1038/s41419-026-09043-y
Cell Mol Immunol. 2026 Jun 25.

Itaconate induces noncanonical AIM2-dependent PANoptosis in sepsis.

Hayeon Kim, SangJoon Lee.

DOI: https://doi.org/10.1038/s41423-026-01428-5