bims-traimu 2026-04-26 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–04–26
thirteen papers selected by
Yantong Wan, Southern Medical University

The role of trained immunity in chronic non-communicable inflammatory diseases.
From Chronic Inflammation to Cancer: The Role of Trained Immunity in IBD-Associated Colorectal Carcinogenesis.
Engineered BCG selectively triggers trained immunity in tumor-associated macrophages and sensitizes glioblastoma to radiotherapy in mice.
The case for exploring innate memory in Plasmodium infection.
Helminths as architects of trained tolerance: implications for human health.
Itaconate modifications: Mechanisms and applications.
Low Density Neutrophil Heterogeneity and Spleen Tyrosine Kinase as a Therapeutic Target in Sepsis.
TREM2 sustains glucose metabolic homeostasis to drive antibacterial defense during sepsis.
Palmitic Acid Promotes Antiviral Innate Immunity via ZDHHC20-Mediated CMPK2 Palmitoylation.
Repeated intradermal lipopolysaccharide challenge responses in healthy volunteers: Implications for clinical pharmacology studies.
Revisiting the macrophage disappearance reaction.
Ligation of TLR2, but not of TLR4 or other Toll-like receptors, induces neutrophil extracellular trap formation in humans.
BCG-trained macrophages promote pan-anti-tumor activity through epigenetic rewiring of NOX2-ROS axis.

Innate Immun. 2026 Jan-Dec;32:32 17534259261446050

The role of trained immunity in chronic non-communicable inflammatory diseases.

Joseph Mucumbitsi, Jean Claude Hakizimana, Marie Gorette Kampire, Callixta Kaneza, Themistocles Bushobozi, Sophie Mukantwari, Jean Mfizi Ngaboyishema, Alex Butera, Abdullateef Isiaka Alagbonsi.

  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.

Keywords:  Epigenetic reprogramming; innate immune memory; metabolic memory; sterile inflammation; trained immunity

DOI:  https://doi.org/10.1177/17534259261446050
Med Sci (Basel). 2026 Apr 17. pii: 202. [Epub ahead of print]14(2):

From Chronic Inflammation to Cancer: The Role of Trained Immunity in IBD-Associated Colorectal Carcinogenesis.

Ferenc Sipos, Györgyi Műzes.

  Trained immunity is a concept that is currently in development and refers to the long-term functional reprogramming of innate immune cells in response to microbial or inflammatory stimuli. This process serves a dual purpose in the gastrointestinal tract, contributing to chronic inflammatory conditions like inflammatory bowel disease and maintaining host defense. The production of pro-inflammatory mediators is augmented by epigenetic and metabolic changes that are induced by the persistent activation of innate immune cells, which is triggered by microbial components and damage-associated signals. Although this increased responsiveness may initially be protective, sustained activation leads to tissue damage, epithelial barrier dysfunction, and chronic inflammation. These mechanisms are significant contributors to colorectal carcinogenesis, particularly in colitis-associated cancer. Through the activation of oncogenic signaling pathways, the establishment of a pro-tumorigenic microenvironment, and an increase in oxidative stress, trained immunity also influences tumor development. Additionally, the systemic reprogramming of hematopoietic progenitor cells has the potential to exacerbate inflammation and facilitate the progression of tumors. The identification of epigenetic and metabolic biomarkers associated with trained immunity can lead to novel diagnostic opportunities. Targeting metabolic and epigenetic pathways, as well as regulating the intestinal microbiota, is a promising therapeutic approach that could enhance the effectiveness of treatments for colorectal cancer while minimizing adverse effects on the immune system. Nevertheless, it is necessary to maintain a delicate equilibrium to suppress pathological inflammation without compromising protective immune responses. In general, trained immunity may represent a potentially relevant mechanistic link between chronic inflammation and colorectal cancer; however, its role remains context-dependent and not yet fully defined.

Keywords:  chronic inflammation; colorectal cancer; epigenetic reprogramming; inflammatory bowel disease; innate immune system; metabolic reprogramming; trained immunity; tumor microenvironment

DOI:  https://doi.org/10.3390/medsci14020202
Nat Commun. 2026 Apr 20.

Engineered BCG selectively triggers trained immunity in tumor-associated macrophages and sensitizes glioblastoma to radiotherapy in mice.

Ke Ren, Ziyang Yuan, Lei Lei, Ziyuan Xiao, Ningyi Ma, Guodong Wang, Ningyi Sun, Tai Yang, Zhiyong Chang, Liang Qin, Ying Xu, Dahai Yu, Lizhou Jia, Haishi Qiao.

Radiotherapy plays a crucial role in antitumor immunity in glioblastoma, yet its efficacy is often limited, resulting in tumor recurrence. Here, we engineer a macrophage membrane-camouflaged Bacillus Calmette-Guérin (BCG) via bioorthogonal chemistry to enhance radiotherapy against glioblastoma. This engineered BCG penetrates the blood-brain barrier, targets tumors, and alleviates hypoxia through intrinsic catalase activity, exerting antitumor effects in both murine orthotopic glioblastoma and humanized mouse models. Notably, it also initiates trained immunity in tumor-associated macrophages. Depletion and adoptive transfer of tumor-associated macrophages demonstrate that trained immunity promotes inflammatory cytokine production, reactive oxygen species release, phagocytosis and the recruitment of CD8+ T cells, ultimately amplifying immune responses to radiotherapy. Moreover, immune checkpoint blockade further augments the antitumor efficacy of engineered BCG combined with radiotherapy. Here, we show that trained immunity in tumor-associated macrophages is a promising strategy to sensitize glioblastoma to radiotherapy and improve treatment outcomes.

DOI: https://doi.org/10.1038/s41467-026-72067-7
Curr Opin Microbiol. 2026 Apr 17. pii: S1369-5274(26)00046-9. [Epub ahead of print]91 102752

The case for exploring innate memory in Plasmodium infection.

Nhi Nt Ho, Tinotenda Tongogara, Tuan M Tran, Alexis Kaushansky, Elizabeth Kk Glennon.

In highly malaria-endemic areas, individuals can receive a bite from a Plasmodium-infected mosquito daily. Yet, most studies in the laboratory only assess a single infection, and our current understanding of malaria immunity does not fully explain how recurrent infections in the field impact pathogenesis and immunity upon re-infection. A growing body of literature suggests innate immune memory, in which epigenetic reprogramming regulates the immune response to sequential infections independently of adaptive immunity, may explain some of the dynamics of recurring Plasmodium infection in endemic areas. Here, we summarize the basic concepts of innate immune memory and findings that support its role in controlling Plasmodium infection and pathogenesis. Furthermore, we postulate that innate memory in non-immune cells, which is only beginning to be described in other disease systems, may have significant consequences in the context of the complex Plasmodium lifecycle.

DOI: https://doi.org/10.1016/j.mib.2026.102752
Clin Transl Immunology. 2026 ;15(3): e70086

Helminths as architects of trained tolerance: implications for human health.

Quinn Moroz, Jorge Lucas Nascimento Souza, Neima Briggs.

  Helminths infect nearly 2 billion people worldwide and are a major cause of chronic morbidity in low-resource regions. Unlike bacterial and viral pathogens that elicit protective memory, helminths actively remodel host immunity to enable their years-long persistence and reinfection. We put forward the concept of 'trained tolerance', which describes the durable yet reversible system-wide immunological programme helminths exert on the host to promote their own survival. In humans, this altered immune set point shapes host responses to concurrent challenges, including cancer immunity, allergy, autoimmunity, coinfections and vaccine effectiveness. Here, we outline research priorities, including defining species-specific immune correlates of protection versus tolerance, integrating longitudinal cohorts and controlled human infection studies with single-cell and spatial profiling, establishing standardised biomarker panels to track immune recalibration after parasite clearance and evaluating the impact of anthelmintic treatment prior to immunisation campaigns to restore germinal centre function and durable protection.

Keywords:  adaptive and innate immunity; allergy; autoimmunity; cancer; coinfection; vaccine responsiveness

DOI:  https://doi.org/10.1002/cti2.70086
J Intensive Med. 2026 Apr;6(2): 114-127

Itaconate modifications: Mechanisms and applications.

Yingyi Yang, Rui Kang, Huiting Zhou, Daolin Tang.

  Itaconate is a mitochondrial metabolite generated from the tricarboxylic acid cycle intermediate cis-aconitate by the enzyme aconitate decarboxylase 1 (ACOD1). Beyond its metabolic role, itaconate has emerged as a critical regulator of immune and inflammatory signaling. Together with its electrophilic derivatives (e.g., 4-octyl itaconate, dimethyl itaconate), it modulates diverse cellular processes through covalent post-translational modifications. These include S-itaconation, a cysteine-directed Michael addition primarily mediated by electrophilic derivatives, and K-itaconation, a lysine-targeted, reversible acylation involving an itaconyl-CoA intermediate derived from itaconate. Such modifications influence multiple immune regulators - including Kelch-like ECH-associated protein 1 (KEAP1), stimulator of interferon response cGAMP interactor 1 (STING1), NLR family pyrin domain containing 3 (NLRP3), glutathione peroxidase 4 (GPX4), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) - thereby modulating inflammation, oxidative stress, and cell death pathways such as pyroptosis and ferroptosis. Preclinical studies demonstrate that itaconate derivatives confer therapeutic benefits in sepsis, colitis, neurodegeneration, autoimmunity, and cancer. By contrast, endogenous itaconate exhibits context-dependent effects, acting as either a pro-resolving or immunostimulatory metabolite. This review integrates current insights into itaconate biosynthesis, molecular targets, post-translational modifications, detection technologies, and translational potential, underscoring its emerging role as a master regulator of immunometabolic reprogramming and inflammatory control.

Keywords:  ACOD1; Disease pathogenesis; Inflammation; Itaconate; Itaconation

DOI:  https://doi.org/10.1016/j.jointm.2025.10.002
JCI Insight. 2026 Apr 21. pii: e201057. [Epub ahead of print]

Low Density Neutrophil Heterogeneity and Spleen Tyrosine Kinase as a Therapeutic Target in Sepsis.

Heather L Teague, Lauren Knabe, Raquel S Da Cruz, Xianglan Yao, Kiana C Allen, Trenton Williams, Cumhur Y Demirkale, Merte Woldehanna, Ernest Evans, Amir Hobson, Jared D Wilkinson, Steven D Nathan, Christopher S King, Jeffrey R Strich.

  Sepsis is a leading cause of death for which host-directed therapies are urgently needed. We performed high-dimensional flow cytometry, measurement of soluble biomarkers, and lipopolysaccharide (LPS) stimulation of neutrophils to characterize neutrophil heterogeneity and function in patients with sepsis. We observed that in sepsis patients, low-density neutrophils (LDNs) are elevated and phenotypically diverse populations of innate immune cells with varying degrees of maturity and myeloperoxidase expression. Spleen tyrosine kinase (SYK) expression was found to be higher in whole blood neutrophils and LDNs of sepsis patients compared to healthy donors. Importantly, SYK+LDNs associated with increased levels of intracellular myeloperoxidase (MPO) and soluble biomarkers. Furthermore, SYK+LDNs correlated with clinical outcomes of sepsis disease severity including sequential organ failure assessment (SOFA) score, mechanical ventilation, and vasopressors. Functionally, the SYK inhibitor R406 suppressed changes in neutrophil features of activation from normal-density neutrophils and LDNs including the SYK+ and SYK- neutrophil subsets and MPO release from LDNs following LPS stimulation of sepsis neutrophils. Combined, these results establish LDNs as a heterogenous population of neutrophils that express high levels of SYK and support SYK inhibition as a novel therapeutic target aimed at suppressing overactive neutrophils in sepsis.

Keywords:  Immunology; Inflammation; Neutrophils

DOI:  https://doi.org/10.1172/jci.insight.201057
iScience. 2026 Apr 17. 29(4): 115415

TREM2 sustains glucose metabolic homeostasis to drive antibacterial defense during sepsis.

ZeHua Wu, XueKe Wang, YiChao Ren, LiHua Shen, YiHang Pan, Yan Zhang, JiaQian Fan, Qiang Shu, Xiangming Fang, QiXing Chen.

  Metabolic disturbances, particularly glucose imbalances, are common in sepsis and are strongly associated with increased mortality. However, the mechanisms underlying glucose dyshomeostasis remain poorly understood. Here, we revealed the role of triggering receptor expressed on myeloid cells 2 (TREM2) in regulating glucose metabolism during sepsis. Macrophage-specific TREM2 deficiency significantly increased the level of abdominal IL-1β, which is predominantly released by pyroptotic peritoneal macrophages. IL-1β then acts on IL-1R1 receptors on pancreatic islet β-cells, promoting insulin release and inducing hypoglycemia. Transfusing TREM2-overexpressing macrophages and administering glucose solutions can restore glucose homeostasis and improve sepsis outcomes in mice. In summary, our study reveals a mechanism by which TREM2 orchestrates glucose metabolism during sepsis and highlights the potential of TREM2 as a therapeutic target for sepsis.

Keywords:  immunology; microbiology; molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2026.115415
Adv Sci (Weinh). 2026 Apr 21. e75209

Palmitic Acid Promotes Antiviral Innate Immunity via ZDHHC20-Mediated CMPK2 Palmitoylation.

Yujia Wang, Zenghui Cui, Yunkai Zhang, Zhiqing Li, Xuetao Cao.

  While immunometabolic crosstalk is critical for antiviral defence, the regulation of this process, particularly through post-translational modifications, remains incompletely understood. How specific metabolites and associated modifications orchestrate antiviral immunity remains unclear. By screening a metabolic chemical library, we identify palmitic acid (PA) as an activator of antiviral immunity in macrophages. PA induces UMP-CMP kinase 2 (CMPK2) palmitoylation, maintaining its mitochondrial localization. CMPK2 is vital for the production of 3'-deoxy-3',4',-didehydrocytidine triphosphate (ddhCTP) and the stabilization of mitochondrial antiviral signaling protein (MAVS), both of which are crucial for defence against RNA viruses. Cmpk2 deficiency impairs IFN-I production and increases viral replication. Furthermore, the palmitoyl transferase ZDHHC20 catalyzes CMPK2 palmitoylation at cysteines 137 and 153, which are depalmitoylated by the thioesterase PPT1. PPT1 deficiency restores CMPK2 palmitoylation and antiviral immunity. Both a palm oil-rich diet and the in vivo administration of the PPT1 inhibitor DC661 increase IFN-I production. Therefore, the PA-ZDHHC20-CMPK2-PPT1 axis enhances the antiviral response, indicating that targeting PPT1 has the potential to treat RNA virus infections.

Keywords:  CMPK2; IFN‐I; immunometabolism; innate immune response; palmitoylation

DOI:  https://doi.org/10.1002/advs.75209
Br J Clin Pharmacol. 2026 Apr 22.

Repeated intradermal lipopolysaccharide challenge responses in healthy volunteers: Implications for clinical pharmacology studies.

Alexandra A J Sillé, Juliette A van den Noort, Iva Lelios, Diana R Pereira, Marzia A Scelsi, Erica S Klaassen, Philipp Schoenenberger, Naomi B Klarenbeek, Pierre-Eric Juif, Pascal Espie, Manon A A Jansen, Matthijs Moerland, Richard W D Welford.

   AIM: Intradermal application of lipopolysaccharide (LPS), a Toll-like receptor 4 agonist, induces a local inflammatory response and is used as a human challenge model to evaluate the pharmacodynamics of investigational medicinal products. While currently applied in a single, parallel-group setting, alternative within-subject designs involving repeated LPS challenges at different skin sites and spaced across multiple timepoints would enable within-subject comparisons, potentially reducing inter-individual variability in pharmacodynamic assessments. We aimed to determine whether intradermal LPS challenges at different sites on the back, with 14-day intervals, would be an optimal design for clinical pharmacology studies.
METHODS: Eight healthy volunteers received seven 5-ng intradermal LPS injections: six on the back on Days 1, 15 and 29 (two per day) and one on the volar forearm on Day 1. Local inflammation was assessed via non-invasive imaging (skin perfusion and erythema) and suction blister fluid (cytokines and leukocytes) at 10- and 24 h post-injection. Systemic responses were evaluated through blood cytokine and leukocyte levels.
RESULTS: Repeated intradermal LPS challenges were well tolerated. Skin perfusion, erythema and local cytokine and chemokine levels were similar across challenges. However, on subsequent challenge days there were shifts in vascular responses and counts of classical monocyte, and other leukocytes in blister fluid were reduced at 10 h on Day 15 compared to Day 1.
CONCLUSION: The results indicate that following Day 1 intradermal LPS challenges, a subtle immune adaptation may occur, potentially limiting the model's reliability for cellular endpoint-focused within-subject pharmacological investigations.

Keywords:  drug development; endotoxin; healthy volunteers; immune adaptation; inflammatory model; innate immunity; intradermal LPS

DOI:  https://doi.org/10.1002/bcp.70572
Trends Immunol. 2026 Apr 21. pii: S1471-4906(26)00072-4. [Epub ahead of print]

Revisiting the macrophage disappearance reaction.

Zhuangzhuang Liu, Charlotte L Scott.

  The macrophage disappearance reaction (MDR) was originally proposed to explain the loss of peritoneal macrophages in inflammation but has since been extended across tissues and diseases. MDR involves multiple processes, including cell death, differentiation, loss of identity, and the formation of aggregates rendering the cells difficult to isolate. This spectrum of modalities, coupled with our increased understanding of how the microenvironment shapes macrophage identities, highlights the need to reassess MDR within the framework of modern macrophage biology. We postulate that rethinking MDR in the context of the tissue niche offers insights into macrophage dynamics and demonstrates that macrophage loss is not a passive outcome of inflammation but rather an active process shaping immune networks, tissue responses, and ultimately organ function.

Keywords:  macrophage disappearance reaction; macrophage heterogeneity; macrophage identity; plasticity; resident and recruited macrophages; tissue niche

DOI:  https://doi.org/10.1016/j.it.2026.03.011
J Immunol. 2026 Apr 15. pii: vkag079. [Epub ahead of print]215(4):

Ligation of TLR2, but not of TLR4 or other Toll-like receptors, induces neutrophil extracellular trap formation in humans.

Hugo Tshivuadi Mosha, Vanessa de Carvalho Oliveira, Olga Tatsiy, Abdelaziz Amrani, Patrick P McDonald.

  Neutrophils are usually the first cells recruited to sites of injury or infection where they mount antimicrobial responses, including the release of neutrophil extracellular traps (NETs). Toll-like receptors play a major role in the recognition of pathogen-associated molecular patterns and all but TLR3 are expressed in neutrophils. Numerous studies have reported that LPS can trigger NET formation; in nearly all cases, however, the ligand was not purified enough to target only TLR4. There also exist isolated reports on the ability of other TLRs to induce NETs. Here we comprehensively revisited the issue of TLR-elicited NET generation using ultrapure ligands. We now report that in humans, NETs are only induced following TLR2 ligation whereas engagement of other TLRs is ineffective (despite eliciting other cellular responses). A widely used (but incompletely purified) LPS preparation potently induced NET generation by binding TLR4, TLR2, and possibly other receptors, confirming previous data from other groups. By contrast, murine NETs are formed upon either TLR2 or TLR4 engagement. Mechanistically, TLR2-triggered NET formation is controlled by signaling kinases that are mobilized early (TAK1, MEK, p38 MAPK) or belatedly (Syk, PI3K, PLCγ2); acts through endogenous factors that bind the RAGE receptor; and involves PAD4 as well as endogenous reactive oxygen species, whereas elastase is dispensable. Conversely, we provide evidence that TLR4 negatively regulates NET formation in humans. Our study shows the surprisingly restricted repertoire of TLRs that can elicit NET formation in humans, and further illustrates how this emblematic neutrophil response differs between humans and rodents.

Keywords:  PAD4; Toll-like receptors; extracellular traps; intracellular signaling; reactive oxygen species

DOI:  https://doi.org/10.1093/jimmun/vkag079
J Exp Clin Cancer Res. 2026 Apr 24.

BCG-trained macrophages promote pan-anti-tumor activity through epigenetic rewiring of NOX2-ROS axis.

Rui-Ming Sun, Yi Yang, Yang-Dian Lai, Hai-Ning Wang, Xiao-Xu Yang, Ping Ji, Ying-Ying Chen, Zhao-Yuan Liu, Florent Ginhoux, Xiao-Yong Fan, Huang-Qi Duan, Hai-Bo Shen, Dan Ye, Shun Lu, Ying Wang, Zi-Ming Li.



Keywords:  BCG-trained immunity; Epigenetic reprogramming; NADPH oxidase; Reactive oxygen species (ROS); Tumor infiltrating macrophages

DOI:  https://doi.org/10.1186/s13046-026-03708-4