bims-traimu Biomed News
on Trained immunity
Issue of 2024‒08‒25
thirteen papers selected by
Yantong Wan, Southern Medical University
  1. Protocol for analyzing BCG-induced trained immunity in murine bone marrow-derived macrophages.
  2. RORα negatively regulates BCG-induced trained immunity.
  3. BCG vaccination alters the epigenetic landscape of progenitor cells in human bone marrow to influence innate immune responses.
  4. Stroke-induced trained immunity spells bad news for the heart.
  5. Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling.
  6. Clinical immunity to malaria involves epigenetic reprogramming of innate immune cells.
  7. Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD+/NADH balance.
  8. The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain.
  9. Tumor editing suppresses innate and adaptive antitumor immunity and is reversed by inhibiting DNA methylation.
  10. Released bacterial ATP shapes local and systemic inflammation during abdominal sepsis.
  11. Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2.
  12. LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization.
  13. Significance of Bacillus Calmette-Guerin (BCG) vaccine intervention for patients with Type 1 Diabetes (T1D): A systematic review and meta-analysis.
  1. STAR Protoc. 2024 Aug 17. pii: S2666-1667(24)00432-5. [Epub ahead of print]5(3): 103267
    Protocol for analyzing BCG-induced trained immunity in murine bone marrow-derived macrophages.
    Jin-Chuan Xu, Zhidong Hu, Xiao-Yong Fan.
      Bacillus Calmette-Guérin (BCG), the only licensed tuberculosis vaccine, provides non-specific protection against non-tuberculosis diseases that is mediated by trained immunity, a functional reprogramming mediated by innate immune memory. Here, we present a protocol for analyzing BCG-induced trained immunity in murine bone marrow-derived macrophages (BMDMs). We describe steps for preparing BCG single bacterial suspensions, isolating BMDM cells, and the training process. This protocol can assist researchers to conveniently utilize BMDM cells to study trained immunity. For complete details on the use and execution of this protocol, please refer to Xu et al.1.
    Keywords:  Cell culture; Cell isolation; Immunology; Microbiology; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2024.103267
  2. Cell Immunol. 2024 Aug 15. pii: S0008-8749(24)00065-0. [Epub ahead of print]403-404 104862
    RORα negatively regulates BCG-induced trained immunity.
    Gizem Kilic, Vasiliki Matzaraki, Ozlem Bulut, Ilayda Baydemir, Anaisa V Ferreira, Katrin Rabold, Simone J C F M Moorlag, Valerie A C M Koeken, L Charlotte J de Bree, Vera P Mourits, Leo A B Joosten, Jorge Domínguez-Andrés, Mihai G Netea.
      Trained immunity is a long-lasting change in the responsiveness of innate immune cells, leading to a stronger response upon an unrelated secondary challenge. Epigenetic, transcriptional, and metabolic reprogramming contribute to the development of trained immunity. By investigating the impact of gene variants on trained immunity responses after Bacillus Calmette-Guérin (BCG) vaccination, we identified a strong association between polymorphisms in the RORA gene and BCG-induced trained immunity in PBMCs isolated from healthy human donors. RORα, encoded by the RORA gene in humans, is a nuclear receptor and a transcription factor, regulating genes involved in circadian rhythm, inflammation, cholesterol, and lipid metabolism. We found that natural RORα agonists in the circulation negatively correlate with the strength of trained immunity responses after BCG vaccination. Moreover, pharmacological inhibition of RORα in human PBMCs led to higher cytokine production capacity and boosted trained immunity induction by BCG. Blocking RORα activity also resulted in morphological changes and increased ROS and lactate production of BCG-trained cells. Blocking lactate dehydrogenase A (LDHA) and glycolysis with sodium oxamate reduced the cytokine production capacity of cells trained with a combination of BCG and the RORα agonist. In conclusion, this study highlights the potential role of RORα in trained immunity, and its impact on human vaccination and diseases should be further investigated.
    Keywords:  BCG; Immunometabolism; RORA; Trained immunity
    DOI:  https://doi.org/10.1016/j.cellimm.2024.104862
  3. Immunity. 2024 Aug 14. pii: S1074-7613(24)00370-4. [Epub ahead of print]
    BCG vaccination alters the epigenetic landscape of progenitor cells in human bone marrow to influence innate immune responses.
    Sarah J Sun, Raúl Aguirre-Gamboa, L Charlotte J de Bree, Joaquin Sanz, Anne Dumaine, Walter J F M van der Velden, Leo A B Joosten, Shabaana Khader, Maziar Divangahi, Mihai G Netea, Luis B Barreiro.
      Although the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo. We showed that BCG alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occurred primarily within uncommitted stem cells. By contrast, changes in chromatin accessibility were most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF) and early growth response (EGR) transcription factors and were highly correlated (r > 0.8) with the interleukin (IL)-1β secretion capacity of paired peripheral blood mononuclear cells (PBMCs). Our findings shed light on BCG vaccination's profound and lasting effects on HSPCs and its influence on innate immune responses and trained immunity.
    Keywords:  BCG vaccination; hematopoietic stem cells; innate immunity; single-cell genomics; trained immunity
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.021
  4. Cell Res. 2024 Aug 20.
    Stroke-induced trained immunity spells bad news for the heart.
    George Hajishengallis, Triantafyllos Chavakis.
      
    DOI:  https://doi.org/10.1038/s41422-024-01018-y
  5. Cell Rep. 2024 Aug 22. pii: S2211-1247(24)01015-5. [Epub ahead of print]43(9): 114664
    Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling.
    Maaike M E Jacobs, Rianne J F Maas, Inge Jonkman, Yutaka Negishi, Willem Tielemans Zamora, Cansu Yanginlar, Julia van Heck, Vasiliki Matzaraki, Joost H A Martens, Marijke Baltissen, Michiel Vermeulen, Judit Morla-Folch, Anna Ranzenigo, William Wang, Martin Umali, Jordi Ochando, Johan van der Vlag, Luuk B Hilbrands, Leo A B Joosten, Mihai G Netea, Willem J M Mulder, Mandy M T van Leent, Musa M Mhlanga, Abraham J P Teunissen, Nils Rother, Raphaël Duivenvoorden.
      Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitro studies, we reveal that single-nucleotide polymorphisms in the proximity of CD40 are linked to trained immunity responses in vivo and that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes.
    Keywords:  CD40-CD40L; CP: Immunology; T cells; innate immunity; monocytes; nanobiologics; trained immunity
    DOI:  https://doi.org/10.1016/j.celrep.2024.114664
  6. PNAS Nexus. 2024 Aug;3(8): pgae325
    Clinical immunity to malaria involves epigenetic reprogramming of innate immune cells.
    Jason Nideffer, Maureen Ty, Michele Donato, Rek John, Richard Kajubi, Xuhuai Ji, Felistas Nankya, Kenneth Musinguzi, Kathleen Dantzler Press, Nora Yang, Kylie Camanag, Bryan Greenhouse, Moses Kamya, Margaret E Feeney, Grant Dorsey, Paul J Utz, Bali Pulendran, Purvesh Khatri, Prasanna Jagannathan.
      The regulation of inflammation is a critical aspect of disease tolerance and naturally acquired clinical immunity to malaria. Here, we demonstrate using RNA sequencing and epigenetic landscape profiling by cytometry by time-of-flight, that the regulation of inflammatory pathways during asymptomatic parasitemia occurs downstream of pathogen sensing-at the epigenetic level. The abundance of certain epigenetic markers (methylation of H3K27 and dimethylation of arginine residues) and decreased prevalence of histone variant H3.3 correlated with suppressed cytokine responses among monocytes of Ugandan children. Such an epigenetic signature was observed across diverse immune cell populations and not only characterized active asymptomatic parasitemia but also correlated with future long-term disease tolerance and clinical immunity when observed in uninfected children. Pseudotime analyses revealed a potential trajectory of epigenetic change that correlated with a child's age and recent parasite exposure and paralleled the acquisition of clinical immunity. Thus, our data support a model whereby exposure to Plasmodium falciparum induces epigenetic changes that regulate excessive inflammation and contribute to naturally acquire clinical immunity to malaria.
    DOI:  https://doi.org/10.1093/pnasnexus/pgae325
  7. Cell Rep. 2024 Aug 20. pii: S2211-1247(24)00999-9. [Epub ahead of print]43(9): 114648
    Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD+/NADH balance.
    Jingjing Tang, Xiao Wang, Shukun Chen, Tianyuan Chang, Yanchao Gu, Fuhua Zhang, Jing Hou, Yi Luo, Mengyuan Li, Jianan Huang, Mohua Liu, Lei Zhang, Yao Wang, Xihui Shen, Lei Xu.
      Metabolic reprogramming is crucial for activating innate immunity in macrophages, and the accumulation of immunometabolites is essential for effective defense against infection. The NAD+/NADH (ratio of nicotinamide adenine dinucleotide and its reduced counterpart) redox couple serves as a critical node that integrates metabolic pathways and signaling events, but how this metabolite couple engages macrophage activation remains unclear. Here, we show that the NAD+/NADH ratio serves as a molecular signal that regulates proinflammatory responses and type I interferon (IFN) responses divergently. Salmonella Typhimurium infection leads to a decreased NAD+/NADH ratio by inducing the accumulation of NADH. Further investigation shows that an increased NAD+/NADH ratio correlates with attenuated proinflammatory responses and enhanced type I IFN responses. Conversely, a decreased NAD+/NADH ratio is linked to intensified proinflammatory responses and restrained type I IFN responses. These results show that the NAD+/NADH ratio is an essential cell-intrinsic factor that orchestrates innate immunity, which enhances our understanding of how metabolites fine-tune innate immunity.
    Keywords:  CP: Immunology; CP: Metabolism; IFN; LPS; NAD(+)/NADH ratio; Salmonella Typhimurium; immunometabolites; lipopolysaccharide; metabolic reprogramming; proinflammatory responses; type I interferon
    DOI:  https://doi.org/10.1016/j.celrep.2024.114648
  8. J Neuroinflammation. 2024 Aug 20. 21(1): 207
    The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain.
    Melanie Ohm, Shirin Hosseini, Niklas Lonnemann, Wei He, Tushar More, Oliver Goldmann, Eva Medina, Karsten Hiller, Martin Korte.
      Despite advances in antimicrobial and anti-inflammatory treatment, inflammation and its consequences remain a major challenge in the field of medicine. Inflammatory reactions can lead to life-threatening conditions such as septic shock, while chronic inflammation has the potential to worsen the condition of body tissues and ultimately lead to significant impairment of their functionality. Although the central nervous system has long been considered immune privileged to peripheral immune responses, recent research has shown that strong immune responses in the periphery also affect the brain, leading to reactive microglia, which belong to the innate immune system and reside in the brain, and neuroinflammation. The inflammatory response is primarily a protective mechanism to defend against pathogens and tissue damage. However, excessive and chronic inflammation can have negative effects on neuronal structure and function. Neuroinflammation underlies the pathogenesis of many neurological and neurodegenerative diseases and can accelerate their progression. Consequently, targeting inflammatory signaling pathways offers potential therapeutic strategies for various neuropathological conditions, particularly Parkinson's and Alzheimer's disease, by curbing inflammation. Here the blood-brain barrier is a major hurdle for potential therapeutic strategies, therefore it would be highly advantageous to foster and utilize brain innate anti-inflammatory mechanisms. The tricarboxylic acid cycle-derived metabolite itaconate is highly upregulated in activated macrophages and has been shown to act as an immunomodulator with anti-inflammatory and antimicrobial functions. Mesaconate, an isomer of itaconate, similarly reduces the inflammatory response in macrophages. Nevertheless, most studies have focused on its esterified forms and its peripheral effects, while its influence on the CNS remained largely unexplored. Therefore, this study investigated the immunomodulatory and therapeutic potential of endogenously synthesized itaconate and its isomer mesaconate in lipopolysaccharide (LPS)-induced neuroinflammatory processes. Our results show that both itaconate and mesaconate reduce LPS-induced neuroinflammation, as evidenced by lower levels of inflammatory mediators, reduced microglial reactivity and a rescue of synaptic plasticity, the cellular correlate of learning and memory processes in the brain. Overall, this study emphasizes that both itaconate and mesaconate have therapeutic potential for neuroinflammatory processes in the brain and are of remarkable importance due to their endogenous origin and production, which usually leads to high tolerance.
    Keywords:  Hippocampus; LPS; Microglia; Neuroinflammation; Synaptic plasticity
    DOI:  https://doi.org/10.1186/s12974-024-03188-3
  9. Nat Immunol. 2024 Aug 21.
    Tumor editing suppresses innate and adaptive antitumor immunity and is reversed by inhibiting DNA methylation.
    Ying Zhang, Pourya Naderi Yeganeh, Haiwei Zhang, Simon Yuan Wang, Zhouyihan Li, Bowen Gu, Dian-Jang Lee, Zhibin Zhang, Athanasios Ploumakis, Ming Shi, Hao Wu, Eric Lieberman Greer, Winston Hide, Judy Lieberman.
      Cancer cells edit gene expression to evade immunosurveillance. However, genome-wide studies of gene editing during early tumorigenesis are lacking. Here we used single-cell RNA sequencing in a breast cancer genetically engineered mouse model (GEMM) to identify edited genes without bias. Late tumors repressed antitumor immunity genes, reducing infiltrating immune cells and tumor-immune cell communications. Innate immune genes, especially interferon-stimulated genes, dominated the list of downregulated tumor genes, while genes that regulate cell-intrinsic malignancy were mostly unedited. Naive and activated CD8+ T cells in early tumors were replaced with exhausted or precursor-exhausted cells in late tumors. Repression of immune genes was reversed by inhibiting DNA methylation using low-dose decitabine, which suppressed tumor growth and restored immune control, increasing the number, functionality and memory of tumor-infiltrating lymphocytes and reducing the number of myeloid suppressor cells. Decitabine induced important interferon, pyroptosis and necroptosis genes, inflammatory cell death and immune control in GEMM and implanted breast and melanoma tumors.
    DOI:  https://doi.org/10.1038/s41590-024-01932-8
  10. Elife. 2024 Aug 20. pii: RP96678. [Epub ahead of print]13
    Released bacterial ATP shapes local and systemic inflammation during abdominal sepsis.
    Daniel Spari, Annina Schmid, Daniel Sanchez-Taltavull, Shaira Murugan, Keely Keller, Nadia Ennaciri, Lilian Salm, Deborah Stroka, Guido Beldi.
      Sepsis causes millions of deaths per year worldwide and is a current global health priority declared by the WHO. Sepsis-related deaths are a result of dysregulated inflammatory immune responses indicating the need to develop strategies to target inflammation. An important mediator of inflammation is extracellular adenosine triphosphate (ATP) that is released by inflamed host cells and tissues, and also by bacteria in a strain-specific and growth-dependent manner. Here, we investigated the mechanisms by which bacteria release ATP. Using genetic mutant strains of Escherichia coli (E. coli), we demonstrate that ATP release is dependent on ATP synthase within the inner bacterial membrane. In addition, impaired integrity of the outer bacterial membrane notably contributes to ATP release and is associated with bacterial death. In a mouse model of abdominal sepsis, local effects of bacterial ATP were analyzed using a transformed E. coli bearing an arabinose-inducible periplasmic apyrase hydrolyzing ATP to be released. Abrogating bacterial ATP release shows that bacterial ATP suppresses local immune responses, resulting in reduced neutrophil counts and impaired survival. In addition, bacterial ATP has systemic effects via its transport in outer membrane vesicles (OMV). ATP-loaded OMV are quickly distributed throughout the body and upregulated expression of genes activating degranulation in neutrophils, potentially contributing to the exacerbation of sepsis severity. This study reveals mechanisms of bacterial ATP release and its local and systemic roles in sepsis pathogenesis.
    Keywords:  ATP; E. coli; OMV; bacterial ATP; immunology; infectious disease; inflammation; microbiology; mouse; sepsis
    DOI:  https://doi.org/10.7554/eLife.96678
  11. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2405746121
    Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2.
    Souradipta Ganguly, Sara Brin Rosenthal, Kei Ishizuka, Ty D Troutman, Theresa V Rohm, Naser Khader, German Aleman-Muench, Yasuyo Sano, Sebastiano Archilei, Pejman Soroosh, Jerrold M Olefsky, Ariel E Feldstein, Tatiana Kisseleva, Rohit Loomba, Christopher K Glass, David A Brenner, Debanjan Dhar.
      While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2+ macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2+ macrophages are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.
    Keywords:  Trem2; fibrosis; lipid associated macrophages (LAM); macrophage; steatohepatitis
    DOI:  https://doi.org/10.1073/pnas.2405746121
  12. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2405845121
    LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization.
    Juan Wang, Jing Wang, Jiuchang Zhong, Hongbin Liu, Weiming Li, Mulei Chen, Li Xu, Wenbin Zhang, Ze Zhang, Zhizhong Wei, Jia Guo, Xinyu Wang, Jianhua Sui, Xingpeng Liu, Sitao Zhang, Xiaodong Wang.
      Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. How macrophages commit to proinflammatory polarization under atherosclerosis conditions is not clear. Report here that the level of a circulating protein, leucine-rich alpha-2 glycoprotein 1 (LRG1), is elevated in the atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD). LRG1 stimulated macrophages to proinflammatory M1-like polarization through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways. The LRG1 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet-induced Apoe-/- mouse atherosclerosis model. An anti-LRG1 neutralizing antibody also effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. LRG1 may therefore serve as an additional biomarker for CAD and targeting LRG1 could offer a potential therapeutic strategy for CAD patients by mitigating the proinflammatory response of macrophages.
    Keywords:  LRG1; atherosclerosis; inflammation; macrophage
    DOI:  https://doi.org/10.1073/pnas.2405845121
  13. Diabetes Metab Syndr. 2024 Aug 12. pii: S1871-4021(24)00163-2. [Epub ahead of print]18(8): 103102
    Significance of Bacillus Calmette-Guerin (BCG) vaccine intervention for patients with Type 1 Diabetes (T1D): A systematic review and meta-analysis.
    Sunil B Korde, Smita R Pillewan, Sanket R Dumbre, Anjali R Bandgar, Prajakta S Shinde, Sunil Gairola, Vandana S Nikam.
      PURPOSE: Immunotherapy is an emerging therapeutic modality for many autoimmune, oncology, and infectious diseases to cure or prevent the underlying causes. Several immunotherapeutic agents are investigated for their beneficial potential in patients with diabetes. However, none have culminated into a successful therapy. The present comprehensive meta-analysis and systematic review covers the last two decades of historical research evaluating the Bacillus Calmette-Guerin (BCG) vaccine as an immunotherapeutic agent in diabetes, along with updated information on similar recent publications.METHOD: A total of 278 articles were retrieved through literature databases, and after applying inclusion and exclusion criteria as per PRISMA guidelines, seven studies were selected for meta-analysis using Cochrane Q statistics.
    RESULTS: Our meta-analysis revealed marginal benefits, lowering glycosylated/glycated haemoglobin (HbA1C) levels and glutamic-acid-decarboxylase (GAD) autoantibodies in BCG treated people with Type 1 Diabetes (T1D) compared to the matched control individuals. The BCG intervention found to be ineffective in regulating C-peptide (connecting peptide) and clinical remission (CR) i.e. improved glycemic regulation, though beneficial tendency was observed.
    CONCLUSION: Our systematic review and meta-analysis revealed benefits of BCG vaccine intervention in T1D patients, including improved HbA1C and GAD autoantibody levels. However, the study has several limitations stemming from BCG vaccine-related factors and patient characteristics. Therefore, a large clinical trial with an enhanced study design is needed to validate the immunity-related benefits of the BCG vaccine for glucose metabolism in patients with T1D.
    DOI:  https://doi.org/10.1016/j.dsx.2024.103102
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