bims-traimu 2026-06-14 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–06–14
eleven papers selected by
Yantong Wan, Southern Medical University

Chitin and its derivative chitosan differently activate porcine innate immune cells.
Airway epithelial dysfunction in asthma pathogenesis: epigenetic mechanisms, inflammatory crosstalk, and therapeutic opportunities.
Guardian of two galaxies: Senescence-associated immune cells control disease tolerance and aging.
Sleep interruption aggravates sepsis by rewiring the macrophage immune response.
Loss of erythrocyte sialic acid in sepsis disrupts inhibitory Siglec interactions, driving neutrophil hyperactivation and NET outspread.
Met-Vision reveals coexisting energetic states in tissue macrophages redistributed by inflammation.
Hormetic fasting extends Caenorhabditis elegans lifespan via H3K27 acetylation of lipid catabolism and antioxidant genes.
Lactate acts as a metabolic brake on inflammation by repressing NLRP3 transcription via NF-κB inhibition.
β-Hydroxybutyric acid impairs host antimicrobial defense by targeting the CEACAM1-NADPH-ROS axis to disrupt macrophage bactericidal activity.
Reframing sepsis through resistance, disease tolerance and damage: a clinically meaningful conceptual shift?
Human vaccine responses regulated by parallel cytokine pathways.

Mol Immunol. 2026 Jun 09. pii: S0161-5890(26)00134-3. [Epub ahead of print]196 44-54

Chitin and its derivative chitosan differently activate porcine innate immune cells.

Nidhal Guendouz, Bert Devriendt.

  In livestock species such as pigs, antibiotics are frequently used during weaning, a period of increased susceptibility to infections. However, the emergence and spread of antimicrobial resistance necessitate alternative strategies to improve animal health. Immune potentiating polysaccharides, including chitin, chitosan, and their derivatives, show promise as functional feed ingredients, yet their direct effects on porcine innate immune cells remain unclear. Here, ex vivo porcine primary neutrophils, monocytes, and monocyte-derived macrophages were used to assess the immunomodulatory properties of structurally distinct chitin-based polymers. In peripheral blood mononuclear cells, neither chitin nor chitosan induced significant secretion of IL-1β, TNF-α, or IL-6, suggesting that only specific subpopulations mediate these effects. Following fractionation, cytokine production was restricted to the CD14⁺ monocyte compartment, where high concentrations of chitosan elicited strong pro-inflammatory responses. To further investigate innate immune programming, trained immunity assays were performed. In monocytes, chitin did not induce training or tolerance, whereas low-molecular-weight, highly deacetylated chitosan promoted a trained phenotype, evidenced by enhanced cytokine production upon lipopolysaccharide restimulation. In contrast, in monocyte-derived macrophages, chitin pretreatment induced a tolerance-like phenotype, characterized by reduced cytokine responses following subsequent stimulation, while chitosan had no significant effect. These findings demonstrate that structural differences in chitin-based polymers determine the magnitude and direction of innate immune responses, supporting their targeted use as functional immunomodulators to enhance health and resilience in livestock.

Keywords:  Chitin; Chitosan; Cytokine secretion; Macrophages; Monocytes; Trained innate immunity

DOI:  https://doi.org/10.1016/j.molimm.2026.06.002
Front Allergy. 2026 ;7 1839974

Airway epithelial dysfunction in asthma pathogenesis: epigenetic mechanisms, inflammatory crosstalk, and therapeutic opportunities.

Bingxue Zhang, Guihua Song, Mengmeng Sun, Yan Zhang, Mingyue Ren.

  Asthma affects over 260 million people worldwide and remains incompletely explained by the traditional T cell-centric immunological model, which offers incomplete mechanistic explanations for disease chronicity, recurrence during clinical remission, and the poor treatment response observed in T2-low phenotypes. Emerging evidence positions the airway epithelium as a central organizer of asthma pathogenesis rather than a passive barrier. This review proposes a unifying framework in which airway epithelial dysfunction and epigenetic memory drive the persistent and relapse-prone nature of asthmatic airways. We first examine how structural barrier defects-including tight junction dysfunction mediated by claudin-18 and E-cadherin loss-initiate and amplify type 2 inflammation through alarmin release (TSLP, IL-33, IL-25) and ILC2 activation. We then review how environmental exposures and inflammatory signals, particularly IL-13, induce durable epigenetic reprogramming of airway epithelial cells through DNA methylation, histone modifications, and non-coding RNAs, establishing molecular imprints that persist beyond the resolution of acute inflammation. Special attention is given to basal progenitor cells as repositories of allergic epigenetic memory, and to the concept of trained innate immunity as a mechanism underlying chronic airway hyperresponsiveness. We further contrast the epigenetic landscapes of T2-high and T2-low asthma, identifying the latter as a critical unmet need for biomarker and therapeutic development. Finally, we discuss translational opportunities, including HDAC inhibitors, miRNA-based therapies, and the potential of anti-alarmin biologics (tezepelumab, itepekimab) and downstream cytokine receptor antagonists (dupilumab) to partially restore epithelial function and progenitor states. We acknowledge that, given current data availability, this review is weighted toward T2-high (eosinophilic) endotypes; mechanistic characterization of T2-low asthma remains an important area for future investigation. This framework reconceptualizes asthma not only as a disorder of dysregulated immunity, but as a disease of maladaptively reprogrammed barrier tissue, with important implications for disease prevention, endotype-specific treatment, and the goal of achieving true biological remission.

Keywords:  DNA methylation; airway epithelial barrier; asthma; biologics; epigenetic memory; epithelial remodeling; trained immunity; type 2 inflammation

DOI:  https://doi.org/10.3389/falgy.2026.1839974
Immunity. 2026 Jun 09. pii: S1074-7613(26)00217-7. [Epub ahead of print]59(6): 1481-1483

Guardian of two galaxies: Senescence-associated immune cells control disease tolerance and aging.

Wolfgang Vivas, Sebastian Weis.

Preservation of host fitness is a common feature of longevity and immunity to infection. In this issue of Immunity, Triana-Martinez et al. reveal that p16High senescence-associated immune cells promote disease tolerance and healthy aging. Mechanistically, this is dependent on Toll-like receptor 7 (TLR7) and stimulator of interferon genes (STING) innate immune signaling controlling adenosine concentrations.

DOI: https://doi.org/10.1016/j.immuni.2026.05.006
J Immunol. 2026 06 07. pii: vkag130. [Epub ahead of print]215(6):

Sleep interruption aggravates sepsis by rewiring the macrophage immune response.

Jacob A Allen, Taniah Ali, Daniela Rodarte, Luiz Garcia, Mark E Murray, Mackenzie Morgan, Chidozie Ugochukwu, Anjali Patel, Sydney Ligon, Alok K Dwivedi, Wendy E Walker.

  Sepsis is the leading cause of death in hospitals and is very common in intensive care units (ICUs). Sleep is frequently interrupted in the hospital setting, especially within the ICU. Patients who sleep poorly have worse outcomes, such as increased mortality and longer hospital stays; however, the molecular basis remains poorly understood. In this study, we utilized a mouse model to investigate the impact of sleep interruption on subsequent sepsis. We found that sleep interruption aggravated sepsis, as evidenced by higher mortality rates (88% in mice with interrupted sleep vs 57% in mice with normal sleep; P = 0.0045) and worse disease scores. This effect occurred in both females and males. Sleep interruption increased circulating T cells and CD8+ T-cell activation during sepsis. Sleep interruption also increased the levels of serum cytokines (including IL-23 before sepsis was induced, and IL-6, TNF-α, MCP-1, and IL-10 after sepsis), and amplified macrophage cytokine production ex vivo. These ex vivo effects were largely dependent on Toll-like receptor 2 (TLR2), and sleep interruption no longer exacerbated sepsis in TLR2 knockout mice. Interestingly, the effects of sleep interruption on sepsis were reversed by 48 hours of recovery sleep, consistent with a mechanism involving altered gene expression rather than epigenetic changes. RNA sequencing identified 680 genes that were significantly up- or downregulated in macrophages from animals subject to sleep interruption, including multiple genes related to pathogen defense and cytokine signaling. Our study confirms that good sleep is essential to maximize sepsis survival and provides insight into the molecular basis whereby poor sleep alters immune function.

Keywords:  macrophage; mouse; sepsis; sleep; transcriptome

DOI:  https://doi.org/10.1093/jimmun/vkag130
Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2536989123

Loss of erythrocyte sialic acid in sepsis disrupts inhibitory Siglec interactions, driving neutrophil hyperactivation and NET outspread.

Anna Such, Weronika Ortmann, Gabriela Burczyk, Jacek Czepiel, Monika Bociaga-Jasik, Paweł Link-Lenczowski, Elzbieta Kolaczkowska.

  Systemic inflammation is accompanied by overwhelming neutrophil activation, resulting in extensive formation of neutrophil extracellular traps (NETs). Although NETs are beneficial for pathogen entrapment, they become detrimental; therefore, their endogenous regulation is pivotal for survival. In this context, the observation that healthy individuals' red blood cells (RBCs) can inhibit NET formation induced by lipopolysaccharide (LPS)-primed neutrophils is noteworthy. However, during systemic inflammation, NET formation in the vasculature is robust despite constant neutrophil exposure to RBCs. Herein, we reveal that for RBCs and neutrophils from septic individuals, but not from those with local inflammation, interactions cease and NET inhibition is abolished. This is observed even if only one cell type originates from an inflamed individual, and occurs in both human and murine cells. Moreover, 6 to 10 d post-sepsis induction (mice) or diagnosis (humans), during the resolution of inflammation, interactions are restored and hence fail during the critical stages of inflammation. Mechanistically, this is not due to passive LPS absorption by RBCs, which would limit its availability for neutrophils. In contrast, the cessation of NET inhibition is due to inflammation-induced RBC desialylation (removal of α2,3-linked sialic acids) and decreased expression of inhibitory Siglec-E/9 and -G, but not Siglec-F/5, on neutrophils. Accordingly, concurrent addition of exogenous polysialic acid (PolySia) and pharmacologically controlled accumulation of Siglec molecules on neutrophils preserves the ability of erythrocytes to inhibit PAD4-dependent NET formation upon interaction with neutrophils of endotoxemic mice. These findings open avenues for clinically controlling NET formation during systemic inflammation, given the abundance of erythrocytes in the blood.

Keywords:  erythrocytes; neutrophil extracellular traps (NETs); neutrophils; sepsis; siglec receptors

DOI:  https://doi.org/10.1073/pnas.2536989123
J Cell Biol. 2026 Aug 03. pii: e202603170. [Epub ahead of print]225(8):

Met-Vision reveals coexisting energetic states in tissue macrophages redistributed by inflammation.

Adriana Lecourieux, Margot Bardou, Zacarias Garcia, Philippe Bousso.

The function of tissue-associated macrophages is tightly linked to their energy metabolism. Yet, the diversity of macrophage metabolic profiles coexisting in tissues at homeostasis or during immune challenges is incompletely understood. Here, we introduce Met-Vision, an imaging-based pipeline for single-cell functional profiling and classification of energy metabolism. Across multiple tissue contexts, we identified that macrophages do not adopt a uniform metabolic profile but typically coexist in four discrete metabolic states with distinct dependence on OXPHOS and metabolic plasticity. Inflammation reconfigured the distribution of macrophage metabolic profiles that remained heterogeneous. Notably, inflammation-derived nitric oxide finely tuned the distribution of macrophage energetic states. These findings challenge the view of homogeneous metabolic activation and reveal a layer of metabolic diversity in tissue at steady state and during inflammation. The ability to stratify macrophage energy metabolic profiles with Met-Vision should help guide the development of metabolism-targeted therapies for inflammatory diseases, cancer, and metabolic disorders.

DOI: https://doi.org/10.1083/jcb.202603170
Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00596-6. [Epub ahead of print]45(6): 117518

Hormetic fasting extends Caenorhabditis elegans lifespan via H3K27 acetylation of lipid catabolism and antioxidant genes.

Yifei Zhou, Fasih M Ahsan, Sainan Li, Mengjiao Song, Jen F Rotti, Armen Yerevanian, Yidong Shen, Alexander A Soukas.

  Exposure to low levels of environmental challenges, known as hormetic stress, fosters subsequent stress resistance and promotes healthy aging in later life. However, specific mechanisms governing transcriptional reprogramming upon hormetic nutrient stress remain elusive. Here, we identify histone H3 lysine 27 acetylation (H3K27ac) as a crucial driver of transcriptomic adaptation to hormetic fasting. Beyond its immediate function of enhancing lipid catabolism for alternative energy sources, stress-induced H3K27ac activates lifelong antioxidant defenses, thereby reducing reactive oxygen species (ROS) produced by stress-induced fatty acid oxidation and their accumulation during aging. Induced H3K27ac at metabolic genes, mediated by the pioneer factor PHA-4/FOXA, the cooperating transcription factor NHR-49/HNF4, and the nucleoporin 50 (NPP-16/NUP50), is crucial for lifespan extension under hormetic nutrient stress in Caenorhabditis elegans. Our findings establish H3K27ac as a key transcriptional switch bridging nutrient status with transcriptomic reprogramming, underpinning the longevity of hormetic fasting through orchestrating lipid catabolism and antioxidant defenses.

Keywords:  CP: Metabolism; CP: Molecular biology; aging; antioxidant defense; epigenetic modification; fasting; histone acetylation; longevity; metabolic rewiring; nuclear pore complex; nutrient stress

DOI:  https://doi.org/10.1016/j.celrep.2026.117518
Inflamm Res. 2026 Jun 11. pii: 137. [Epub ahead of print]75(1):

Lactate acts as a metabolic brake on inflammation by repressing NLRP3 transcription via NF-κB inhibition.

Hsin-An Lin, Hsin-Chung Lin, Chih-Yung Chiou, Hao-Hsuan Peng, Yu-Jen Chen, Bo-Ying Bao, Kuen-Jou Tsai, Chao-Feng Lin, Chieh-Tien Shih, Sheng-I Hu, Kuo-Yang Huang, Lih-Chyang Chen.

   OBJECTIVE: Activation of the NLRP3 inflammasomes couples glycolytic metabolism to IL-1β-driven inflammation, but how pathologically elevated lactate feeds back on this pathway is unclear.
METHODS: Using real-time bioenergetic Seahorse XF analysis, epigenetic profiling, and molecular signaling assays, we investigated the regulatory role of lactate in mouse bone marrow-derived macrophages (BMDMs) and human THP-1-derived macrophages.
RESULTS: Pathophysiological concentrations of lactate suppressed ASC speck formation, caspase-1 activation, and IL-1β secretion induced by ATP, nigericin, or monosodium urate crystals. This inhibition was associated with a reversible downregulation of NLRP3 expression, whereas ASC, pro-caspase-1, and pro-IL-1β levels remained unaffected. Mechanistically, this suppressive effect was independent of the GPR81 receptor and reactive oxygen species (ROS). Instead, lactate utilized the monocarboxylate transporter (MCT) axis to fundamentally reprogram cellular metabolism, leading to the coordinated suppression of aerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). The resulting decline in cellular ATP levels impaired ATP-dependent NF-κB p65 phosphorylation and subsequent NLRP3 promoter activity. Notably, while lactate globally increased histone lactylation and acetylation-including localized enrichment at the NLRP3 promoter-these epigenetic shifts were insufficient to overcome the metabolic-driven repression of NF-κB-dependent transcription.
CONCLUSION: Our findings identify lactate as a metabolic negative-feedback signal that restrains NLRP3 transcriptional priming by disrupting metabolic fitness. This study clarifies how the lactate-MCT-ATP- NF-κB axis serves as a critical metabolic checkpoint to limit inflammasome-driven inflammation in metabolically stressed microenvironments.

Keywords:  GPR81; Lactate; Lactylation; NF-κB; NLRP3 inflammasome

DOI:  https://doi.org/10.1007/s00011-026-02290-x
Biochem Pharmacol. 2026 Jun 09. pii: S0006-2952(26)00488-0. [Epub ahead of print] 118152

β-Hydroxybutyric acid impairs host antimicrobial defense by targeting the CEACAM1-NADPH-ROS axis to disrupt macrophage bactericidal activity.

Tao Zhong, Ke Deng, Zishan Peng, Jiamin Li, Shuntian Lei, Mingxia Li, Sainan Chen, Jing Cai, Jianbin Guan, Ping Chang, Jingjing Yang, Dongping Li, Xingxing Liu, Zhanguo Liu.

  During bacterial infections, the immune function of macrophages in the host is crucial for eliminating bacteria. Metabolic disturbances can directly interfere with the normal function of host immune cells. However, it is unknown whether β-hydroxybutyric acid (BHBA), an important nutrient metabolite in humans, affects the bactericidal capacity of macrophages and the overall bacterial load in the infected host. Our clinical data show that circulating BHBA levels are higher in septic patients upon admission and positively correlate with increased infection-related parameters, such as procalcitonin (PCT) and high-sensitivity C-reactive protein (hsCRP). A similar clinical phenomenon was observed in mice suffering from bacterial peritonitis. Further, animal and cell experiments confirmed that BHBA stimulation could impair the antibacterial defense response of hosts by disrupting the bactericidal activity of macrophages. Interestingly, BHBA could disrupt the nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species (ROS)-mediated bactericidal activity of macrophages by binding to the membrane protein carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1), ultimately affecting the bacterial load in the host. In conclusion, we identify BHBA as an endogenous negative pharmacological ligand that directly targets CEACAM1 as a macrophage druggable receptor, thereby disrupting the NADPH-ROS bactericidal axis. This BHBA-CEACAM1-NADPH-ROS pharmacological cascade impairs host antimicrobial defense, providing a biochemically tractable target for the development of novel anti‑infective therapies.

Keywords:  Bacterial infection; Bactericidal activity; CEACAM1; Macrophage; Reactive oxygen species; β-Hydroxybutyric acid

DOI:  https://doi.org/10.1016/j.bcp.2026.118152
Intensive Care Med. 2026 Jun 11.

Reframing sepsis through resistance, disease tolerance and damage: a clinically meaningful conceptual shift?

Bruno Evrard, Evangelos Giamarellos-Bourboulis, Antoine Roquilly.

DOI: https://doi.org/10.1007/s00134-026-08517-z
Nat Immunol. 2026 Jun 12.

Human vaccine responses regulated by parallel cytokine pathways.

Guangbo Chen, Jing Guo, John Heath, Tyler R Prestwood, Woo Joo Kwon, Ashley R Smith, Tran T Nguyen, Karan R Kathuria, Elsa Sola, AbuBakr Sangare, Vamsee Mallajosyula, Ryan Furuichi Fong, Azam Mohsin, Lei Chen, Oviya Siva, Cindy Padilla, Mingdian Tan, Cornelia L Dekker, Philip Grant, Ying Lu, Harry B Greenberg, William H Robinson, Catherine Blish, Shai S Shen-Orr, Ahmad Salehi, Holden T Maecker, Purvesh Khatri, Paul J Utz, Yueh-Hsiu Chien, Mark M Davis.

Human vaccine responses vary widely, but the determinants remain incompletely defined. Here we analyzed 66 cytokines across four inactivated influenza vaccine (IIV) cohorts over five seasons (n = 581) and identified baseline serum interleukin (IL)-18 and interferon (IFN)-β as correlates of day 28 antibody responses. To test causality, we evaluated 19 cytokines in human tonsil and spleen organoids and found that type I IFNs, IL-21 and IL-12, but not IL-18 or IFNγ, enhanced antibody production. The addition of IFNβ to IIV recapitulated key features of the live-vaccine cytokine program. IL-12 and IL-21 defined a parallel pathway independent of type I IFNs, with IL-12 inducing IL-21 in humans, unlike in mice. Delivery of IL-21 or IFNβ via mRNA lipid nanoparticles in vivo promoted long-lived plasma cell formation. Together, these findings define parallel pathways that regulate vaccine immunity. Our approach unites high-throughput organoid testing and human cohort studies, establishing a human-centric platform to identify adjuvant candidates.

DOI: https://doi.org/10.1038/s41590-026-02547-x