bims-traimu 2026-10-04 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–10–04
fifteen papers selected by
Yantong Wan, Southern Medical University

Pharmacological control of inflammation via innate immune memory manipulation.
The BCG Vaccine: Pharmacological Biotechnology and Expanding Immunological Horizons.
Trained immunity and related memory responses in lung health and disease.
Heat-killed Mycobacterium tuberculosis-induced trained immunity elicits antitumor activity in PBMCs from colon cancer patients with unresponsiveness to anti-PD-1 in vitro.
Type 2 immune history trains lung macrophages for viral disease tolerance.
Systemic immune programming in the life course of childhood asthma: a new perspective on monocyte pre-activation and trained immunity.
Trained Immunity as a Mechanistic Bridge Between Uremic Toxins, Atherosclerosis, and Vascular Calcification in Chronic Kidney Disease.
Low hypoxia tolerance as a determinant of the proinflammatory phenotype: a trained immunity perspective.
Correction: Immuno-inflammatory-metabolic interactions in cardiovascular diseases: a review from basic mechanisms to clinical translation.
Immune boosting to combat Alzheimer's disease: Position statement.
The effects of IFNγ on tissue physiology through structural cells.
scH16S-Seq Maps Klebsiella pneumoniae-Associated Myeloid States and Reveals a CD38-NAD Immunometabolic Axis That Impairs Lysosomal Acidification in Sepsis.
LAPTM5 Downregulation-Driven VAMP8 Phosphorylation Impairs Autophagosome-Lysosome Fusion and Aggravates Septic Acute Lung Injury.
Population-scale immune multiome atlas reveals regulatory disease mechanisms.
Immunophenotyping by Single-Cell CITE-Seq.

Curr Opin Pharmacol. 2026 Sep 15. pii: S1471-4892(26)00071-8. [Epub ahead of print]91 102675

Pharmacological control of inflammation via innate immune memory manipulation.

Chirag Sharma, Sheenam Sharma, Sumeet Gupta.

Chronic inflammation underlies several common diseases although it is inadequately managed by conventional anti-inflammatory therapies that often suppress immune responses and have long-term adverse effects. Innate immune memory encompasses trained immunity and tolerance, which provide a comprehensive framework for persistent maladaptive innate responses that drive the pathogenesis of neurodegenerative disorders, oncological, cardiometabolic, and autoimmune diseases. This Invited Mini-Review elucidates the molecular mechanisms of innate immune memory including epigenetic reprogramming of chromatin configurations, metabolic rewiring towards glycolytic or oxidative metabolic pathways and the signaling of pattern recognition receptors (PRRs) and the NLRP3 inflammasome that reinforce either enhanced or diminished innate responsiveness. We subsequently discuss pharmacological strategies for selective modulation of innate immune memory. Epigenetic modulators including histone deacetylase (HDAC) and Bromodomain and Extra- Terminal Domain (BET) inhibitors may modify aberrant chromatin programs, while metabolic modulators like metformin and statins can influence their cellular bioenergetics and inflammatory response. Direct NLRP3 inflammasome inhibitors including MCC950 and INF-39 target maladaptive NLRP3 inflammasome signaling. MCC 950 was stopped at the preclinical stage due to hepatotoxicity. Early clinical studies of trained immunity include Bacillus Calmette-Guerin (BCG) vaccine and metabolic modulation. These studies provide evidence that innate immunity programming can be altered in humans, but clinical disease modifying efficacy has not yet been established. We examine translational obstacles and provide a strategy for precision immunopharmacology that incorporates molecular biomarkers, cell-type- and disease-specific targeting, and combinatorial methods to achieve selective immune reprogramming. The development of targeted modulators for innate immune memory will require robust biomarker frameworks. Such approaches may provide more effective and durable therapeutic advances for chronic inflammatory disorders while reducing global immunosuppression.

DOI: https://doi.org/10.1016/j.coph.2026.102675
Front Biosci (Elite Ed). 2026 Sep 15. 18(3): 49594

The BCG Vaccine: Pharmacological Biotechnology and Expanding Immunological Horizons.

Yibo Liu, Melodie Pepper, Christopher Khatchadourian, Luke Sanders, Jackson Lewis, Morgan Trapp, Vishwanath Venketaraman.

  Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health challenge, particularly in low- and middle-income countries. The Bacillus Calmette-Guérin (BCG) vaccine, developed from attenuated Mycobacterium bovis (M. bovis) and introduced in 1921, is the only licensed vaccine for TB prevention. Although BCG provides strong protection against morbid forms of pediatric TB, its efficacy against adult pulmonary TB is variable. Emerging evidence indicates that BCG exerts broader immunological effects beyond TB prevention, including non-specific immune protection mediated through trained immunity. BCG-induced trained immunity induces epigenetic reprogramming of innate immune cells which enhances host defense against heterologous pathogens. Advances in pharmacological biotechnology, including recombinant BCG platforms, genetic modification, and novel delivery systems, have demonstrated improved antigen presentation, durability of immune memory, and expanded clinical utility. Beyond TB, BCG remains a cornerstone immunotherapy for non-muscle-invasive bladder cancer and shows promising immunomodulatory potential in autoimmune diseases such as type 1 diabetes and multiple sclerosis. While adverse effects are generally mild, they tend to be more pronounced in immunocompromised individuals. This review examines the historical development, biotechnological production, immunological mechanisms, and expanding therapeutic applications of BCG. We synthesized findings on strain variability, manufacturing processes, and immune responses, highlighting the induction of T helper 1 (Th1)-mediated cellular immunity through interferon gamma (IFN-γ) and interleukin-12 (IL-12), macrophage activation, and granuloma formation. Overall, BCG represents both a critical public health intervention and a model system for advancing immune-based therapies.

Keywords:  BCG; biotechnology; bladder cancer; immunotherapy; interferon gamma; multiple sclerosis; public health; trained immunity; tuberculosis

DOI:  https://doi.org/10.31083/FBE49594
Front Immunol. 2026 ;17 1937777

Trained immunity and related memory responses in lung health and disease.

Xin Sun, Dan Zhao, Lei Zhang, Jiao Liu, Ting Liu, Yao Liu, Anying Xiong, Jiahui Li, Qin Ran, Xiang He, Min Wu, Guoping Li, Junyi Wang.

  Immune memory has long been attributed to adaptive immunity, but trained immunity has broadened this view by showing that innate immune cells can retain altered function after prior stimulation and mount an enhanced response upon rechallenge. In the lung, prior local exposures can alter resident alveolar macrophages, whereas systemic immune stimulation can reprogramme bone-marrow progenitors and alter their myeloid output. Epithelial signals and alveolar-capillary barrier integrity help determine whether these changes protect tissue or promote injury. Reported metabolic pathways and chromatin features differ among cell types and experimental models; mTOR- and HIF-1α-mediated glycolysis and changes in H3K4me3 or H3K27ac can support altered innate responses. These responses may improve host defence or preserve tissue function without reducing pathogen burden, but can also contribute to barrier injury, chronic inflammation and fibrosis; in established tumours, ongoing local signals support immunosuppressive and angiogenic myeloid functions. We compare trained immunity in pulmonary myeloid cells, including trained alveolar macrophages, with other forms of alveolar macrophage memory, innate lymphoid memory-like responses and memory in pulmonary epithelial and stromal cells, and examine how these responses shape pulmonary infection, acute lung injury, chronic airway inflammation, pulmonary fibrosis and lung tumours.

Keywords:  alveolar macrophages; immunometabolism; lung diseases; pulmonary innate immunity; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1937777
Front Immunol. 2026 ;17 1911032

Heat-killed Mycobacterium tuberculosis-induced trained immunity elicits antitumor activity in PBMCs from colon cancer patients with unresponsiveness to anti-PD-1 in vitro.

Gülce Bıçakcıoğlu, Laura Bravo-Robles, Pablo Mata-Martínez, Jaime Fernández, Verónica Terrón-Arcos, Natalia González, Inés Rubio, Rebeca Abad-Moret, Sylwia Bilas, Esteban Díaz, Ramón Cantero-Cid, Eduardo López-Collazo, Carlos Del Fresno.

   Introduction: Trained immunity (TI) is a form of innate immune memory characterized by boosted innate immune responses to secondary heterologous challenges following an initial stimulus. Several inducers, including fungal β-glucan and the Bacillus Calmette-Guérin (BCG) vaccine, induce TI in human peripheral blood mononuclear cells (PBMCs). Although the potential of TI in colon cancer has been explored in murine models, its relevance in patients remains poorly understood.
Methods: Building on our previous demonstration that heat-killed Mycobacterium tuberculosis (HKMtb) induces TI, we applied a standardised training protocol to PBMCs from colon cancer patients (CC patients) and healthy volunteers (HV). Cytokine responses to heterologous stimulation were assessed using multiplex assays. To evaluate functional antitumour relevance, we performed in vitro tumour-killing assays against the SW480 colon cancer cell line, in the presence or absence of anti-PD-1 treatment, and characterised the associated cytokine milieu.
Results: HKMtb-trained PBMCs from CC patients exhibited a partially preserved TI phenotype against secondary heterologous challenges, with increased TNF and IFN-γ and reduced IL-10, comparable to HV. By contrast, IL-6 and IL-1β production were not enhanced. Notably, HKMtb-induced training significantly increased the tumour-killing capacity of PBMCs from both CC patients and HV. In CC patients, this effect was accompanied by a specific heightened production of IL-12p70 and IP-10. Furthermore, whereas the anti-PD-1 treatment alone failed to induce a significant antitumour response in PBMCs from CC patients compared with HV, HKMtb-induced TI overcame this lack of response. Of note, this was again associated with an enhanced IL-12p70 and IP-10 profile.
Conclusion: These findings provide proof of concept that HKMtb-induced TI enhances the antitumour activity of PBMCs from CC patients that are unresponsive to PD-1 blockade in vitro, supporting its potential as a promising immunomodulatory strategy in non-responsive CC patients.

Keywords:  HKMtb; anti-PD-1; colon cancer; immunotherapy; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1911032
Nature. 2026 Sep 30.

Type 2 immune history trains lung macrophages for viral disease tolerance.

Payal Damani-Yokota, Yavor Yordanov, Eduardo D Bernier, Chaitra Sreenivasaiah, Alireza Khodadadi-Jamayran, Matthias C Kugler, Stephen T Yeung, Stacey Bartlett, Valeria Mezzano, Eric Bartnicki, Mingjun Liu, Fei Chen, William C Gause, Aristotelis Tsirigos, Iannis Aifantis, Mila B Ortigoza, Bettina Nadorp, Musa M Mhlanga, Kamal M Khanna.

Severe respiratory viral disease varies widely among individuals and often reflects immunopathology rather than inadequate pathogen control, suggesting that previous immune history can prime the lungs towards disease tolerance. Here we show that nerve- and airway-associated macrophages (NAMs), a subset of interstitial macrophages, expand ephemerally after type 2 inflammation induced by Nippostrongylus brasiliensis. We therefore hypothesized that NAMs acquire epigenetically imprinted trained immunity and tested this using a heterologous challenge model in which mice that were previously infected with N. brasiliensis were challenged 4-6 weeks later with lethal H1N1 influenza. All of the N. brasiliensis-conditioned mice survived, whereas all of the unconditioned controls succumbed by days 5-6. Protection occurred without reduced viral burden or enhanced T cell responses, instead tracking with reduced immunopathology, amplified type 2 cues, increased efferocytosis and accelerated tissue repair. Using NAM-DTR mice, we show that conditioned NAMs are necessary and sufficient for protection: depletion or replacement with unconditioned NAMs abrogated survival, whereas adoptive transfer of conditioned NAMs conferred tolerance without enhancing viral clearance. Genomic analyses implicated an IL-4-STAT6-PPARγ and ARG1 chromatin program that imprints a pro-resolving and reparative NAM state driving tissue repair, type 2 immunity and efferocytosis during lethal respiratory viral infections. Finally, meta-analysis of human lung single-cell atlases from cohorts of healthy individuals and individuals with IPF and COPD revealed context-dependent NAM-like repair programs. These findings establish local trained immunity in lung-resident macrophages as a mechanism of disease tolerance and a therapeutic entry point for severe inflammatory respiratory infections.

DOI: https://doi.org/10.1038/s41586-026-11060-y
Front Immunol. 2026 ;17 1895388

Systemic immune programming in the life course of childhood asthma: a new perspective on monocyte pre-activation and trained immunity.

Ran Ma, Kaiwen Zheng, Yingqian Zhang.

   Background: Childhood asthma has traditionally been characterized as a localized chronic airway inflammatory disease, with structural remodeling viewed merely as a downstream consequence of persistent inflammation. However, clinical evidence revealing significant structural changes in the airways of children as young as 2.5 years old challenges this paradigm, suggesting that the developmental origins of asthma are established much earlier through systemic mechanisms. While local adaptive immune cascades undoubtedly amplify mucosal pathology, emerging paradigms emphasize that systemic immune reprogramming plays a foundational role in dictating early structural divergence.
Objective: To address these anomalies, this review proposes the "Systemic Priming and Homeostasis in Pediatric Asthma" (SPHPA) model to elucidate how early-life environmental exposures translate into lifelong pathological imprints.
Results: We highlight the pivotal role of the lung-bone marrow axis, where early-life triggers-such as respiratory syncytial virus or human rhinovirus infections and early-life allergens-induce trained immunity in hematopoietic stem cells (HSCs). This systemic programming pre-activates the monocyte-macrophage lineage prior to their recruitment to the lungs. Central to this process is the LYN-SHIP-1-Trib1 signaling circuit, where LYN acts as a molecular gatekeeper. We discuss the non-canonical "functional flip" of SHIP-1 from an anti-inflammatory inhibitor to a pro-inflammatory scaffold under stressful pulmonary microenvironments, fueled by metabolic reprogramming events such as proline biosynthesis and histone lactylation (H3K18la). Upon homing to the lungs, these primed monocytes undergo pathogenic alternative activation (M2-like macrophage polarization) via the SHIP-1-STAT5-Trib1 circuit, directly driving airway smooth muscle (ASM) hypertrophy, goblet cell hyperplasia, and reticular basement membrane (RBM) thickening even before the establishment of chronic mucosal inflammation.
Conclusion: Understanding systemic monocyte pre-activation provides a novel window for early intervention. Future strategies should shift from localized anti-inflammatory treatments toward resetting systemic innate immune memory using conformation-specific ligands and epigenetic modulators, potentially reversing the trajectory of severe pediatric asthma.

Keywords:  LYN-SHIP-1 signaling; airway remodeling; childhood asthma; lung-bone marrow axis; metabolic-epigenetic reprogramming; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1895388
Cardiovasc Toxicol. 2026 09 30. pii: 122. [Epub ahead of print]26(10):

Trained Immunity as a Mechanistic Bridge Between Uremic Toxins, Atherosclerosis, and Vascular Calcification in Chronic Kidney Disease.

Junyan Zhang, Yitong Chen, Sibei Tao, Minggang Zhou, Chen Li, Li Rao, Yong He, Zhongxiu Chen.

  Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD), largely driven by accelerated atherosclerosis and vascular calcification. These complications cannot be fully explained by traditional cardiovascular risk factors, indicating that CKD-specific mechanisms may contribute to persistent vascular inflammation. Trained immunity, a long-lasting functional reprogramming of innate immune cells mediated by metabolic and epigenetic remodeling, has emerged as a plausible mechanistic framework linking uremic toxin accumulation to cardiovascular injury. However, the level of evidence differs substantially across individual toxins. Indoxyl sulfate currently has the most direct evidence for classical trained immunity, whereas the evidence for p-cresyl sulfate, homocysteine, S-adenosylhomocysteine, and parts of trimethylamine N-oxide (TMAO) biology remains more indirect or hypothesis-generating. Uremic toxins may therefore act as endogenous danger signals that potentially prime monocytes, macrophages, and endothelial cells toward a hyper-inflammatory state. Because these trained phenotypes may be epigenetically durable, conventional dialysis and downstream anti-inflammatory therapies may be insufficient to reverse cardiovascular risk in CKD. This review summarizes the graded mechanistic evidence potentially linking uremic toxin-induced trained immunity to atherosclerosis and vascular calcification and discusses emerging therapeutic strategies targeting toxin burden, metabolic pathways, epigenetic remodeling, and myeloid-specific drug delivery. These approaches remain investigational in this setting, and evidence that they specifically modify uremic toxin-induced trained immunity in patients is currently lacking.

Keywords:  Atherosclerosis; Chronic kidney disease; Trained immunity; Uremic toxins; Vascular calcification

DOI:  https://doi.org/10.1007/s12012-026-10189-6
Front Immunol. 2026 ;17 1922856

Low hypoxia tolerance as a determinant of the proinflammatory phenotype: a trained immunity perspective.

Dzhuliia Dzhalilova, Nikolai Fokichev, Olga Makarova.

  The connection between hypoxia and inflammation is well established at the local level, with HIF (hypoxia-inducible factor) playing a central role, which controls both the cellular response to oxygen deficiency and immune cell functioning. The literature contains extensive data regarding the roles of the transcription factors HIF, NF-κB (a key regulator of inflammatory processes) and NRF2 (a master regulator of antioxidant defense), as well as the roles of oxidative stress level and mitochondrial functional features, in the response to oxygen deficiency and the development of inflammation. Meanwhile, at the systemic level, organisms differ according to hypoxia tolerance, which may determine differences in the functioning of these factors. Hypoxia-susceptible organisms are characterized by higher oxidative stress levels, HIF and glycolysis activity, and distinct mitochondrial functional features. These characteristics may underlie a baseline proinflammatory phenotype and are associated with innate immune cell function and the activation of trained immunity. For instance, under the systemic hypoxia, particularly during the ascent to high altitude, some individuals exhibit increased blood proinflammatory cytokine levels, which is usually connected with high-altitude disease development. A critical unsolved question is whether low hypoxia tolerance is a cause or a consequence of the systemic proinflammatory phenotype, or whether both are driven by an upstream factor, such as mitochondrial dysfunction. This review summarizes current literature data on the connection between initial organism hypoxia tolerance and the proinflammatory phenotype and examines the role of oxidative stress, mitochondria, and trained immunity in these processes.

Keywords:  high altitude; hypoxia tolerance; immune system; inflammation; mitochondria; oxidative stress; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1922856
Front Immunol. 2026 ;17 1924972

Correction: Immuno-inflammatory-metabolic interactions in cardiovascular diseases: a review from basic mechanisms to clinical translation.

Xingshun Zhu, Fengmei Zhang, Yuxin Wei, Yan Zhao, Jiawei Guo.

  [This corrects the article DOI: 10.3389/fimmu.2026.1818835.].

Keywords:  Allostatic load; cardiovascular disease; immune inflammation; lifestyle intervention; metabolic reprogramming; thrombo-inflammation; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1924972
J Alzheimers Dis. 2026 Sep 29. 13872877261472830

Immune boosting to combat Alzheimer's disease: Position statement.

Vaccines for Dementia Study Group

  The societal cost of Alzheimer's disease (AD) and related dementias is immense, but there are no effective treatments. Emerging evidence suggests that AD brain pathology may be triggered by microbial infection, and that the diagnostic protein deposits in AD brain represent an antimicrobial defense mechanism. This raises the prospect of protection against AD through stimulation of the immune system. Specifically, non-specific activation through 'trained immunity' or 'immunopotentiation' is now known to offer protection against unrelated pathogens as well as against diverse diseases. Earlier findings that vaccine recipients are at reduced risk of developing AD have now been replicated around the world. Protection has been reported for diverse types of vaccines, and the effect sizes are clinically meaningful. Although these studies are predominantly observational, and are thus at risk of confounders such as 'healthy vaccinee' bias, several studies based on 'natural experiments' avoid this bias and provide stronger evidence that vaccine administration can reduce dementia risk. Most such vaccines can be obtained for a few dollars, although others are a little more expensive. But the cost of vaccination is entirely trivial compared to the financial burden of AD. Both clinical trials of immunopotentiation in AD and further research into the underlying mechanisms will be essential. This Position Statement briefly summarizes current knowledge and recommends that immune boosting should be placed at the top of the AD public health R&D agenda.

Keywords:  Alzheimer's disease; BCG; dementia; immunopotentiation; microbe; position statement; trained immunity; vaccination

DOI:  https://doi.org/10.1177/13872877261472830
Nat Rev Immunol. 2026 Sep 29.

The effects of IFNγ on tissue physiology through structural cells.

Irah L King, Bana Jabri, Amanda W Lund, Andrew Wang.

Interferon-γ (IFNγ) is classically defined by its potent ability to enhance the antimicrobial and tumour-killing activities of innate and adaptive immune cells, establishing it as an archetypal pro-inflammatory type 1 cytokine. However, as the most conserved of the interferons throughout evolution, it is possible that IFNγ may have a more fundamental physiological role beyond these immune functions. A rapidly growing body of literature now indicates that IFNγ acts extensively on non-haematopoietic, structural cells to regulate organ function, tissue homeostasis and context-dependent immune adaptation. These findings position IFNγ as a primary coordinator of diverse defence strategies, including host resistance, disease tolerance and trained immunity. In this Perspective, we examine how IFNγ signalling in non-haematopoietic cells complements or alters its canonical immune functions and argue that defining the context-specific and cell-specific actions of IFNγ is essential to inform therapeutic approaches targeting IFNγ that enhance immunity while preserving tissue function.

DOI: https://doi.org/10.1038/s41577-026-01357-4
Adv Sci (Weinh). 2026 Sep 30. e78127

scH16S-Seq Maps Klebsiella pneumoniae-Associated Myeloid States and Reveals a CD38-NAD Immunometabolic Axis That Impairs Lysosomal Acidification in Sepsis.

Yangguang Li, Yilong Yu, Fang Qin, Shenxing Li, Xuanheng Li, Peizhao Liu, Juanhan Liu, Haiqing Liu, Songqi Jing, Jianghao Zou, Sicheng Li, Jiayang Li, Tao Zheng, Yun Zhao, Jianan Ren, Xiuwen Wu.

  Sepsis arises from heterogeneous host-cell states that influence bacterial clearance, yet single-cell transcriptomic approaches do not directly connect microbial signals with host transcriptional programs. This study introduces single-cell host-bacterial 16S co-sequencing (scH16S-seq), which couples host transcriptomes with barcode-resolved bacterial 16S-derived UMI signals to resolve bacterial signal-enriched host-cell states. Applied to Klebsiella pneumoniae (KP) sepsis, scH16S-seq mapped cell-associated bacterial 16S-derived signals to discrete CD38+ myeloid states, including Acod1+ monocyte-derived macrophages, Lyve1+ interstitial macrophages, and hypoxic neutrophils sharing inflammatory, hypoxic, and metabolically stressed programs. Increased myeloid CD38 expression is also observed across human sepsis cohorts. Mechanistically, KP induces CD38-associated NAD+depletion, mitochondrial bioenergetic failure, reduced ATP, and impaired lysosomal acidification. CD38 inhibition, NAD-related metabolic intervention, or Cd38 deficiency restores NAD homeostasis and mitochondrial function, whereas blockade of mitochondrial ATP synthesis or V-ATPase-dependent acidification attenuates lysosomal and antibacterial rescue. Lyz2-Cre-mediated Cd38 deletion improves bacterial control and sepsis outcomes in vivo. Together, scH16S-seq resolves KP 16S signal-enriched myeloid states and identifies a targetable CD38-NAD-mitochondrial-lysosomal axis linking immunometabolic dysfunction to impaired antibacterial defense in sepsis.

Keywords:  CD38; Klebsiella pneumoniae; nicotinamide; scH16S‐seq; sepsis

DOI:  https://doi.org/10.1002/advs.78127
Adv Sci (Weinh). 2026 Sep 27. e78024

LAPTM5 Downregulation-Driven VAMP8 Phosphorylation Impairs Autophagosome-Lysosome Fusion and Aggravates Septic Acute Lung Injury.

Lang Jiang, Qilan Li, Hao Liu, Xuehui Gao, Hongyu Nie, Lang Chen, Mei He, Xuefeng Li, Xiangming Fang, Jiqian Xu, Hao Zhang, Jiahong Xia, You Shang.

  Sepsis-induced acute lung injury (ALI) is a lethal inflammatory condition with limited therapeutic options. Macrophage autophagic homeostasis is essential to constrain septic ALI inflammation, though its upstream regulation remains elusive. Here, we report that lysosomal-associated protein transmembrane 5 (LAPTM5) is markedly downregulated in peripheral blood mononuclear cells (PBMCs) from septic ALI patients and alveolar macrophages (AMs) of septic mice, with its expression correlating inversely with the SOFA score. Macrophage-specific depletion of Laptm5 exacerbated mouse ALI symptoms, whereas AAV-mediated Laptm5 overexpression yielded diametrically opposite effects. Mechanistically, LPS stimulation promotes FOXB1 nuclear accumulation, which in turn represses the transcription and protein expression of LAPTM5. Furthermore, LAPTM5 acts as a molecular scaffold bridging PGAM5 and VAMP8, mediating PGAM5-dependent VAMP8 dephosphorylation to promote autophagosome-lysosome fusion and autophagic flux. This cascade clears damaged mitochondria, thereby mitigating intracellular oxidative stress and inflammation. This study defines macrophage LAPTM5 as a critical autophagy regulator that mitigates septic ALI, providing a potential avenue for future therapeutic exploration.

Keywords:  ALI; LAPTM5; autophagy; inflammation; macrophage; sepsis

DOI:  https://doi.org/10.1002/advs.78024
Nature. 2026 Sep 30.

Population-scale immune multiome atlas reveals regulatory disease mechanisms.

BioBank Japan Project

Most disease-associated genetic variants lie in non-coding regions1,2, yet mechanistic insights are limited by the lack of an empirical framework for characterizing the molecular consequences of regulatory variation. Single-cell molecular quantitative trait locus (QTL) mapping3,4 connects variants to gene regulation but lacks the power and simultaneous measurements to trace mechanisms from chromatin to expression5. Here we show that population-scale simultaneous profiling of chromatin accessibility and gene expression across immune cells reveals regulatory architectures connecting variants to disease. From paired single-nucleus assay for transposase-accessible chromatin-sequencing (snATAC-seq) and single-nucleus RNA-sequencing (snRNA-seq) analysis of 10 million peripheral blood mononuclear cells in 1,108 Finnish individuals6, we identify 51,083 cis-expression QTLs for 20,829 genes, 338,100 cis-chromatin accessibility QTLs for 210,584 peaks, 119,094 putative causal variants and 593,765 peak-gene links. Variants completing chromatin-to-expression cascades show twice the disease colocalization of chromatin-only effects, with massively parallel reporter assays7 validating 10,428 fine-mapped molecular QTLs. At evolutionarily constrained genes, we identify multilayered regulatory buffering, in which chromatin accessibility changes occur with normal effect sizes, but transmission to expression is attenuated through weaker, more numerous enhancer-gene links. This reconciles why disease variants preferentially target constrained genes despite apparent expression QTL depletion8-11. Analysis using a massively parallel reporter assay7 confirms that this buffering acts downstream of the regulatory element, with constraint operating at the chromatin-to-expression interface rather than on intrinsic cis-regulatory activity. Our atlas provides testable hypotheses for over half of immune disease associations, illustrated by cascades at autoimmune loci (TICAM1 and RHOH) and Finnish-enriched variants (TNRC18 and IL21R).

DOI: https://doi.org/10.1038/s41586-026-11078-2
Methods Mol Biol. 2027 ;3087 331-372

Immunophenotyping by Single-Cell CITE-Seq.

Wilson Dos-Santos Bele, Sandra Curras-Alonso, Fabien Delahaye.

  Single-cell transcriptomics has revolutionized our understanding of cellular heterogeneity by enabling high-resolution gene expression profiling at the individual cell level. However, traditional single-cell RNA sequencing (scRNA-seq) lacks direct protein quantification, limiting comprehensive immunophenotyping. Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) overcomes this limitation by integrating antibody-derived tag (ADT) quantification with scRNA-seq, allowing simultaneous measurement of surface protein and gene expression from the same cell. This multimodal approach enhances immune cell characterization, revealing new functional states and rare subpopulations in complex biological systems. Here, we provide a detailed protocol for performing CITE-seq, from sample preparation to sequencing and data analysis. We highlight key experimental considerations, discuss challenges related to antibody selection and batch effects, and provide troubleshooting strategies to ensure robust and reproducible results. The integration of transcriptomic and proteomic data through CITE-seq provides unparalleled insights into cellular function, with broad applications in immunology, oncology, and systems biology.

Keywords:  Antibody-derived tags; CITE-seq; Cellular heterogeneity; High-throughput sequencing; Immune cell characterization; Immunophenotyping; Multimodal profiling; Single-cell RNA sequencing; Single-cell proteomics; Transcriptomics

DOI:  https://doi.org/10.1007/978-1-0716-5607-5_17