bims-traimu 2025-06-08 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–06–08
ten papers selected by
Yantong Wan, Southern Medical University

Innate immune memory in macrophage differentiation and cardiovascular diseases.
Arginine metabolism supports metabolic reprogramming in trained immunity.
Immune mechanisms mediating the heterologous effects of BCG vaccination: a systematic review.
Long-term Reprogramming and Altered Ontogeny of Classical Monocytes Mediates Enhanced Lung Injury in Sepsis Survivor Mice.
Maladaptive Trained Immunity of Adipose Tissue Macrophages Unraveling the Links to Obesity, T2DM, and Beyond.
Branched-chain ketoacid antioxidants mediate disease tolerance to sepsis.
Lipid droplet-enriched luminogens enable adoptive macrophage transfer for treatment of bacterial sepsis.
Hepatic Nuclear Factor Erythroid 2 Related Factor 1 Activity Promotes Host Defense in Endotoxemia and Bacterial Sepsis.
Panose prevents acute-on-chronic liver failure by reducing bacterial infection in mice.
PGK1 phosphorylates NLRP3 and mediates inflammasome activation independent of its glycolytic activity.

Inflamm Regen. 2025 Jun 03. 45(1): 17

Innate immune memory in macrophage differentiation and cardiovascular diseases.

Yukiteru Nakayama, Katsuhito Fujiu.

  Innate immune memory (trained immunity) refers to the ability of innate immune cells, such as monocytes and macrophages, to retain a long-term imprint of a prior stimulus through epigenetic and metabolic adaptations, enabling amplified responses upon restimulation. Recent studies have classified innate immune memory into central and peripheral types. Central innate immune memory originates in hematopoietic stem cells (HSCs) within the bone marrow, where epigenetic reprogramming generates a sustained inflammatory bias, contributing to chronic diseases such as atherosclerosis, heart failure, and stroke. Peripheral innate immune memory occurs in monocytes or macrophages that acquire heightened responsiveness after repeated exposure to stimuli in peripheral tissues. This review explores the mechanisms underlying both central and peripheral innate immune memory, their roles in chronic inflammatory diseases, focusing on cardiovascular diseases, and potential strategies to target innate immune memory for therapeutic purposes. Advancing the understanding of these processes could facilitate the development of novel approaches to control inflammatory diseases and immune-related disorders.

Keywords:  Central innate immune memory; Heart failure; Macrophage; Peripheral innate immune memory

DOI:  https://doi.org/10.1186/s41232-025-00382-5
J Leukoc Biol. 2025 Jun 04. pii: qiaf080. [Epub ahead of print]

Arginine metabolism supports metabolic reprogramming in trained immunity.

Laura M Merlo Pich, Athanasios Ziogas, Anaisa V Ferreira, Nicholas Sumpter, Andrei Sarlea, Sarantos Kostidis, Leo A B Joosten, Mihai G Netea.

  Trained immunity, also termed innate immune memory, is supported by metabolic rewiring of innate immune cells, altering their bioenergetic profile and ultimately their functions. While amino acids such as arginine are known to possess immunomodulatory properties, their role in trained immunity remains largely unexplored. Primary human monocytes were trained with β-glucan in a medium enriched with or deprived of arginine or supplemented with an arginase inhibitor. After a resting period, trained cells were restimulated with LPS. Arginine deprivation or arginase inhibition during β-glucan-training impaired the amplification of IL-6 and TNF cytokine response to LPS, while they did not affect the cells' phagocytotic capacity. Arginine deprivation also significantly reduced the oxygen consumption rate of trained cells, without affecting glycolysis. Genetic studies revealed polymorphisms near genes coding for arginine-metabolizing enzymes modulated induction of trained immunity, highlighting the role of arginine-derived metabolites in trained immunity. These findings demonstrate that arginine and its metabolites are involved in the induction of trained immunity. Understanding metabolic mechanisms involved in trained immunity could provide insights into new therapeutic strategies for harnessing arginine deprivation to modulate inflammatory disorders.

Keywords:  arginine; metabolism; monocytes; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiaf080
Front Immunol. 2025 ;16 1567111

Immune mechanisms mediating the heterologous effects of BCG vaccination: a systematic review.

Louis Torracinta, Nino Gogichadze, Rachel Tanner.

   Introduction: BCG vaccination can have heterologous or non-specific effects (NSE) that confer resistance against pathogens other than its target Mycobacterium tuberculosis, but the underlying mechanisms are not fully understood.
Methods: We conducted a systematic review synthesising existing literature on immune mechanisms mediating the heterologous/NSE of BCG. Searches were conducted using MEDLINE and Scopus.
Results: 1032 original records were identified, of which 67 were deemed eligible. Several potentially relevant immune pathways were identified, although there may be variation by pathogen. Recent studies have focused on trained immunity whereby innate cells, or the hematopoietic stem and progenitor cells from which they are derived, undergo epigenetic and metabolic reprogramming allowing them to respond more effectively to antigen exposures unrelated to the original stimulus. However, other processes such as granulopoiesis and cross-reactive adaptive immunity may also play a role. Heterologous immunity and NSEs may be influenced by several endogenous and exogenous variables.
Discussion: We discuss the quality of available data, the importance of understanding mechanisms of heterologous protection, and its implications for vaccination strategies.
Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42023400375, identifier CRD42023400375.

Keywords:  BCG; T cells; heterologous effects of vaccination; humoral immunity; trained immunity; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2025.1567111
bioRxiv. 2025 May 21. pii: 2025.05.16.654442. [Epub ahead of print]

Long-term Reprogramming and Altered Ontogeny of Classical Monocytes Mediates Enhanced Lung Injury in Sepsis Survivor Mice.

Scott J Denstaedt, Breanna McBean, Alan P Boyle, Brett C Arenberg, Matthias Mack, Bethany B Moore, Michael W Newstead, Benjamin H Singer, Jennifer Cano, Hallie C Prescott, Helen S Goodridge, Rachel L Zemans.

Prior infection elicits durable reprogramming in myeloid cells and their progenitors; however, the long-term consequences of this reprogramming are not well understood. We previously established a murine model of sepsis survival induced by cecal ligation and puncture which results in enhanced lung injury responses to lipopolysaccharide. In this model, classical monocytes from post-sepsis mice display persistently enhanced cytokine expression after lipopolysaccharide. To test the hypothesis that inflammatory reprogramming of monocytes mediates enhanced lung injury in post-sepsis mice, depletion and/or adoptive transfer was performed three weeks and three months after sepsis. Transcriptomic and epigenomic pathways associated with monocyte reprogramming and shifts in novel monocyte subsets were determined after sepsis in mice and humans. Monocytes from post-sepsis mice mediated enhanced LPS-induced lung injury and promoted neutrophil degranulation. Prior sepsis enhanced JAK-STAT signaling and AP-1 binding in monocytes, shifting toward the neutrophil-like monocyte subset and their progenitors. Similar neutrophil-like monocyte shifts were observed in adult sepsis patients and monocyte counts were predictive of 90-day mortality. We conclude that sepsis induces inflammatory memory affecting bone marrow progenitors and monocyte subsets predisposing to lung injury. These observations serve as a foundation for future investigations on neutrophil-like monocytes and inflammatory program interaction in tissue injury responses.
Summary: Sepsis shifts the immune program and ontogeny of monocytes and their progenitors contributing to long-term risk for new organ injury.

DOI: https://doi.org/10.1101/2025.05.16.654442
Am J Physiol Endocrinol Metab. 2025 Jun 04.

Maladaptive Trained Immunity of Adipose Tissue Macrophages Unraveling the Links to Obesity, T2DM, and Beyond.

Siyi Chen, Jiayao Fu, Jiayu Yan, Ruowen Zhao, Chunhua Qian, Zulalai Yisimayili, Junhua Wu.

  Maladaptive Trained Immunity and associated chronic low-grade inflammation contribute to metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), and cardiometabolic disorders. The heterogeneity and plasticity of adipose tissue macrophages (ATMs) are essential for preserving adipose tissue (AT) homeostasis. The obese AT microenvironment trains ATMs to undergo adaptive changes, especially transition to a maladaptive state and exacerbates the inflammation associated with obesity and T2DM. This review focuses on the pivotal role of ATMs in propagating local inflammation from AT to distant organs, a process that is central to the systemic effects of obesity. Additionally, we emphasize the potential of targeted therapeutic interventions that leverage the axes of maladaptive trained immunity. The advancement of IL-1ß and NLRP3 targeted agents represents an innovative and promising research frontier, with the potential to transform immunotherapy for metabolic disorders.

Keywords:  Adipose Tissue Macrophages; Chronic Low-Grade Inflammation; Maladaptive Trained Immunity; Metabolic Disorders; Obesity

DOI:  https://doi.org/10.1152/ajpendo.00071.2025
bioRxiv. 2025 May 22. pii: 2025.05.22.654748. [Epub ahead of print]

Branched-chain ketoacid antioxidants mediate disease tolerance to sepsis.

Aditya Misra, Efi M Weitman, Michal Weitman, Jeannette R Brook, Joseph M Rone, Boryana Petrova, Randall T Mertens, Narae Hwang, Katherin Zambrano Vera, Mark A Perrella, Rebecca M Baron, Naama Kanarek, Roni Nowarski.

Metabolic adaptation is crucial for surviving systemic infection and withstanding the pathological host response to infection known as sepsis. The liver orchestrates key metabolic adaptation programs that enable disease tolerance in sepsis, yet the impact of liver metabolites on sepsis susceptibility is not well understood. By broadly profiling liver metabolite landscapes in mice surviving or succumbing to bacterial sepsis, we found that dysregulation of the branched-chain amino acid metabolite family is associated with sepsis non-survival. Administration of branched-chain ketoacids (BCKAs) during Klebsiella pneumoniae -induced sepsis in mice enhanced survival, yet not through enhanced bacterial clearance or BCKA catabolism. Instead, BCKAs served as antioxidants by directly neutralizing hydrogen peroxide, preventing tissue lipid peroxidation. Targeted metabolomics in sepsis patients revealed low BCKA abundance as an early prognostic biomarker of sepsis non-survival. Our results identify BCKAs as a systemic shield against oxidative damage and highlight new metabolite targets to enhance disease tolerance to sepsis.

DOI: https://doi.org/10.1101/2025.05.22.654748
Sci Adv. 2025 Jun 06. 11(23): eadt8376

Lipid droplet-enriched luminogens enable adoptive macrophage transfer for treatment of bacterial sepsis.

Xianglong Liu, Guobin Qi, Minyang Zhao, Min Li, Bowen Li, Duo Mao, Bin Liu.

Bacterial sepsis, a life-threatening systemic inflammatory response to infection affecting over 30 million people annually, is exacerbated by antibiotic resistance and immune suppression. Here, we report a small luminescent molecule, TPA2PyPh, as a potent antibacterial agent and its potential for lipid droplet-engineered macrophage transfer strategy in treating bacterial sepsis. Engineered macrophages, created by directly incubating TPA2PyPh with macrophages, enabled the luminogen to precisely bind to intracellular lipid droplets. Upon engulfment of bacteria, these TPA2PyPh-loaded macrophages use natural lipid uptake mechanisms to deliver the luminogen to intracellular bacteria, disrupting their membranes and inserting into the bacterial DNA, thereby inducing bacterial elimination. Our findings show that the adoptive transfer of TPA2PyPh-loaded macrophages substantially diminishes bacterial burden in septic mice and substantially reduces mortality rates. This study demonstrates the potential of TPA2PyPh as an effective antibacterial agent and supports the use of adoptive lipid droplet-engineered macrophage transfer as an effective approach for treating sepsis and managing severe infectious diseases.

DOI: https://doi.org/10.1126/sciadv.adt8376
Cell Mol Gastroenterol Hepatol. 2025 May 29. pii: S2352-345X(25)00091-8. [Epub ahead of print] 101550

Hepatic Nuclear Factor Erythroid 2 Related Factor 1 Activity Promotes Host Defense in Endotoxemia and Bacterial Sepsis.

Michael J Trites, Lei Li, Uche Njoku, May G Akl, Aidan Hydomako, Scott B Widenmaier.

   BACKGROUND & AIMS: Sepsis and endotoxemia cause mortality by inducing organ dysfunction and damage. Liver defends against such insults by mediating metabolic adaptations that promote stress and damage control. The mechanisms underlying liver defenses may require coordinated actions between cellular and systemic stress-defense programming. Here, we investigated whether the stress defending transcription factors nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2) in hepatocytes protect against endotoxemia and sepsis.
METHODS: We used mice injected with Escherichia coli-derived lipopolysaccharide (endotoxemia), or Escherichia coli (sepsis). Hepatic Nrf1 and Nrf2 activity was examined, and we also genetically altered their activity and examined corresponding effects on survival, body temperature, cytokines and liver inflammation, liver gene and protein expression, and liver-related metabolism.
RESULTS: Hepatic Nrf1 and Nrf2 activity was reduced in endotoxemia and sepsis, and deficiency for hepatic Nrf1, but not Nrf2, promoted severe hypothermia and mortality. Conversely, increasing hepatic Nrf1 activity mitigated hypothermia and improved survival. These effects were linked to very low-density lipoprotein (VLDL) secretion and triglyceride metabolism. In endotoxemia, hepatic Nrf1 deficiency reduced VLDL secretion whereas increased hepatic Nrf1 activity enhanced VLDL secretion. Administering a VLDL secretion inhibitor, lomitapide, or inhibitor of circulating triglyceride hydrolysis, poloxamer 407, diminished protective effects of hepatic Nrf1 activity, whereas administering intralipid rescued the lomitapide-injected mice. Gene expression profiling indicate Nrf1 promotes this effect by regulating stress-defense programming.
CONCLUSIONS: Mortality in endotoxemia and sepsis is exacerbated by impaired hepatic Nrf1 activity. Interventions increasing hepatic Nrf1 activity promote liver defenses that protect against sepsis-associated hypothermia and mortality.

Keywords:  Nrf1 (Nfe2l1); disease tolerance; hypothermia; liver; metabolism; survival; very low-density lipoprotein

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101550
J Clin Invest. 2025 Jun 03. pii: e184653. [Epub ahead of print]

Panose prevents acute-on-chronic liver failure by reducing bacterial infection in mice.

Jiaxin Li, Shihao Xie, Meiling Chen, Changze Hong, Yuqi Chen, Fengyuan Lyu, Niexin Tang, Tianqi Chen, Lingyan Zhao, Weihao Zou, Hongjuan Peng, Jingna Bao, Peng Gu, Bernd Schnabl, Jinjun Chen, Peng Chen.

  Acute-on-chronic liver failure (ACLF) is a leading cause of global liver-related mortality. Bacterial infection, especially in patients with decompensated cirrhosis (DC), commonly triggers ACLF and is difficult to treat with antibiotics. Therefore, finding alternative strategies for preventing and managing bacterial infection is an urgent priority. Here, we observed that infected DC patients and ACLF mice exhibited lower fecal panose levels than uninfected controls. Megamonas funiformis (M. funiformis), with 4α-glucanosyltransferase (4αGT) as a key enzyme for panose production, was identified as a potential panose producer. Animal experiments demonstrated that panose efficiently reduced liver injury and extended survival in ACLF mice by mitigating bacterial infection. Further results revealed that panose enhanced resistance to bacterial infection by inhibiting oxidative stress-induced gut barrier disruption, thereby limiting bacterial dissemination. Mechanistically, panose interacted with the solute carrier family 7 member 11 (SLC7A11, also known as xCT) protein to boost antioxidant glutathione (GSH) levels in intestinal epithelial cells. These findings highlight panose's potential in preventing bacterial infection, offering a valuable insight into mitigating ACLF progression.

Keywords:  Bacterial infections; Hepatology; Metabolism; Microbiology; Tight junctions

DOI:  https://doi.org/10.1172/JCI184653
Cell Rep. 2025 Jun 04. pii: S2211-1247(25)00556-X. [Epub ahead of print]44(6): 115785

PGK1 phosphorylates NLRP3 and mediates inflammasome activation independent of its glycolytic activity.

Zemeng Ma, Yuxuan Wu, Zebing Rao, Chenhua Han, Naishuang Sun, Jinzhou Li, Qiang Zeng, Zaikui Zhang, Ding Ding, Jiajun Qiao, Wenjing Li, Yifeng Fang, Shuo Yang, Jiahuang Li, Jing Zhang, Yunzi Chen.

  Glycolysis is a critical player in the inflammatory response. Phosphoglycerate kinase 1 (PGK1) is an essential enzyme in the glycolysis pathway. However, little is known about its role in inflammatory response. In this study, we report PGK1 as a kinase that directly regulates NLRP3 inflammasome activation in response to lipopolysaccharide (LPS) stimulation via non-glycolytic function. We identified a novel phosphorylation modification of PGK1 at S271, mediated by protein kinase CK2. Importantly, phosphorylation at S271 serves as a molecular switch that activates PGK1's kinase function, activating it to phosphorylate NLRP3. This PGK1-mediated phosphorylation at S448/S449 of NLRP3 subsequently recruits USP14 to facilitate NLRP3 deubiquitination, thereby promoting NLRP3 inflammasome activation. Using PGK1S271A/S271A transgenic mouse model, we further demonstrated that blocking S271 phosphorylation conferred significant protection against LPS-induced endotoxemia and alum-induced peritonitis. Our findings reveal a novel regulatory role of PGK1 in inflammation and provide potential therapeutic strategies for NLRP3-driven diseases.

Keywords:  CK2; CP: Immunology; CP: Metabolism; NLRP3; PGK1; USP14; inflammasome; phosphorylation

DOI:  https://doi.org/10.1016/j.celrep.2025.115785