bims-traimu Biomed News
on Trained immunity
Issue of 2024–04–07
twelve papers selected by
Yantong Wan, Southern Medical University
  1. Multi-omics analysis reveals that linoleic acid metabolism is associated with variations of trained immunity induced by distinct BCG strains.
  2. Discovering adaptive features of innate immune memory.
  3. Hypoxia inducible factor-1α regulates microglial innate immune memory and the pathology of Parkinson's disease.
  4. Forged in the Fire: Lasting Impacts of Inflammation on Hematopoietic Progenitors.
  5. Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors.
  6. Mycobacterium bovis BCG as immunostimulating agent prevents the severe form of chronic experimental Chagas disease.
  7. Microbial cancer immunotherapy reprograms hematopoietic stem cells to enhance anti-tumor immunity.
  8. The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis.
  9. Widespread S-persulfidation in activated macrophages as a protective mechanism against oxidative-inflammatory stress.
  10. Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function.
  11. Maternal circadian rhythm disruption affects neonatal inflammation via metabolic reprograming of myeloid cells.
  12. Approaches for studying human macrophages.
  1. Sci Adv. 2024 Apr 05. 10(14): eadk8093
    Multi-omics analysis reveals that linoleic acid metabolism is associated with variations of trained immunity induced by distinct BCG strains.
    Jin-Chuan Xu, Zhen-Yan Chen, Xue-Jiao Huang, Juan Wu, Huan Huang, Liang-Fei Niu, Hui-Ling Wang, Jian-Hui Li, Douglas B Lowrie, Zhidong Hu, Shui-Hua Lu, Xiao-Yong Fan.
      Trained immunity is one of the mechanisms by which BCG vaccination confers persistent nonspecific protection against diverse diseases. Genomic differences between the different BCG vaccine strains that are in global use could result in variable protection against tuberculosis and therapeutic effects on bladder cancer. In this study, we found that four representative BCG strains (BCG-Russia, BCG-Sweden, BCG-China, and BCG-Pasteur) covering all four genetic clusters differed in their ability to induce trained immunity and nonspecific protection. The trained immunity induced by BCG was associated with the Akt-mTOR-HIF1α axis, glycolysis, and NOD-like receptor signaling pathway. Multi-omics analysis (epigenomics, transcriptomics, and metabolomics) showed that linoleic acid metabolism was correlated with the trained immunity-inducing capacity of different BCG strains. Linoleic acid participated in the induction of trained immunity and could act as adjuvants to enhance BCG-induced trained immunity, revealing a trained immunity-inducing signaling pathway that could be used in the adjuvant development.
    DOI:  https://doi.org/10.1126/sciadv.adk8093
  2. Immunol Rev. 2024 Apr 02.
    Discovering adaptive features of innate immune memory.
    Mina Sadeghi, Maziar Divangahi.
      Conventionally, it was thought that innate immunity operated through a simple system of nonspecific responses to an insult. However, this perspective now seems overly simplistic. It has become evident that intricate cooperation and networking among various cells, receptors, signaling pathways, and protein complexes are essential for regulating and defining the overall activation status of the immune response, where the distinction between innate and adaptive immunity becomes ambiguous. Given the evolutionary timeline of vertebrates and the success of plants and invertebrates which depend solely on innate immunity, immune memory cannot be considered an innovation of only the lymphoid lineage. Indeed, the evolutionary innate immune memory program is a conserved mechanism whereby innate immune cells can induce a heightened response to a secondary stimulus due to metabolic and epigenetic reprogramming. Importantly, the longevity of this memory phenotype can be attributed to the reprogramming of self-renewing hematopoietic stem cells (HSCs) in the bone marrow, which is subsequently transmitted to lineage-committed innate immune cells. HSCs reside within a complex regulated network of immune and stromal cells that govern their two primary functions: self-renewal and differentiation. In this review, we delve into the emerging cellular and molecular mechanisms as well as metabolic pathways of innate memory in HSCs, which harbor substantial therapeutic promise.
    Keywords:   Mycobacterium tuberculosis ; BCG; HSC metabolism; adaptive immunity; evolutionary immunology; hematopoiesis; hematopoietic stem cells; innate immune memory; interferon pathways; interleukin‐1; trained immunity; β‐glucan
    DOI:  https://doi.org/10.1111/imr.13328
  3. J Neuroinflammation. 2024 Mar 30. 21(1): 80
    Hypoxia inducible factor-1α regulates microglial innate immune memory and the pathology of Parkinson's disease.
    Hongtian Dong, Xiaoshuang Zhang, Yufei Duan, Yongtao He, Jiayin Zhao, Zishan Wang, Jinghui Wang, Qing Li, Guangchun Fan, Zhaolin Liu, Chenye Shen, Yunhe Zhang, Mei Yu, Jian Fei, Fang Huang.
      Neuroinflammation is one of the core pathological features of Parkinson's disease (PD). Innate immune cells play a crucial role in the progression of PD. Microglia, the major innate immune cells in the brain, exhibit innate immune memory effects and are recognized as key regulators of neuroinflammatory responses. Persistent modifications of microglia provoked by the first stimuli are pivotal for innate immune memory, resulting in an enhanced or suppressed immune response to second stimuli, which is known as innate immune training and innate immune tolerance, respectively. In this study, LPS was used to establish in vitro and in vivo models of innate immune memory. Microglia-specific Hif-1α knockout mice were further employed to elucidate the regulatory role of HIF-1α in innate immune memory and MPTP-induced PD pathology. Our results showed that different paradigms of LPS could induce innate immune training or tolerance in the nigrostriatal pathway of mice. We found that innate immune tolerance lasting for one month protected the dopaminergic system in PD mice, whereas the effect of innate immune training was limited. Deficiency of HIF-1α in microglia impeded the formation of innate immune memory and exerted protective effects in MPTP-intoxicated mice by suppressing neuroinflammation. Therefore, HIF-1α is essential for microglial innate immune memory and can promote neuroinflammation associated with PD.
    Keywords:  Hif-1α; Innate immune memory; Microglia; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s12974-024-03070-2
  4. Exp Hematol. 2024 Apr 03. pii: S0301-472X(24)00074-2. [Epub ahead of print] 104215
    Forged in the Fire: Lasting Impacts of Inflammation on Hematopoietic Progenitors.
    Ruoqiong Cao, Apoorva Thatavarty, Katherine Y King.
      Quiescence and differentiation of hematopoietic stem and progenitor cells (HSPC) can be modified by systemic inflammatory cues. Such cues can not only yield short term changes in HSPCs such as in supporting emergency granulopoiesis but can also promote lasting influences on the HSPC compartment. First, inflammation can be a driver for clonal expansion, promoting clonal hematopoiesis for certain mutant clones, reducing overall clonal diversity, and reshaping the composition of the HSPC pool with significant health consequences. Second, inflammation can generate lasting cell-autonomous changes in HSPCs themselves, leading to changes in the epigenetic state, metabolism, and the function of downstream innate immune cells. This concept, termed "trained immunity," suggests that inflammatory stimuli can alter subsequent immune responses leading to improved innate immunity or, conversely, autoimmunity. Both of these concepts have major implications in human health. Here we review current literature about the lasting effects of inflammation on the HSPC compartment and opportunities for future advancement in this fast-developing field.
    Keywords:  Clonal Hematopoiesis; Hematopoiesis; epigenetics; inflammation; metabolism; trained immunity
    DOI:  https://doi.org/10.1016/j.exphem.2024.104215
  5. Immunol Rev. 2024 Apr 03.
    Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors.
    Bikash Mishra, Lionel B Ivashkiv.
      Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis-associated immunoparalysis. Training, priming, and tolerance regulate similar "signature" inflammatory genes such as TNF, IL6, and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating JAK-STAT signaling and interferon-stimulated genes, also play a key role in regulating training, priming, and tolerance via chromatin-mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-γ-mediated priming, affects regulation of AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a "training-priming continuum" model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1.
    Keywords:  chromatin; epigenetics; innate immune training; interferon; monocytes; priming
    DOI:  https://doi.org/10.1111/imr.13330
  6. Front Immunol. 2024 ;15 1380049
    Mycobacterium bovis BCG as immunostimulating agent prevents the severe form of chronic experimental Chagas disease.
    Minerva Arce-Fonseca, Dulce Mata-Espinosa, Alberto Aranda-Fraustro, José Luis Rosales-Encina, Mario Alberto Flores-Valdez, Olivia Rodríguez-Morales.
       Introduction: There is currently no vaccine against Chagas disease (ChD), and the medications available confer multiple side effects. Mycobacterium bovis Bacillus Calmette-Guérin (BCG) produces balanced Th1, Th2, and Th17 modulatory immune responses and has improved efficacy in controlling chronic infections through nonspecific immunity. We aimed to improve the response to infection by inducing a stronger immune response and greater protection against the parasite by trained immunity.
    Methods: BALB/c mice were immunized with BCG subcutaneously, and 60 days later, they were infected with Trypanosoma cruzi intraperitoneally. An evaluation of the progression of the disease from the acute to the chronic stage, analyzing various aspects such as parasitemia, survival, clinical status, and humoral and cellular immune response, as well as the appearance of visceral megas and the histopathological description of target organs, was performed.
    Results: Vaccination reduced parasitemia by 70%, and 100% survival was achieved in the acute stage; although the presentation of clinical signs was reduced, there was no increase in the antibody titer or in the differential production of the isotypes.
    Conclusion: Serum cytokine production indicated a proinflammatory response in infected animals, while in those who received BCG, the response was balanced by inducing Th1/Th2-type cytokines, with a better prognosis of the disease in the chronic stage.
    Keywords:  BCG; Chagas disease; Trypanosoma cruzi; immunomodulator; trained/nonspecific immunity; vaccination
    DOI:  https://doi.org/10.3389/fimmu.2024.1380049
  7. bioRxiv. 2024 Mar 21. pii: 2024.03.21.586166. [Epub ahead of print]
    Microbial cancer immunotherapy reprograms hematopoietic stem cells to enhance anti-tumor immunity.
    Andrew W Daman, Anthony C Antonelli, Gil Redelman-Sidi, Lucinda Paddock, Jin Gyu Cheong, Leonardo F Jurado, Anna Benjamin, Song Jiang, Dughan Ahimovic, Shireen Khayat, Michael J Bale, Oleg Loutochin, Victor A McPherson, Dana Pe'er, Maziar Divangahi, Eugene Pietzak, Steven Z Josefowicz, Michael S Glickman.
      Mycobacterium bovis BCG is the vaccine against tuberculosis and an immunotherapy for bladder cancer. When administered intravenously, BCG reprograms bone marrow hematopoietic stem and progenitor cells (HSPCs), leading to heterologous protection against infections. Whether HSPC-reprogramming contributes to the anti-tumor effects of BCG administered into the bladder is unknown. We demonstrate that BCG administered in the bladder in both mice and humans reprograms HSPCs to amplify myelopoiesis and functionally enhance myeloid cell antigen presentation pathways. Reconstitution of naive mice with HSPCs from bladder BCG-treated mice enhances anti-tumor immunity and tumor control, increases intratumoral dendritic cell infiltration, and synergizes with checkpoint blockade. We conclude that bladder BCG acts systemically, reprogramming HSPC-encoded innate immunity, highlighting the broad potential of modulating HSPC phenotypes to improve tumor immunity.
    One Sentence Summary: BCG administered in the bladder reprograms bone marrow HSPCs and contributes to tumor control via enhanced myeloid cells.
    DOI:  https://doi.org/10.1101/2024.03.21.586166
  8. Proc Natl Acad Sci U S A. 2024 Apr 09. 121(15): e2400675121
    The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis.
    Yannick Cyr, Fazli K Bozal, José Gabriel Barcia Durán, Alexandra A C Newman, Letizia Amadori, Panagiotis Smyrnis, Morgane Gourvest, Dayasagar Das, Michael Gildea, Ravneet Kaur, Tracy Zhang, Kristin M Wang, Richard Von Itter, P Martin Schlegel, Samantha D Dupuis, Bernard F Sanchez, Ann Marie Schmidt, Edward A Fisher, Coen van Solingen, Chiara Giannarelli, Kathryn J Moore.
      Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that IRG1 is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1β. Mechanistically, absence of Irg1 increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1β release. Conversely, supplementation of the Irg1-itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1β levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.
    Keywords:  atherosclerosis; immunometabolism; innate immunity; macrophage; neutrophil
    DOI:  https://doi.org/10.1073/pnas.2400675121
  9. Redox Biol. 2024 Mar 13. pii: S2213-2317(24)00101-0. [Epub ahead of print]72 103125
    Widespread S-persulfidation in activated macrophages as a protective mechanism against oxidative-inflammatory stress.
    Talal Salti, Ilana Braunstein, Yael Haimovich, Tamar Ziv, Moran Benhar.
      Acute inflammatory responses often involve the production of reactive oxygen and nitrogen species by innate immune cells, particularly macrophages. How activated macrophages protect themselves in the face of oxidative-inflammatory stress remains a long-standing question. Recent evidence implicates reactive sulfur species (RSS) in inflammatory responses; however, how endogenous RSS affect macrophage function and response to oxidative and inflammatory insults remains poorly understood. In this study, we investigated the endogenous pathways of RSS biogenesis and clearance in macrophages, with a particular focus on exploring how hydrogen sulfide (H2S)-mediated S-persulfidation influences macrophage responses to oxidative-inflammatory stress. We show that classical activation of mouse or human macrophages using lipopolysaccharide and interferon-γ (LPS/IFN-γ) triggers substantial production of H2S/RSS, leading to widespread protein persulfidation. Biochemical and proteomic analyses revealed that this surge in cellular S-persulfidation engaged ∼2% of total thiols and modified over 800 functionally diverse proteins. S-persulfidation was found to be largely dependent on the cystine importer xCT and the H2S-generating enzyme cystathionine γ-lyase and was independent of changes in the global proteome. We further investigated the role of the sulfide-oxidizing enzyme sulfide quinone oxidoreductase (SQOR), and found that it acts as a negative regulator of S-persulfidation. Elevated S-persulfidation following LPS/IFN-γ stimulation or SQOR inhibition was associated with increased resistance to oxidative stress. Upregulation of persulfides also inhibited the activation of the macrophage NLRP3 inflammasome and provided protection against inflammatory cell death. Collectively, our findings shed light on the metabolism and effects of RSS in macrophages and highlight the crucial role of persulfides in enabling macrophages to withstand and alleviate oxidative-inflammatory stress.
    Keywords:  Cell death; Inflammation; M1 macrophages; Oxidative stress; Persulfides
    DOI:  https://doi.org/10.1016/j.redox.2024.103125
  10. J Clin Invest. 2024 Apr 04. pii: e171002. [Epub ahead of print]
    Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function.
    Candice Quin, Erica N DeJong, Elina K Cook, Yi Zhen Luo, Caitlyn Vlasschaert, Sanathan Sadh, Amy Jm McNaughton, Marco M Buttigieg, Jessica A Breznik, Allison E Kennedy, Kevin Zhao, Jeffrey Mewburn, Kimberly J Dunham-Snary, Charles Ct Hindmarch, Alexander G Bick, Stephen L Archer, Michael J Rauh, Dawn Me Bowdish.
      Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP impacts risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2 knockout (Tet2-/-) and floxed control mice (Tet2f/f) with Streptococcus pneumoniae. As with human CHIP carriers, Tet2-/- mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S. pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in Tet2-/- mice. We delineated the transcriptional landscape of Tet2-/- neutrophils and found that while inflammation-related pathways were upregulated in Tet2-/- neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake and neutrophil extracellular trap (NET) formation by Tet2-/- neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments.
    Keywords:  Immunology; Infectious disease; Innate immunity
    DOI:  https://doi.org/10.1172/JCI171002
  11. Nat Metab. 2024 Apr 01.
    Maternal circadian rhythm disruption affects neonatal inflammation via metabolic reprograming of myeloid cells.
    Zhaohai Cui, Haixu Xu, Fan Wu, Jiale Chen, Lin Zhu, Zhuxia Shen, Xianfu Yi, Jinhao Yang, Chunhong Jia, Lijuan Zhang, Pan Zhou, Mulin Jun Li, Lu Zhu, Shengzhong Duan, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou.
      Disruption of circadian rhythm during pregnancy produces adverse health outcomes in offspring; however, the role of maternal circadian rhythms in the immune system of infants and their susceptibility to inflammation remains poorly understood. Here we show that disruption of circadian rhythms in pregnant mice profoundly aggravates the severity of neonatal inflammatory disorders in both male and female offspring, such as necrotizing enterocolitis and sepsis. The diminished maternal production of docosahexaenoic acid (DHA) and the impaired immunosuppressive function of neonatal myeloid-derived suppressor cells (MDSCs) contribute to this phenomenon. Mechanistically, DHA enhances the immunosuppressive function of MDSCs via PPARγ-mediated mitochondrial oxidative phosphorylation. Transfer of MDSCs or perinatal supplementation of DHA relieves neonatal inflammation induced by maternal rhythm disruption. These observations collectively demonstrate a previously unrecognized role of maternal circadian rhythms in the control of neonatal inflammation via metabolic reprograming of myeloid cells.
    DOI:  https://doi.org/10.1038/s42255-024-01021-y
  12. Trends Immunol. 2024 Apr 04. pii: S1471-4906(24)00032-2. [Epub ahead of print]
    Approaches for studying human macrophages.
    Yuzhou Bao, Guanlin Wang, Hanjie Li.
      Macrophages are vital tissue components involved in organogenesis, maintaining homeostasis, and responses to disease. Mouse models have significantly improved our understanding of macrophages. Further investigations into the characteristics and development of human macrophages are crucial, considering the substantial anatomical and physiological distinctions between mice and humans. Despite challenges in human macrophage research, recent studies are shedding light on the ontogeny and function of human macrophages. In this opinion, we propose combinations of cutting-edge approaches to examine the diversity, development, niche, and function of human tissue-resident macrophages. These methodologies can facilitate our exploration of human macrophages more efficiently, ideally providing new therapeutic avenues for macrophage-relevant disorders.
    Keywords:  hematopoiesis; human macrophage; human organoids; macrophage development; single-cell technologies; tissue-resident macrophage
    DOI:  https://doi.org/10.1016/j.it.2024.02.007
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