bims-traimu Biomed News
on Trained immunity
Issue of 2024–11–17
fourteen papers selected by
Yantong Wan, Southern Medical University
  1. Interleukin-1β induces trained innate immunity in human hematopoietic progenitor cells in vitro.
  2. Interleukin-10 inhibits important components of trained immunity in human monocytes.
  3. Trained immunity in the bone marrow: Hub of autoimmunity.
  4. The effect of BCG vaccination in the elderly on infectious and non-infectious immune-mediated diseases.
  5. Mycobacterium tuberculosis Antigen Rv1471 Induces Innate Immune Memory and Adaptive Immunity against Infection.
  6. A model of proximate protection against pathogenic infection through shared immunity.
  7. Trained immunity-based vaccines: A vision from the one health initiative.
  8. A GSDMD agonist boosts specific antitumor immunity.
  9. Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness.
  10. Probiotic bacteria-released extracellular vesicles enhance macrophage phagocytosis in polymicrobial sepsis by activating the FPR1/2 pathway.
  11. Itaconate promotes an unexpected tumor immune escape mechanism.
  12. Toll-Like Receptors Agonists: First-Line Defense Tools in the Pandemic Preparedness Arsenal?
  13. Long-term effects of continuous low dose-rate gamma-ray irradiation on mouse hematopoietic cells.
  14. 4-Octyl itaconate inhibits vascular calcification partially via modulation of HMOX-1 signaling.
  1. Stem Cell Reports. 2024 Sep 25. pii: S2213-6711(24)00266-2. [Epub ahead of print]
    Interleukin-1β induces trained innate immunity in human hematopoietic progenitor cells in vitro.
    Daniela Flores-Gomez, Willemijn Hobo, Diede van Ens, Elise L Kessler, Boris Novakovic, Nicolaas P M Schaap, Wim H C Rijnen, Leo A B Joosten, Mihai G Netea, Niels P Riksen, Siroon Bekkering.
      Innate immune cells can develop a long-lasting hyperresponsive phenotype, termed trained immunity, mediated by epigenetic and metabolic reprogramming. In mice, exposure to Bacille Calmette-Guérin (BCG), β-glucan, or Western diet induces trained immunity by reprogramming hematopoietic progenitor cells (HPCs), through interleukin-1β (IL-1β) signaling in the bone marrow (BM). We investigated whether IL-1β induces trained immunity in primary human BM-derived HPCs in vitro. We exposed human BM-derived HPCs to IL-1β for 4 h. HPCs were expanded and differentiated into monocytes followed by functional and transcriptomic characterization. IL-1β-exposed HPCs showed higher granulocyte-macrophage colony-forming units. The monocyte offspring produced more tumor necrosis factor (TNF) and IL-1β after restimulation with lipopolysaccharide (LPS) and Pam3Cys and is metabolically more active. Transcriptomic analysis showed upregulation of key atherogenic and inflammatory pathways. In conclusion, brief exposure of human BM-derived HPCs to IL-1β in vitro induces a trained immunity phenotype.
    Keywords:  IL-1β; bone marrow; hematopoietic progenitor cells; macrophages; monocytes; trained immunity
    DOI:  https://doi.org/10.1016/j.stemcr.2024.09.004
  2. J Leukoc Biol. 2024 Nov 12. pii: qiae240. [Epub ahead of print]
    Interleukin-10 inhibits important components of trained immunity in human monocytes.
    Rutger J Röring, Flavia Scognamiglio, Lisanne C de Jong, Laszlo A Groh, Vasiliki Matzaraki, Valerie A C M Koeken, Leo A B Joosten, Athanasios Ziogas, Mihai G Netea.
      Trained immunity induces antigen-agnostic enhancement of host defense and protection against secondary infections, but inappropriate activation can contribute to the pathophysiology of inflammatory diseases. Tight regulation of trained immunity is therefore needed to avoid pathology, but little is known about the endogenous processes that modulate it. Here, we investigated the potential of IL-10, a prototypical anti-inflammatory cytokine, to inhibit trained immunity. IL-10 induced tolerance and inhibited trained immunity in primary human monocytes at both functional and transcriptional levels. Inhibition of STAT3, a signaling route that mediates IL-10 signals, induced trained immunity. IL-10 downregulated glycolytic and oxidative metabolism in monocytes, but did not impact the metabolic effects of β-glucan-induced trained immunity. Furthermore, IL-10 prevented increased ROS production in BCG-induced training, but did not influence phagocytosis upregulation. In a cohort study of healthy volunteers vaccinated with BCG, genetic variants that influenced IL-10 or its receptor modulated BCG-induced trained immunity. Furthermore, circulating IL-10 concentrations were negatively correlated with induction of trained immunity after BCG vaccination in a sex-specific manner. In conclusion, IL-10 inhibited several, albeit not all, immunological functions amplified after induction of trained immunity. Follow-up studies should explore the precise molecular mechanism that mediate the effects of IL-10 on trained immunity. Addressing these knowledge gaps is an important step towards optimizing IL-10's potential as a therapeutic target in diseases characterized by inappropriate induction of trained immunity.
    Keywords:  IL-10; cytokines; tolerance; trained immunity
    DOI:  https://doi.org/10.1093/jleuko/qiae240
  3. Cell Stem Cell. 2024 Nov 07. pii: S1934-5909(24)00370-9. [Epub ahead of print]31(11): 1555-1557
    Trained immunity in the bone marrow: Hub of autoimmunity.
    Mihai G Netea, Leo A B Joosten.
      An inappropriate induction of trained immunity in the bone marrow progenitors of immune cells has been described to underlie chronic inflammatory processes. Mills and colleagues' recently published paper in Cell Stem Cell shows that maladaptive trained immunity drives inflammation in autoimmune processes,1 opening a new area of research in autoimmunity.
    DOI:  https://doi.org/10.1016/j.stem.2024.10.008
  4. J Infect. 2024 Nov 06. pii: S0163-4453(24)00279-2. [Epub ahead of print]89(6): 106344
    The effect of BCG vaccination in the elderly on infectious and non-infectious immune-mediated diseases.
    Elisabeth A Dulfer, Konstantin Föhse, Esther J M Taks, Simone J C F M Moorlag, Eva L Koekenbier, Josephine S van de Maat, Jaap Ten Oever, Jacobien J Hoogerwerf, Cornelis H van Werkhoven, Marc J M Bonten, Astrid van Hylckama Vlieg, Frits R Rosendaal, Mihai G Netea.
       OBJECTIVES: Previous research has suggested beneficial heterologous effects of the Bacillus Calmette-Guérin (BCG) vaccine on non-mycobacterial infections and other immune-mediated diseases. During the COVID-19 pandemic, randomized controlled trials BCG-PRIME (n = 5349) and BCG-CORONA-ELDERLY (n = 1907) investigated the impact of BCG on SARS-CoV-2 infections in older individuals. We extended the follow-up in these studies by one year (BCG-Long Term study), to assess the overall effects of BCG vaccination on infectious and immune-mediated diseases in individuals aged over 60.
    METHODS: Prior participants were invited to complete a one-year follow-up survey after their completion of the original trial. Data on vaccinations, hospital admissions, infectious episodes, and new medical diagnoses were collected and compared between BCG- and placebo-vaccinated participants. Variables of interest were combined with the previous trial databases and analyzed using relative risks (RR) and an adjusted Cox regression model accounting for participation probability.
    RESULTS: The response in the follow-up survey was 60%, including 4238 individuals in the final analysis (2317 had received BCG and 1921 placebo). Incidence and severity of infectious diseases and other diagnoses, including cardiovascular diseases and cancer, did not differ between the groups. The proportion of individuals hospitalized for cardiac arrhythmias after BCG was two-fold higher than reported after placebo (1.6% versus 0.8%, RR 2.0 (95% confidence interval 1.1-3.6)). Cardiac arrhythmia-related hospitalizations were primarily due to exacerbation of pre-existing arrhythmias.
    CONCLUSION: The results of the present study confirm that BCG has no relevant effect on non-mycobacterial infectious diseases and other immune-mediated diseases in a population of generally mycobacteria-naïve older Dutch individuals in the two years following vaccination. However, our study suggests that BCG may aggravate pre-existing cardiac arrhythmia, which warrants further investigation.
    Keywords:  BCG; Geriatric medicine; Immune-mediated diseases; Infectious diseases; Non-specific effects; Trained immunity
    DOI:  https://doi.org/10.1016/j.jinf.2024.106344
  5. J Infect Dis. 2024 Nov 14. pii: jiae572. [Epub ahead of print]
    Mycobacterium tuberculosis Antigen Rv1471 Induces Innate Immune Memory and Adaptive Immunity against Infection.
    Xuejiao Huang, Juan Wu, Jinchuan Xu, Huiling Wang, Zhenyan Chen, Xiao-Yong Fan, Zhidong Hu.
      Protein subunit vaccines form a key pipeline for developing novel tuberculosis (TB) vaccines. Mycobacterium tuberculosis (Mtb) contains approximately 4000 individual proteins. However, only approximately 100 have been evaluated as antigens in the clinical and preclinical stages of vaccine development. Trained immunity-targeting vaccines induce innate immune memory against heterologous infections and enhance antigen-specific adaptive immune responses. However, no trained immunity-targeting subunit TB vaccine has been reported yet. This study tested Rv1471, a thioredoxin secreted by Mtb, as a candidate TB vaccine antigen due to its capacity to stimulate mouse bone marrow-derived macrophages (BMDMs). Rv1471 induced functional and phenotypic maturation of BMDMs in vitro, reflected by the increased production of inflammatory cytokines and surface expression of co-stimulatory molecules. Transcription analysis of Rv1471-trained BMDMs indicated that innate immune memory was activated through pathways of Akt-mTOR-HIF-1α and aerobic glycolysis. Rv1471 also enhanced innate immune memory responses and protection against intracellular infections of different mycobacteria. In a murine model of TB, immunization with Rv1471 formulated with liposomal DDA/MPLA adjuvant produced robust antigen-specific multi-functional CD4+ and CD8+ T-cell immune responses and had substantial protective efficacy against Mtb challenge. Analysis of recall immunity showed that the Rv1471 subunit vaccine triggered robust T-cell immunity post Mtb infection. These findings support the development of an innate immune memory-targeting subunit TB vaccine to increase TB vaccine efficacy.
    Keywords:   Mycobacterium tuberculosis ; Rv1471; innate immune memory; subunit vaccine; trained immunity
    DOI:  https://doi.org/10.1093/infdis/jiae572
  6. mBio. 2024 Nov 11. e0304624
    A model of proximate protection against pathogenic infection through shared immunity.
    Douglas F Nixon, Margarita Kyza-Karavioti, Sreeradha Mallick, Lillia Daley, Nathaniel Hupert, Nathaniel D Bachtel, Ioannis Eleftherianos.
      Drosophila melanogaster exhibits innate immune priming, a mechanism leading to protection upon repeated challenge with a given pathogen. However, whether immunological priming can be propagated from a challenged host to naive bystanders is unknown. Here, we show that priming half a vial of D. melanogaster adult flies with non-pathogenic Escherichia coli bacteria leads to protection of the whole vial from a lethal dose of the insect pathogen, Photorhabdus luminescens. The protective effect observed in these bystander flies was similar in magnitude to that of the E. coli primed hosts themselves but did not require transfer of E. coli to occur. This work broadens the scope of how immunological priming can occur and suggests that infected hosts can produce signals that influence immunity in their neighbors, leading to a shared immune collective.IMPORTANCEHere, we have introduced the new concept of shared immunity and priming by proximity. These findings are of particular significance because they indicate that the presence of compromised hosts can increase the response to the pathogenic challenge of healthy individuals that cohabitate within close distance. This shared immunity may involve proximate boosting of the host's immune defenses via the sensing of specific chemical, behavioral, or microbial signals. Determining the breadth, mechanistic basis, and translatability of these findings has the potential to transform biomedical research and public health.
    Keywords:  Drosophila; bacterial infection; immunity; shared immunity; shared protection
    DOI:  https://doi.org/10.1128/mbio.03046-24
  7. Vaccine. 2024 Nov 08. pii: S0264-410X(24)01187-3. [Epub ahead of print]43(Pt 2): 126505
    Trained immunity-based vaccines: A vision from the one health initiative.
    Miriam Angulo, Carlos Angulo.
      Trained immunity-based vaccines (TIbV or TRIMbV) represent a novel approach to combating infectious diseases. The innate immune system in animals, including humans, exhibits "memory-like" functions. Remarkably, the immunological mechanisms -both epigenetic and metabolic-) underlying this memory enables immune cells to develop defensive and protective outcomes against unspecific pathogenic infections. Under this context, the One Health initiative promotes integrative efforts to combat zoonotic (and anthropozoonotic) diseases, which is critical because 3 of 4 animal infections are transmitted to humans. Therefore, TIbV constitutes a potential affordable approach to control zoonotic pathologies, especially under pandemic scenarios. This review describes the state-of-the-art TIbV and their hurdles, opportunities, and prospects for the One Health initiative to prevent, control, and treat infectious diseases.
    Keywords:  Diseases; Innate immune memory; Novel vaccines
    DOI:  https://doi.org/10.1016/j.vaccine.2024.126505
  8. Cell Res. 2024 Nov 13.
    A GSDMD agonist boosts specific antitumor immunity.
    Yingying Zhang, Jiahuai Han.
      
    DOI:  https://doi.org/10.1038/s41422-024-01051-x
  9. Commun Biol. 2024 Nov 10. 7(1): 1484
    Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness.
    Jianjun Chang, Zijie Li, Hui Yuan, Xuejiao Wang, Jingyi Xu, Pingting Yang, Ling Qin.
      Sleepiness is commonly associated with neuroinflammation; however, the underlying neuroregulatory mechanisms remain unclear. Previous research suggests that the paraventricular thalamus (PVT) plays a crucial role in regulating sleep-wake dynamics; thus, neurological abnormalities in the PVT may contribute to neuroinflammation-induced sleepiness. To test this hypothesis, we performed electroencephalography recordings in mice treated with lipopolysaccharide (LPS) and found that the mice exhibited temporary sleepiness lasting for 7 days. Using the Fos-TRAP method, fiber photometry recordings, and immunofluorescence staining, we detected temporary PVT neuron hypoactivation and microglia activation from day 1 to day 7 post-LPS treatment. Combining the results of bulk and single-cell RNA sequencing, we found upregulation of aconitate decarboxylase 1 (Acod1) in PVT microglia post-LPS treatment. To investigate the role of Acod1, we manipulated Acod1 gene expression in PVT microglia via stereotactic injection of short hairpin RNA adenovirus. Knockdown of Acod1 exacerbated inflammation, neuronal hypoactivation, and sleepiness. Itaconate is a metabolite synthesized by the enzyme encoded by Acod1. Finally, we confirmed that exogenous administration of an itaconate derivative, 4-octyl itaconate, could inhibit microglia activation, alleviate neuronal dysfunction, and relieve sleepiness. Our findings highlight PVT's role in inflammation-induced sleepiness and suggest Acod1 as a potential therapeutic target for neuroinflammation.
    DOI:  https://doi.org/10.1038/s42003-024-07215-0
  10. Mol Med. 2024 Nov 14. 30(1): 216
    Probiotic bacteria-released extracellular vesicles enhance macrophage phagocytosis in polymicrobial sepsis by activating the FPR1/2 pathway.
    Ruiyao Zhu, Yu Zhang, Xiaohong Wang, Benjamin D Liu, Debabrata Chowdhury, Zhixin Li, Mingliang Pan, Tianqing Peng, Jing Chen, Wei Huang, Liying Zhan, Guo-Chang Fan.
       BACKGROUND: Sepsis-induced organ failure and high mortality are largely ascribed to the failure of bacterial clearance from the infected tissues. Recently, probiotic bacteria-released extracellular vesicles (BEVs) have been implicated as critical mediators of intercellular communication which are widely involved in the regulation of the inflammatory response. However, their functional role in macrophage phagocytosis during sepsis has never been explored.
    METHODS: BEVs were collected from three different strains of probiotics including Lactiplantibacillus plantarum WCFS1 (LP WCFS1), Lactobacillus rhamnosus Gorbach-Goldin (LGG), and Escherichia coli Nissle 1917 (EcN), or from LGG cultured under three pH conditions (pH5-acid, pH6.5-standard, pH8-akaline) through differential centrifugation, filtration, and ultracentrifugation of their culture supernatants. In vitro phagocytosis was measured in Raw264.7 cells and bone marrow-derived macrophages using pHrodo red E. coli BioParticles. The in vivo therapeutic effects of BEVs were tested using a feces-injection-in-peritoneum (FIP) model of polymicrobial sepsis.
    RESULTS: LGG-derived EVs (BEVLGG) were the best among these three probiotics BEVs in stimulating macrophages to take up bacteria. Furthermore, BEVLGG collected from pH8 culture condition (BEVpH8) exhibited the strongest capacity of phagocytosis, compared with BEVpH5 and BEVpH6.5. Treatment of septic mice with BEVpH8 significantly prolonged animal survival; increased bacterial clearance from the blood, peritoneal lavage fluid, and multiple organs; and decreased serum levels of pro-inflammatory cytokines/chemokines, as well as reduced multiple organ injuries, in comparison with control-treated septic mice. Mechanistically, RNA-seq and bioinformatic analysis identified that the FPR1/2 signaling was remarkably activated, along with its downstream pathways (PI3K-Akt-MARCO and NADPH-ROS) in BEVpH8-treated macrophages, compared with control cells. Accordingly, pre-addition of Boc2, a specific antagonist of FPR1/FPR2, to macrophages significantly attenuated BEVpH8-mediated phagocytosis, compared to controls.
    CONCLUSIONS: This study demonstrates that LGG-derived BEVs may have therapeutic effects against sepsis-induced organ injury and mortality through enhancing FPR1/2-mediated macrophage phagocytosis.
    Keywords:  Extracellular vesicles; FPR1/2 signaling; Macrophage phagocytosis; Probiotic Lactobacillus rhamnosus GG; Sepsis
    DOI:  https://doi.org/10.1186/s10020-024-00959-9
  11. Cancer Cell. 2024 Oct 30. pii: S1535-6108(24)00399-4. [Epub ahead of print]
    Itaconate promotes an unexpected tumor immune escape mechanism.
    Lara Haase, Christian Frezza.
      Itaconate is a metabolite produced by macrophages upon infection and acts as an antimicrobial molecule. In this issue of Cancer Cell, Lin et al. found that itaconate produced by tumor-associated macrophages is taken up by cancer cells via the transporter solute carrier family 13 member 3 (SLC13A3), promoting resistance to immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1016/j.ccell.2024.10.011
  12. Arch Iran Med. 2024 Nov 01. 27(11): 629-632
    Toll-Like Receptors Agonists: First-Line Defense Tools in the Pandemic Preparedness Arsenal?
    Farrokh Habibzadeh, Parham Habibzadeh, Mihai G Netea, Mahboobeh Yadollahie.
      
    DOI:  https://doi.org/10.34172/aim.31792
  13. Radiat Prot Dosimetry. 2024 Nov 13. 200(16-18): 1603-1607
    Long-term effects of continuous low dose-rate gamma-ray irradiation on mouse hematopoietic cells.
    Takanori Yanai, Syouko Kanaiwa-Kudo, Akiko Abe, Mikio Saitou, Shingo Nakamura, Satoshi Tanaka, Jun-Ichiro Komura, Toshiyuki Kobayashi.
      The present work investigates the long-term effects of continuous low dose-rate (20 mGy/day to total doses of 1-8 Gy) gamma-ray exposure on the hematopoietic cells of specific pathogen-free C3H/HeN mice. Peripheral white blood cell (WBC) counts decreased on days 206, 471, and 486, with no significant changes in red blood cell (RBC) and platelet (PLT) counts. The number of colony forming units (CFU-S and CFU-GM) in the bone marrow and spleen from irradiated mice decreased with increasing total dose on day-12 and day-7. The decrease in bone marrow CFU-S persisted throughout the 400-day irradiation period and did not show any recovery up to 210 days postirradiation. These findings suggest that the effects of low-dose-rate (LDR) radiation on the hematopoietic system remain long after the 400-day irradiation was completed. Further investigation showed no significant difference in life spans of non-irradiated W/Wv (c-kit-deficient) mice inoculated with hematopoietic stem cells from irradiated (20 mGy/day for 400 days) or nonirradiated wild-type mice. These results suggest that the effects of continuous low-dose-rate irradiation are more pronounced in hematopoietic stromal cells than in HSCs themselves.
    DOI:  https://doi.org/10.1093/rpd/ncae153
  14. Eur J Pharmacol. 2024 Nov 10. pii: S0014-2999(24)00812-4. [Epub ahead of print] 177122
    4-Octyl itaconate inhibits vascular calcification partially via modulation of HMOX-1 signaling.
    Qianqian Dong, Fang Liu, Jiahui Zhu, Mingxi Li, An Chen, Liyun Feng, Zirong Lan, Yuanzhi Ye, Lihe Lu, Qingchun Liang, Jianyun Yan.
      Vascular calcification frequently occurs in patients with chronic conditions such as chronic kidney disease (CKD), diabetes, and hypertension and represents a significant cause of cardiovascular events. Thus, identifying effective therapeutic targets to inhibit the progression of vascular calcification is essential. 4-Octyl itaconate (4-OI), a derivative of itaconate, exhibits anti-inflammatory and antioxidant activity, both of which play an essential role in the progression of vascular calcification. However, the role and molecular mechanisms of 4-OI in vascular calcification have not yet been elucidated. In this study, we investigated the effects of exogenous 4-OI on vascular calcification using vascular smooth muscle cells (VSMCs), arterial rings, and mice. Alizarin red staining and western blot revealed that 4-OI inhibited calcification and osteogenic differentiation of human VSMCs. Similarly, 4-OI inhibited calcification of rat arterial rings and VitD3-overloaded mouse aortas. Mechanistically, RNA sequencing analysis revealed that 4-OI treatment is most likely to affect heme oxygenase 1 (HMOX-1) mRNA expression. The study demonstrated that 4-OI treatment increased HMOX-1 mRNA and protein levels, but suppressed inflammation and oxidative stress in VSMCs under osteogenic conditions. Moreover, 4-OI treatment. HMOX-1 knockdown by siRNA or treatment with the HMOX-1 inhibitor ZnPP9 significantly reversed the suppression effect on calcification of VSMCs and aortas of VitD3-overloaded mice by 4-OI. Furthermore, HMOX-1 knockdown by siRNA markedly abrogated the inhibitory effect of 4-OI on inflammation in VSMCs. These findings suggest that 4-OI alleviates vascular calcification and inhibits oxidative stress and inflammation through modulation of HMOX-1, indicating its potential as a therapeutic target for vascular calcification.
    Keywords:  4-Octyl itaconate; heme oxygenase 1; inflammation; oxidative stress; vascular calcification
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177122
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