bims-traimu Biomed News
on Trained immunity
Issue of 2024–11–10
eleven papers selected by
Yantong Wan, Southern Medical University
  1. Resveratrol Potentiates BCG-induced Trained Immunity in Human Monocytes.
  2. Single high-fat challenge and trained innate immunity: A randomized controlled cross-over trial.
  3. Long-term monocyte activation after coronary artery bypass grafting: an exploratory prospective observational study.
  4. Alveolar epithelial cells shape lipopolysaccharide-induced inflammatory responses and reprogramming of alveolar macrophages.
  5. Linking metabolic and epigenetic changes in immune tolerance.
  6. Single cell RNA-seq reveals cellular and transcriptional heterogeneity in the splenic CD11b+Ly6Chigh monocyte population expanded in sepsis-surviving mice.
  7. Identification of two repurposed drugs targeting GSDMD oligomerization interface I to block pyroptosis.
  8. Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade.
  9. Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia.
  10. Extracellular vesicle-packaged PD-L1 impedes macrophage-mediated antibacterial immunity in preexisting malignancy.
  11. Bacterial toxins induce non-canonical migracytosis to aggravate acute inflammation.
  1. J Leukoc Biol. 2024 Nov 04. pii: qiae241. [Epub ahead of print]
    Resveratrol Potentiates BCG-induced Trained Immunity in Human Monocytes.
    Ozlem Bulut, Ilayda Baydemir, Gizem Kilic, Jorge Domínguez-Andrés, Mihai G Netea.
      Resveratrol is a natural polyphenol derived from plants such as grapes and berries. In addition to its role in plants during injury and infection, various cardioprotective, neuroprotective, and longevity-promoting effects were reported in diverse model organisms. The primary target of resveratrol is the deacetylase Sirtuin 1 (SIRT1), which regulates many immunological processes, including BCG-induced trained immunity response in humans. We, therefore, investigated the effect of resveratrol on trained immunity induced by BCG, β-glucan, C. albicans, or oxidized low-density lipoprotein (oxLDL). Using an in-vitro model of trained immunity with monocytes obtained from healthy donors, we demonstrate that resveratrol amplifies BCG-induced trained immunity regarding IL-6 and TNFα production after a secondary challenge. Although resveratrol did not improve and even limited glycolysis, oxidative phosphorylation, and reactive oxygen species production, it enhanced the permissive epigenetic mark H3K27Ac on IL-6 and TNFα promoters. In contrast to BCG-induced trained immunity, resveratrol potently inhibited training induced by β-glucan, C. albicans, oxLDL, and muramyl dipeptide (MDP), a peptidoglycan component of BCG. Resveratrol's unique boosting effect on BCG training depended on BCG being alive and metabolically active. These results suggest that resveratrol might amplify the effects of BCG vaccination, which should be mechanistically characterized further. In addition, resveratrol could alleviate oxLDL-induced training of innate immune cells in atherosclerosis, and in-vivo studies of trained immunity combined with resveratrol are warranted to explore these therapeutic possibilities.
    Keywords:  BCG; immunometabolism; resveratrol; trained immunity
    DOI:  https://doi.org/10.1093/jleuko/qiae241
  2. iScience. 2024 Nov 15. 27(11): 111103
    Single high-fat challenge and trained innate immunity: A randomized controlled cross-over trial.
    Julia van Tuijl, Julia I P van Heck, Harsh Bahrar, Wieteke Broeders, Johan Wijma, Yvonne M Ten Have, Martin Giera, Heidi Zweers-van Essen, Laura Rodwell, Leo A B Joosten, Mihai G Netea, Lydia A Afman, Siroon Bekkering, Niels P Riksen.
      Brief exposure of monocytes to atherogenic molecules, such as oxidized lipoproteins, triggers a persistent pro-inflammatory phenotype, named trained immunity. In mice, transient high-fat diet leads to trained immunity, which aggravates atherogenesis. We hypothesized that a single high-fat challenge in humans induces trained immunity. In a randomized controlled cross-over study, 14 healthy individuals received a high-fat or reference shake, and blood was drawn before and after 1, 2, 4, 6, 24, and 72 h. Incubation of donor monocytes with the post-high-fat-shake serum induced trained immunity, regulated via Toll-like receptor 4. This was not mediated via triglyceride-rich lipoproteins, C12, 14, and 16, or metabolic endotoxemia. In vivo, however, the high-fat challenge did not affect monocyte phenotype and function. We conclude that a high-fat challenge leads to alterations in the serum composition that have the potential to induce trained immunity in vitro. However, this does not translate into a (persistent) hyperinflammatory monocyte phenotype in vivo.
    Keywords:  Health sciences; Human Physiology; Human metabolism
    DOI:  https://doi.org/10.1016/j.isci.2024.111103
  3. Immunol Lett. 2024 Nov 01. pii: S0165-2478(24)00115-9. [Epub ahead of print] 106941
    Long-term monocyte activation after coronary artery bypass grafting: an exploratory prospective observational study.
    Wieteke Broeders, Julia van Tuijl, Harmke B Duindam, Annemieke M Peters van Ton, Marlies P Noz, Peter Pickkers, Wilson F Abdo, Mihai G Netea, Siroon Bekkering, Niels P Riksen.
      Major surgery such as coronary artery bypass grafting (CABG) is associated with an increased post-operative risk of atherosclerotic cardiovascular events. Cells of the innate immune system can adopt a long-lasting pro-inflammatory and atherogenic phenotype after brief exposure to exogenous or endogenous inflammatory stimuli, a process called "trained immunity". We hypothesized that the surgery-induced inflammation leads to sustained alterations in monocyte function, which promote the subsequent occurrence of cardiovascular events. Blood from 13 patients undergoing elective CABG was obtained before, 3-7 days (median 4) after, and 6-8 weeks (median 6) weeks after surgery. At 3-7 days postoperatively, circulating C-reactive protein (CRP) concentration, leukocyte counts and ex vivo Peripheral Blood Mononuclear Cell (PBMC) IL-6, TNFα and IL-1Ra production after stimulation (with various inflammatory stimuli) were significantly increased. Simultaneously, there was a reduction in monocyte HLA-DR expression. 6-8 weeks after CABG there was an ongoing systemic pro-inflammatory state with higher CRP concentrations, increased stimulated ex vivo PBMC IL-6 production, changes in monocytes subsets, and a higher expression of CCR2 on monocytes compared to baseline. In conclusion, CABG induces a persistent systemic inflammatory reaction with a sustained activated monocyte phenotype. This might contribute to the increased atherosclerotic cardiovascular event risk observed in cardiac surgery patients.
    Keywords:  CABG; atherosclerotic cardiovascular events; monocytes; trained immunity
    DOI:  https://doi.org/10.1016/j.imlet.2024.106941
  4. Eur J Immunol. 2024 Nov 05. e2350378
    Alveolar epithelial cells shape lipopolysaccharide-induced inflammatory responses and reprogramming of alveolar macrophages.
    Wei Jiang, Yeying Chen, Cheng-Yun Yu, Benkun Zou, Yimeng Lu, Qian Yang, Zihui Tang, Weiying Mao, Jing Li, Han Han, Lingyun Shao, Jiashun Zeng, Yiwei Chu, Jianguo Tang, Mingfang Lu.
      Alveolar macrophages (AMs) are sentinels in the airways, where they sense and respond to invading microbes and other stimuli. Unlike macrophages in other locations, AMs can remain responsive to Gram-negative lipopolysaccharides (LPS) after they have responded to LPS in vivo (they do not develop "endotoxin tolerance"), suggesting that the alveolar microenvironment may influence their responses. Although alveolar epithelial cells (AECs) normally limit AMs' innate responses, preventing inflammation induced by harmless antigens in the lung, how AECs influence the innate responses of AMs to infectious agents has been uncertain. Here we report that (1) after exposure to aspirated (intranasal instillation) LPS, AMs increase their responses to TLR agonists and elevate their phagocytic and bactericidal activities in mice; (2) Aspirated LPS pre-exposure increases host resistance to pulmonary infection caused by Gram-negative bacteria and the protection effect lasts for at least 35 days; (3) LPS stimulation of AECs both increases AMs' innate immune responses and prevents AMs from developing tolerance in vitro; (4) Upon LPS stimulation, AMs secreted TNF-α induces AECs to release GM-CSF, which potentiates AMs' response. These experiments have revealed a previously unappreciated role that AECs may play in boosting the innate responses of AMs and promoting resistance to pulmonary infections.
    Keywords:  Alveolar epithelial cells (AECs); Alveolar macrophages (AMs); Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF); Macrophage reprogramming
    DOI:  https://doi.org/10.1002/eji.202350378
  5. Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2419751121
    Linking metabolic and epigenetic changes in immune tolerance.
    Frederick J Sheedy, Eva Kaufmann.
      
    DOI:  https://doi.org/10.1073/pnas.2419751121
  6. Mol Med. 2024 Nov 06. 30(1): 202
    Single cell RNA-seq reveals cellular and transcriptional heterogeneity in the splenic CD11b+Ly6Chigh monocyte population expanded in sepsis-surviving mice.
    Haruki Watanabe, Minakshi Rana, Myoungsun Son, Pui Yan Chiu, Yurong Fei-Bloom, Kwangmin Choi, Betty Diamond, Barbara Sherry.
       BACKGROUND: Sepsis survivors exhibit immune dysregulation that contributes to poor long-term outcomes. Phenotypic and functional alterations within the myeloid compartment are believed to be a contributing factor. Here we dissect the cellular and transcriptional heterogeneity of splenic CD11b+Ly6Chigh myeloid cells that are expanded in mice that survive the cecal ligation and puncture (CLP) murine model of polymicrobial sepsis to better understand the basis of immune dysregulation in sepsis survivors.
    METHODS: Sham or CLP surgeries were performed on C57BL/6J and BALB/c mice. Four weeks later splenic CD11b+Ly6Chigh cells from both groups were isolated for phenotypic (flow cytometry) and functional (phagocytosis and glycolysis) characterization and RNA was obtained for single-cell RNA-seq (scRNA-seq) and subsequent analysis.
    RESULTS: CD11b+Ly6Chigh cells from sham and CLP surviving mice exhibit phenotypic and functional differences that relate to immune function, some of which are observed in both C57BL/6J and BALB/c strains and others that are not. To dissect disease-specific and strain-specific distinctions within the myeloid compartment, scRNA-seq analysis was performed on CD11b+Ly6Chigh cells from C57BL/6J and BALB/c sham and CLP mice. Uniform Manifold Approximation and Projection from both strains identified 13 distinct clusters of sorted CD11b+Ly6Chigh cells demonstrating significant transcriptional heterogeneity and expressing gene signatures corresponding to classical-monocytes, non-classical monocytes, M1- or M2-like macrophages, dendritic-like cells, monocyte-derived dendritic-like cells, and proliferating monocytic myeloid-derived suppressor cells (M-MDSCs). Frequency plots showed that the percentages of proliferating M-MDSCs (clusters 8, 11 and 12) were increased in CLP mice compared to sham mice in both strains. Pathway and UCell score analysis in CLP mice revealed that cell cycle and glycolytic pathways were upregulated in proliferating M-MDSCs in both strains. Notably, granule protease genes were upregulated in M-MDSCs from CLP mice. ScRNA-seq analyses also showed that phagocytic pathways were upregulated in multiple clusters including the classical monocyte cluster, confirming the increased phagocytic capacity in CD11b+Ly6Chigh cells from CLP mice observed in ex vivo functional assays in C57BL/6J mice.
    CONCLUSION: The splenic CD11b+Ly6Chigh myeloid populations expanded in survivors of CLP sepsis correspond to proliferating cells that have an increased metabolic demand and gene signatures consistent with M-MDSCs, a population known to have immunosuppressive capacity.
    Keywords:  CD11b+Ly6Chigh ; CLP; Glycolysis; Phagocytosis; Sepsis; scRNA-seq
    DOI:  https://doi.org/10.1186/s10020-024-00970-0
  7. Cell Chem Biol. 2024 Oct 26. pii: S2451-9456(24)00437-9. [Epub ahead of print]
    Identification of two repurposed drugs targeting GSDMD oligomerization interface I to block pyroptosis.
    Yingchao Hu, Honghui Li, Xiangyu Zhang, Yuxian Song, Jun Liu, Jie Pu, Shuang Wen, Hongyang Xu, Hongliang Xin, Bingwei Wang, Shuo Yang.
      As an executor of pyroptosis, gasdermin D (GSDMD) plays a critical role in inflammatory diseases and cancer. Thus, GSDMD is currently being widely explored as a drug target. Existing inhibitors targeting GSDMD, such as necrosulfonamide, disulfiram, and fumarate, primarily prevent pyroptosis by modifying human/mouse C191/C192 in the N-terminal fragment of GSDMD. However, cysteine modification can prevent the function of important proteins or enzymes, thereby leading to adverse reactions. Here, we chose an alternative key intervention site for GSDMD activation, which is located at the oligomerization interface I of its pore-forming structure. Through high-throughput virtual and experimental screening and in combination with efficacy and pharmacological validation, we have identified two safe, specific "repurposed drugs" that potently suppress GSDMD-mediated pyroptosis. Moreover, the candidates exhibited synergistic therapeutic effects of "1 + 1>2" in murine sepsis and tumorigenesis models. These recently identified GSDMD inhibitors hold great promise for clinical translation in the development of anti-inflammatory and anti-cancer immunotherapies.
    Keywords:  GSDMD; anti-cancer inhibitors; anti-inflammatory; oligomerization interface I
    DOI:  https://doi.org/10.1016/j.chembiol.2024.10.002
  8. Nat Commun. 2024 Nov 06. 15(1): 9575
    Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade.
    Mayra Cruz Tleugabulova, Sandra P Melo, Aaron Wong, Alexander Arlantico, Meizi Liu, Joshua D Webster, Julia Lau, Antonie Lechner, Basak Corak, Jonathan J Hodgins, Venkata S Garlapati, Marco De Simone, Ben Korin, Shimrit Avraham, Jessica Lund, Surinder Jeet, Alexander Reiss, Hannah Bender, Cary D Austin, Spyros Darmanis, Zora Modrusan, Hans Brightbill, Steffen Durinck, Michael S Diamond, Christoph Schneider, Andrey S Shaw, Maximilian Nitschké.
      Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells, and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Previously, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2, has been described in several models of organ injury and cancer, and has been linked to fibrosis in mice and humans. Here, we show that Notch2 blockade, given systemically or locally, leads to an increase in this putative pro-fibrotic macrophage in the lung and that this macrophage state can only be adopted by monocytically derived cells and not resident alveolar macrophages. Using a bleomycin and COVID-19 model of lung injury and fibrosis, we find that the expansion of these macrophages before lung injury does not promote fibrosis but rather appears to ameliorate it. This suggests that these damage-associated macrophages are not, by themselves, drivers of fibrosis in the lung.
    DOI:  https://doi.org/10.1038/s41467-024-53700-9
  9. PLoS Pathog. 2024 Nov 05. 20(11): e1012614
    Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia.
    Cui Wang, Jun Wen, Zijun Yan, Yujun Zhou, Zhande Gong, Ying Luo, Zhenkui Li, Kang Zheng, Haijun Zhang, Nan Ding, Chuan Wang, Cuiming Zhu, Yimou Wu, Aihua Lei.
      Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in which neutrophils play a critical role. Immune-responsive gene 1 (IRG1), responsible for itaconate production, has emerged as an important regulator of inflammation and infection, but its role during M. pneumoniae infection remains unknown. Here, we reveal that itaconate is an endogenous pro-inflammatory metabolite during M. pneumoniae infection. Irg1 knockout (KO) mice had lower levels of bacterial burden, lactate dehydrogenase (LDH), and pro-inflammatory cytokines compared with wild-type (WT) controls after M. pneumoniae infection. Neutrophils were the major cells producing itaconate during M. pneumoniae infection in mice. Neutrophil counts were positively correlated with itaconate concentrations in bronchoalveolar lavage fluid (BALF) of patients with severe M. pneumoniae pneumonia. Adoptive transfer of Irg1 KO neutrophils, or administration of β-glucan (an inhibitor of Irg1 expression), significantly attenuated M. pneumoniae pneumonia in mice. Mechanistically, itaconate impaired neutrophil bacterial killing and suppressed neutrophil apoptosis via inhibiting mitochondrial ROS. Moreover, M. pneumoniae induced Irg1 expression by activating NF-κB and STAT1 pathways involving TLR2. Our data thus identify Irg1/itaconate pathway as a potential therapeutic target for the treatment of M. pneumoniae pneumonia.
    DOI:  https://doi.org/10.1371/journal.ppat.1012614
  10. Cell Rep. 2024 Oct 26. pii: S2211-1247(24)01254-3. [Epub ahead of print]43(11): 114903
    Extracellular vesicle-packaged PD-L1 impedes macrophage-mediated antibacterial immunity in preexisting malignancy.
    He-Jing Zhang, Lingxin Zhu, Qi-Hui Xie, Lin-Zhou Zhang, Jin-Yuan Liu, Yang-Ying-Fan Feng, Zhuo-Kun Chen, Hou-Fu Xia, Qiu-Yun Fu, Zi-Li Yu, Gang Chen.
      Malignancies can compromise systemic innate immunity, but the underlying mechanisms are largely unknown. Here, we find that tumor-derived small extracellular vesicles (sEVs; TEVs) deliver PD-L1 to host macrophages, thereby impeding antibacterial immunity. Mice implanted with Rab27a-knockdown tumors are more resistant to bacterial infection than wild-type controls. Injection of TEVs into mice impairs macrophage-mediated bacterial clearance, increases systemic bacterial dissemination, and enhances sepsis score in a PD-L1-dependent manner. Mechanistically, TEV-packaged PD-L1 inhibits Bruton's tyrosine kinase/PLCγ2 signaling-mediated cytoskeleton reorganization and reactive oxygen species generation, impacting bacterial phagocytosis and killing by macrophages. Neutralizing PD-L1 markedly normalizes macrophage-mediated bacterial clearance in tumor-bearing mice. Importantly, circulating sEV PD-L1 levels in patients with tumors can predict bacterial infection susceptibility, while patients with tumors treated with αPD-1 exhibit fewer postoperative infections. These findings identify a mechanism by which cancer cells dampen host innate immunity-mediated bacterial clearance and suggest targeting TEV-packaged PD-L1 to reduce bacterial infection susceptibility in tumor-bearing conditions.
    Keywords:  Bruton’s tyrosine kinase; CP: Cancer; CP: Immunology; PD-L1; ROS; antibacterial immunity; cytoskeleton; macrophage; tumor-derived extracellular vesicle
    DOI:  https://doi.org/10.1016/j.celrep.2024.114903
  11. Cell Discov. 2024 Nov 05. 10(1): 112
    Bacterial toxins induce non-canonical migracytosis to aggravate acute inflammation.
    Diyin Li, Qi Yang, Jianhua Luo, Yangyushuang Xu, Jingqing Li, Liang Tao.
      Migracytosis is a recently described cellular process that generates and releases membrane-bound pomegranate-like organelles called migrasomes. Migracytosis normally occurs during cell migration, participating in various intercellular biological functions. Here, we report a new type of migracytosis induced by small GTPase-targeting toxins. Unlike classic migracytosis, toxin-induced migrasome formation does not rely on cell migration and thus can occur in both mobile and immobile cells. Such non-canonical migracytosis allows the cells to promptly respond to microbial stimuli such as bacterial toxins and effectors and release informative cellular contents in bulk. We demonstrated that C. difficile TcdB3 induces liver endothelial cells and Kupffer cells to produce migrasomes in vivo. Moreover, the migracytosis-defective Tspan9‒/‒ mice show less acute inflammation and lower lethality rate in the toxin challenge assay. Therefore, we propose that the non-canonical migracytosis acts as a new mechanism for mammalian species to sense and exacerbate early immune response upon microbial infections.
    DOI:  https://doi.org/10.1038/s41421-024-00729-1
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