bims-traimu Biomed News
on Trained immunity
Issue of 2023–08–13
ten papers selected by
Yantong Wan, Southern Medical University
  1. Lipopolysaccharide Tolerance in Human Primary Monocytes and Polarized Macrophages.
  2. Remembering foods and foes: emerging principles of transcriptional memory.
  3. In Vivo Zymosan Treatment Induces IL15-Secreting Macrophages and KLRG1-Expressing NK Cells in Mice.
  4. Interpreting the results of trials of BCG vaccination for protection against COVID-19.
  5. Resolving neutrophils due to TRAM deletion renders protection against experimental sepsis.
  6. The Dual Role of ACOD1 in Inflammation.
  7. Transcriptomic Effects of Low-Dose Inorganic Arsenic Exposure on Murine Bone Marrow-Derived Macrophages.
  8. Histone Deacetylase Inhibitor (SAHA) Reduces Mortality in an Endotoxemia Mouse Model by Suppressing Glycolysis.
  9. Novel tripeptide RKH derived from Akkermansia muciniphila protects against lethal sepsis.
  10. A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis.
  1. Int J Mol Sci. 2023 Jul 30. pii: 12196. [Epub ahead of print]24(15):
    Lipopolysaccharide Tolerance in Human Primary Monocytes and Polarized Macrophages.
    Hui Li, Annette Breedijk, Nadine Dietrich, Katja Nitschke, Jonas Jarczyk, Philipp Nuhn, Bernhard K Krämer, Benito A Yard, Jan Leipe, Sibylle Hauske.
      Innate immune memory allows macrophages to adequately respond to pathogens to which they have been pre-exposed. To what extent different pattern recognition receptors, cytokines and resolution signals influence innate immune memory needs further elucidation. The present study assessed whether lipopolysaccharide (LPS) tolerance in monocytes and macrophages is affected by these factors. Human CD14+ cells were isolated from peripheral blood, stimulated by LPS and re-stimulated after 3 days of resting. Hereafter, immune-responsive gene 1 (IRG-1), heme oxygenase 1 (HO-1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) expression were assessed. Our study revealed the following findings: (1) While pre-stimulation with the Toll-like receptor 4 ligand LPS inhibits the induction of IRG-1, TNF-α and IL-6 expression, pre-stimulation with TLR 1/2 ligands only affects cytokine production but not IRG-1 expression upon subsequent TLR4 engagement. (2) Prior TNF-α stimulation does not affect LPS tolerance but rather increases LPS-mediated cytokine expression. (3) Dimethyl itaconate (DMI) inhibits the expression of IRG-1 in a dose-dependent manner but does not affect TNF-α or IL-6 expression. (4) Docosahexaenoic acid (DHA) partly inhibits IRG-1 expression in monocytes but not in M(IFNγ) and M(IL-4) polarized macrophages. LPS tolerance is not affected in these cells by DHA. The data presented in this study partly corroborate and extend previous findings on innate immune memory and warrant further studies on LPS tolerance to gain a better understanding of innate immune memory at the molecular level.
    Keywords:  DHA; DMI; LPS tolerance; TLR agonists; innate immune memory; macrophages; monocytes; trained immunity
    DOI:  https://doi.org/10.3390/ijms241512196
  2. Cell Death Differ. 2023 Aug 10.
    Remembering foods and foes: emerging principles of transcriptional memory.
    Sahar S H Tehrani, Anna Kogan, Pawel Mikulski, Lars E T Jansen.
      Transcriptional memory is characterized by a primed cellular state, induced by an external stimulus that results in an altered expression of primed genes upon re-exposure to the inducing signal. Intriguingly, the primed state is heritably maintained across somatic cell divisions even after the initial stimulus and target gene transcription cease. This phenomenon is widely observed across various organisms and appears to enable cells to retain a memory of external signals, thereby adapting to environmental changes. Signals range from nutrient supplies (food) to a variety of stress signals, including exposure to pathogens (foes), leading to long-term memory such as in the case of trained immunity in plants and mammals. Here, we review these priming phenomena and our current understanding of transcriptional memory. We consider different mechanistic models for how memory can work and discuss existing evidence for potential carriers of memory. Key molecular signatures include: the poising of RNA polymerase II machinery, maintenance of histone marks, as well as alterations in nuclear positioning and long-range chromatin interactions. Finally, we discuss the potential adaptive roles of transcriptional memory in the organismal response to its environment from nutrient sensing to trained immunity.
    DOI:  https://doi.org/10.1038/s41418-023-01200-6
  3. Molecules. 2023 Jul 31. pii: 5779. [Epub ahead of print]28(15):
    In Vivo Zymosan Treatment Induces IL15-Secreting Macrophages and KLRG1-Expressing NK Cells in Mice.
    Hyun Jung Park, Sung Won Lee, Yun Hoo Park, Tae-Cheol Kim, Sujin Lee, Seyeong Lee, Luc Van Kaer, Seokmann Hong.
      Beta-glucan (β-glucan) is a natural polysaccharide produced by fungi, bacteria, and plants. Although it has been reported that β-glucan enhances innate immune memory responses, it is unclear whether different types of β-glucans display similar immune effects. To address this issue, we employed zymosan (β-1,3-glycosidic linkage) and pustulan (β-1,6-glycosidic linkage) to investigate their in vivo effects on innate memory immune responses. We examined the changes of innate memory-related markers in macrophages and natural killer (NK) cells, two immune cell types that display innate memory characteristics, at two different time points (16 h and 7 days) after β-glucan stimulation. We found that short-term (16 h) zymosan treatment significantly induced macrophages to upregulate IL15 production and increased surface IL15Rα expression on NK cells. In addition, long-term (7 days) zymosan treatment significantly induced macrophages to upregulate the expression of innate memory-related markers (e.g., TNFα, HIF1α, and mTOR) and induced NK cells to express enhanced levels of KLRG1, known as an innate memory-like marker. Our results provide support that zymosan can be an effective adjuvant to promote innate memory immune responses, providing a bridge between innate and adaptive immune cells to enhance various immune responses such as those directed against tumors.
    Keywords:  beta-glucan; macrophages; natural killer cells; pustulan; zymosan
    DOI:  https://doi.org/10.3390/molecules28155779
  4. J Infect Dis. 2023 Aug 10. pii: jiad316. [Epub ahead of print]
    Interpreting the results of trials of BCG vaccination for protection against COVID-19.
    Christie Ca Noble, Nicole L Messina, Laure F Pittet, Nigel Curtis.
      BCG vaccination has beneficial off-target ('non-specific') effects on non-mycobacterial infections. On this premise, trials set out to investigate whether BCG provides off-target protection against COVID-19. A literature search identified eleven randomised 'BCG COVID-19' trials, with conflicting results. Factors including participant age, sex and comorbidities, BCG vaccination strain and dose, outcome measure and duration of follow up likely explain the inconsistencies. The findings of these trials and the differences in their study design are discussed using the PICOT framework to highlight these factors. Understanding how to control these factors to best exploit BCG's off-target effects will be important in designing future trials and intervention strategies.
    Keywords:  BCG vaccination; COVID-19; SARS-CoV-2; off-target effects
    DOI:  https://doi.org/10.1093/infdis/jiad316
  5. Inflamm Res. 2023 Aug 10.
    Resolving neutrophils due to TRAM deletion renders protection against experimental sepsis.
    RuiCi Lin, Jing Wang, Yajun Wu, Ziyue Yi, Yao Zhang, Liwu Li.
       OBJECTIVE: Proper inflammation resolution is crucial to prevent runaway inflammation during sepsis and reduce sepsis-related mortality/morbidity. Previous studies suggest that deleting TRAM, a key TLR4 signaling adaptor, can reprogram the first inflammatory responder cell-neutrophil from an inflammatory state to a resolving state. In this study, we aim to examine the therapeutic potential of TRAM-deficient neutrophils in vivo with recipient mice undergoing experimental sepsis.
    MATERIAL AND METHODS: Wild-type or Tram-/- mice were intraperitoneally injected with cecal slurry to induce either severe or mild sepsis. Phenotypic examinations of sepsis and neutrophil characteristics were examined in vivo and ex vivo. The propagations of resolution from donor neutrophils to recipient cells such as monocytes, T cells, and endothelial cells were examined through co-culture assays in vitro. The efficacies of Tram-/- neutrophils in reducing inflammation were studied by transfusing either wild-type or Tram-/- neutrophils into septic recipient mice.
    RESULTS: Tram-/- septic mice had improved survival and attenuated injuries within the lung and kidney tissues as compared to wild-type septic mice. Wild-type septic mice transfused with Tram-/- resolving neutrophils exhibited reduced multi-organ damages and improved cellular homeostasis. In vitro co-culture studies revealed that donor Tram-/- neutrophils can effectively propagate cellular homeostasis to co-cultured neighboring monocytes, neutrophils, T cells as well as endothelial cells.
    CONCLUSIONS: Neutrophils with TRAM deletion render effective reprogramming into a resolving state beneficial for ameliorating experimental sepsis, with therapeutic potential in propagating cellular and tissue homeostasis as well as treating sepsis.
    Keywords:  Adoptive transfer; Neutrophils; Sepsis; TRAM; Therapeutics
    DOI:  https://doi.org/10.1007/s00011-023-01779-z
  6. J Immunol. 2023 08 15. 211(4): 518-526
    The Dual Role of ACOD1 in Inflammation.
    Runliu Wu, Jiao Liu, Daolin Tang, Rui Kang.
      Immunometabolism is an interdisciplinary field that focuses on the relationship between metabolic pathways and immune responses. Dysregulated immunometabolism contributes to many pathological settings, such as cytokine storm or immune tolerance. Aconitate decarboxylase 1 (ACOD1, also known as immunoresponsive gene 1), the mitochondrial enzyme responsible for catalyzing itaconate production, was originally identified as a bacterial LPS-inducible gene involved in innate immunity in mouse macrophages. We now know that the upregulation of ACOD1 expression in immune or nonimmune cells plays a context-dependent role in metabolic reprogramming, signal transduction, inflammasome regulation, and protein modification. The emerging function of ACOD1 in inflammation and infection is a double-edged sword. In this review, we discuss how ACOD1 regulates anti-inflammatory or proinflammatory responses in an itaconate-dependent or -independent manner. Further understanding of ACOD1 expression and function may pave the way for the development of precision therapies for inflammatory diseases.
    DOI:  https://doi.org/10.4049/jimmunol.2300101
  7. bioRxiv. 2023 Jul 27. pii: 2023.07.26.550543. [Epub ahead of print]
    Transcriptomic Effects of Low-Dose Inorganic Arsenic Exposure on Murine Bone Marrow-Derived Macrophages.
    Emily J Illingworth, Alexandra Maertens, Fenna C M Sillé.
      Both tissue-resident macrophages and monocytes recruited from the bone marrow that transform into tissue-resident cells play critical roles in mediating homeostasis as well as in the pathology of inflammatory diseases. Inorganic arsenic (iAs) is the most common drinking water contaminant worldwide and represents a major public health concern. Several diseases that macrophages have implicated involvement in are caused by iAs exposure, including cardiovascular disease, cancer, and increased risk of infectious disease. Therefore, understanding the effects of iAs exposure on macrophages can help us better grasp the full range of arsenic immunotoxicity and better design therapeutic targets for iAs-induced diseases particularly in exposed populations. In this study, we analyzed the transcriptome of low dose iAs-exposed male and female murine bone marrow-derived macrophages (BMDMs) with either M0, M1, or M2 stimulation. We identified differentially expressed genes by iAs in a sex- and stimulation-dependent manner and used bioinformatics tools to predict protein-protein interactions, transcriptional regulatory networks, and associated biological processes. Overall, our data suggest that M1-stimulated, especially female-derived, BMDMs are most susceptible to iAs exposure. Most notably, we observed significant downregulation of major proinflammatory transcription factors, like IRF8, and its downstream targets, as well as genes encoding proteins involved in pattern recognition and antigen presentation, such as TLR7, TLR8, and H2-D1, potentially providing causal insight regarding arsenic's role in perturbing immune responses to infectious diseases. We also observed significant downregulation of genes involved in processes crucial to coordinating a proinflammatory response including leukocyte migration, differentiation, and cytokine and chemokine production and response. Finally, we discovered that 24 X-linked genes were dysregulated in iAs-exposed female stimulation groups compared to only 3 across the iAs-exposed male stimulation groups. These findings elucidate the potential mechanisms underlying the sex-differential iAs-associated immune-related disease risk.
    DOI:  https://doi.org/10.1101/2023.07.26.550543
  8. Int J Mol Sci. 2023 Aug 04. pii: 12448. [Epub ahead of print]24(15):
    Histone Deacetylase Inhibitor (SAHA) Reduces Mortality in an Endotoxemia Mouse Model by Suppressing Glycolysis.
    Yunchen Wu, Yudan He, Chen Liu, Charlotte Ehle, Aishwarya Iyer-Bierhoff, Bing Liu, Thorsten Heinzel, Shaojun Xing.
      Sepsis is a life-threatening medical emergency triggered by excessive inflammation in response to an infection. High mortality rates and limited therapeutic options pose significant challenges in sepsis treatment. Histone deacetylase inhibitors (HDACi), such as suberoylanilide hydroxamic acid (SAHA), have been proposed as potent anti-inflammatory agents for treating inflammatory diseases. However, the underlying mechanisms of sepsis treatment remain poorly understood. In this study, we investigated the effects of SAHA treatment in the lipopolysaccharide (LPS)-induced endotoxemia mouse model as it closely mimics the early stages of the systemic inflammation of sepsis. Our results demonstrate a reduced inflammatory mediator secretion and improved survival rates in mice. Using quantitative acetylomics, we found that SAHA administration increases the acetylation of lactate dehydrogenase (LDHA), and consequently inhibits LDHA activity. Notably, the reduced enzyme activity of LDHA results in a reduced rate of glycolysis. Furthermore, our experiments with bone marrow-derived macrophages (BMDMs) show that SAHA administration reduced oxidative stress and extracellular ATP concentrations, ultimately blunting inflammasome activation. Overall, our study provides insights into the mechanism underlying SAHA's therapeutic effects in sepsis treatment and highlights LDHA as a potential target for developing novel sepsis treatment.
    Keywords:  SAHA; glycolysis; liver; macrophage; sepsis
    DOI:  https://doi.org/10.3390/ijms241512448
  9. Gut. 2023 Aug 08. pii: gutjnl-2023-329996. [Epub ahead of print]
    Novel tripeptide RKH derived from Akkermansia muciniphila protects against lethal sepsis.
    Shihao Xie, Jiaxin Li, Fengyuan Lyu, Qingming Xiong, Peng Gu, Yuqi Chen, Meiling Chen, Jingna Bao, Xianglong Zhang, Rongjuan Wei, Youpeng Deng, Hongzheng Wang, Zhenhua Zeng, Zhongqing Chen, Yongqiang Deng, Zhuoshi Lian, Jie Zhao, Wei Gong, Ye Chen, Ke-Xuan Liu, Yi Duan, Yong Jiang, Hong-Wei Zhou, Peng Chen.
       OBJECTIVE: The pathogenesis of sepsis is complex, and the sepsis-induced systemic proinflammatory phase is one of the key drivers of organ failure and consequent mortality. Akkermansia muciniphila (AKK) is recognised as a functional probiotic strain that exerts beneficial effects on the progression of many diseases; however, whether AKK participates in sepsis pathogenesis is still unclear. Here, we evaluated the potential contribution of AKK to lethal sepsis development.
    DESIGN: Relative abundance of gut microbial AKK in septic patients was evaluated. Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) injection were employed to establish sepsis in mice. Non-targeted and targeted metabolomics analysis were used for metabolites analysis.
    RESULTS: We first found that the relative abundance of gut microbial AKK in septic patients was significantly reduced compared with that in non-septic controls. Live AKK supplementation, as well as supplementation with its culture supernatant, remarkably reduced sepsis-induced mortality in sepsis models. Metabolomics analysis and germ-free mouse validation experiments revealed that live AKK was able to generate a novel tripeptide Arg-Lys-His (RKH). RKH exerted protective effects against sepsis-induced death and organ damage. Furthermore, RKH markedly reduced sepsis-induced inflammatory cell activation and proinflammatory factor overproduction. A mechanistic study revealed that RKH could directly bind to Toll-like receptor 4 (TLR4) and block TLR4 signal transduction in immune cells. Finally, we validated the preventive effects of RKH against sepsis-induced systemic inflammation and organ damage in a piglet model.
    CONCLUSION: We revealed that a novel tripeptide, RKH, derived from live AKK, may act as a novel endogenous antagonist for TLR4. RKH may serve as a novel potential therapeutic approach to combat lethal sepsis after successfully translating its efficacy into clinical practice.
    Keywords:  inflammation; intestinal microbiology; macrophages; probiotics; sepsis
    DOI:  https://doi.org/10.1136/gutjnl-2023-329996
  10. Cell Mol Immunol. 2023 Aug 09.
    A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis.
    Peng Gu, Ruofan Liu, Qin Yang, Li Xie, Rongjuan Wei, Jiaxin Li, Fengyi Mei, Tao Chen, Zhenhua Zeng, Yan He, Hongwei Zhou, Hongjuan Peng, Kutty Selva Nandakumar, Huikuan Chu, Yong Jiang, Wei Gong, Ye Chen, Bernd Schnabl, Peng Chen.
      The gut microbiome is recognized as a key modulator of sepsis development. However, the contribution of the gut mycobiome to sepsis development is still not fully understood. Here, we demonstrated that the level of Candida albicans was markedly decreased in patients with bacterial sepsis, and the supernatant of Candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture (CLP)-challenged mice and Escherichia coli-challenged pigs. Integrative metabolomics and the genetic engineering of fungi revealed that Candida albicans-derived phenylpyruvate (PPA) enhanced the bactericidal activity of macrophages and reduced organ damage during sepsis. Mechanistically, PPA directly binds to sirtuin 2 (SIRT2) and increases reactive oxygen species (ROS) production for eventual bacterial clearance. Importantly, PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in patients. Our findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development.
    Keywords:  Bacterial clearance; Candida albicans; Macrophage; Phenylpyruvate; Sepsis
    DOI:  https://doi.org/10.1038/s41423-023-01070-5
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