bims-traimu Biomed News
on Trained immunity
Issue of 2024–09–29
eleven papers selected by
Yantong Wan, Southern Medical University
  1. Trained immunity-based vaccines for infections and allergic diseases.
  2. Insights into the multifaceted role of interleukin-37 on human immune cell regulation.
  3. Repeated LPS induces training and tolerance of microglial responses across brain regions.
  4. Mucosal Trained-Immunity Based Vaccines: Cutting Recurrent Infections in Autoimmune Patients on Immunosuppression.
  5. Inflammatory Memory in Epidermal Stem Cells - A New Strategy for Recurrent Inflammatory Skin Diseases.
  6. Optimising vaccine immunogenicity in ageing populations: key strategies.
  7. ScRNA-seq reveals trained immunity-engaged Th17 cell activation against Edwardsiella piscicida-induced intestinal inflammation in teleost.
  8. Myeloid cells take ischemic insult to heart.
  9. Hunting down the elusive cytosolic-DNA sensor.
  10. Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
  11. Comparative Effectiveness of Bacillus Calmette-Guérin and Sequential Intravesical Gemcitabine and Docetaxel for Treatment-naïve Intermediate-risk Non-muscle-invasive Bladder Cancer.
  1. J Allergy Clin Immunol. 2024 Sep 18. pii: S0091-6749(24)00979-5. [Epub ahead of print]
    Trained immunity-based vaccines for infections and allergic diseases.
    Leticia Martín-Cruz, Cristina Benito-Villalvilla, Alba Angelina, José Luis Subiza, Oscar Palomares.
      Trained immunity has emerged as a new concept in immunology associated with the memory of innate immune cells and linked to specific metabolic and epigenetic reprogramming of these cells. Trained immunity may confer nonspecific and sustained protection against a broad range of pathogens, and recent findings show that it might also be involved in allergy mechanisms. Some conventional vaccines have demonstrated trained immunity induction as the mechanism underlying their heterologous protection. The development of novel vaccines especially designed for this purpose (trained immunity-based vaccines) might be useful in the absence of conventional vaccines or in specific clinical settings. Under certain circumstances, trained immunity could lead to persistent inflammatory innate immune cell responses in allergic subjects, which could be associated with the development and worsening of allergy by promoting and amplifying aberrant type 2 immune responses. In other cases, trained immunity may help promote healthy immune responses to allergens, such as type 1 responses that counterbalance type 2 inflammation or regulatory T cells that induce tolerance. Trained immunity-based allergen vaccines could become the next generation of allergen-specific immunotherapy vaccines, harnessing the potential of trained immunity to induce allergen tolerance. The identification and characterization of proper training inducers might well pave the way for the development of novel immunotherapies.
    Keywords:  Trained Immunity-based Vaccines (TIbV); allergic diseases; infectious diseases; metabolic and epigenetic rewiring; trained tolerance-based vaccines
    DOI:  https://doi.org/10.1016/j.jaci.2024.09.009
  2. Clin Immunol. 2024 Sep 20. pii: S1521-6616(24)00477-7. [Epub ahead of print]268 110368
    Insights into the multifaceted role of interleukin-37 on human immune cell regulation.
    Lisa U Teufel, Vasiliki Matzaraki, Lukas Folkman, Rob Ter Horst, Simone J C F M Moorlag, Catharina M Mulders-Manders, Mihai G Netea, Thomas Krausgruber, Leo A B Joosten, Rob J W Arts.
      Autoinflammatory diseases, while having a variety of underlying causes, are mediated by dysfunctional innate immune responses. Therefore, standard treatments target innate cytokines or block their receptors. Despite excellent responses in some patients, first-line treatments fail in others, for reasons which remain to be understood. We studied the effects of IL-37, an anti-inflammatory cytokine, on immune cells using multi-omics profiling of 325 healthy adults. Our findings show that IL-37 is associated with inflammation control and generally reduced immune cell activity. Further, genetic variants in IL37 are associated with impaired trained immunity, a memory phenotype of innate immune cells contributing to autoinflammation. To underpin the medical potential of IL-37, an explorative cohort of seven autoinflammatory disorders was built. In vitro stimulation experiments argue for recombinant IL-37 as a potential therapy in IL-6-, and IL-22-driven conditions. Concluding, IL-37 is highlighted as a cytokine with broad anti-inflammatory functions, implicating its potential as therapeutic intervention.
    Keywords:  Autoinflammation; BCG; Inflammation; Interleukin (IL)-37; Trained immunity
    DOI:  https://doi.org/10.1016/j.clim.2024.110368
  3. J Neuroinflammation. 2024 Sep 20. 21(1): 233
    Repeated LPS induces training and tolerance of microglial responses across brain regions.
    Jennifer Kim, Olivia Sullivan, Kristen Lee, Justin Jao, Juan Tamayo, Abdullah Muhammad Madany, Brandon Wong, Paul Ashwood, Annie Vogel Ciernia.
       BACKGROUND: Neuroinflammation is involved in the pathogenesis of almost every central nervous system disorder. As the brain's innate immune cells, microglia fine tune their activity to a dynamic brain environment. Previous studies have shown that repeated bouts of peripheral inflammation can trigger long-term changes in microglial gene expression and function, a form of innate immune memory.
    METHODS AND RESULTS: In this study, we used multiple low-dose lipopolysaccharide (LPS) injections in adult mice to study the acute cytokine, transcriptomic, and microglia morphological changes that contribute to the formation of immune memory in the frontal cortex, hippocampus, and striatum, as well as the long-term effects of these changes on behavior. Training and tolerance of gene expression was shared across regions, and we identified 3 unique clusters of DEGs (2xLPS-sensitive, 4xLPS-sensitive, LPS-decreased) enriched for different biological functions. 2xLPS-sensitive DEG promoters were enriched for binding sites for IRF and NFkB family transcription factors, two key regulators of innate immune memory. We quantified shifts in microglia morphological populations and found that while the proportion of ramified and rod-like microglia mostly remained consistent within brain regions and sexes with LPS treatment, there was a shift from ameboid towards hypertrophic morphological states across immune memory states and a dynamic emergence and resolution of events of microglia aligning end-to-end with repeated LPS.
    CONCLUSIONS: Together, findings support the dynamic regulation of microglia during the formation of immune memories in the brain and support future work to exploit this model in brain disease contexts.
    Keywords:  Gene expression; Gene regulation; Innate immune memory; Microglia; Microglia morphology
    DOI:  https://doi.org/10.1186/s12974-024-03198-1
  4. J Allergy Clin Immunol. 2024 Sep 20. pii: S0091-6749(24)00985-0. [Epub ahead of print]
    Mucosal Trained-Immunity Based Vaccines: Cutting Recurrent Infections in Autoimmune Patients on Immunosuppression.
    Gloria Candelas, Ángela Villegas, Silvia Sánchez-Ramón.
      
    Keywords:  Immunosuppressed Patients; Mucosal Vaccines; Recurrent Infections; Systemic Autoimmune Rheumatic Diseases; Trained Immunity
    DOI:  https://doi.org/10.1016/j.jaci.2024.09.011
  5. J Inflamm Res. 2024 ;17 6635-6643
    Inflammatory Memory in Epidermal Stem Cells - A New Strategy for Recurrent Inflammatory Skin Diseases.
    Qian Gao, Ping-Sheng Hao.
      The ability of the skin to "remember" has been a potential mechanism for studying recurrent skin diseases. While it has been thought that the ability to retain past encounters is the prerogative of immune cells, it has recently been discovered that skin tissue stem cells can also take on this task. Epithelial stem cells undergoing inflammation retain their "memory" through epigenetic reprogramming and exhibit rapid epithelialization and epidermal proliferation upon secondary stimulation. This is a non-specific memory modality independent of conventional immune memory, in which histone modifications (acetylation and methylation) and specific transcription factors (AP-1 and STAT3) are involved in the establishment of inflammatory memories, and AIM2/Caspase-1/IL-1β mainly performs the rapid effects of memory. This finding is intriguing for addressing recurrent inflammatory skin diseases, which may explain the fixed-site recurrence of inflammatory skin diseases and develop new therapeutic strategies in the future. However, more research is still needed to decipher the mysteries of memory.
    Keywords:  epigenetics; inflammatory memory; recurrent inflammatory skin diseases; skin tissue stem cells
    DOI:  https://doi.org/10.2147/JIR.S478987
  6. Lancet Infect Dis. 2024 Sep 23. pii: S1473-3099(24)00497-3. [Epub ahead of print]
    Optimising vaccine immunogenicity in ageing populations: key strategies.
    Guangzhen Jiang, Yushu Zou, Dongyu Zhao, Jingyou Yu.
      Vaccination has been shown to be the most effective means of preventing infectious diseases, although older people commonly have a suboptimal immune response to vaccines and thus impaired protection against subsequent adverse outcomes. This Review provides an overview of the existing mechanistic insights into compromised vaccine response for respiratory infectious diseases in older people, defined as aged 65 years and older, including immunosenescence, epigenetic regulation, trained immunity, and gut microbiota. We further summarise the latest proven or potential strategies to strengthen weakened immunogenicity. Insights from these analyses will be conducive to the development of the next generation of vaccines.
    DOI:  https://doi.org/10.1016/S1473-3099(24)00497-3
  7. Microbiol Res. 2024 Sep 21. pii: S0944-5013(24)00313-6. [Epub ahead of print]289 127912
    ScRNA-seq reveals trained immunity-engaged Th17 cell activation against Edwardsiella piscicida-induced intestinal inflammation in teleost.
    Jin Yang, Shu Cui, Boning Shao, Yanbo Zhao, Zhuang Wang, Qin Liu, Yuanxing Zhang, Dahai Yang.
      Mucosal immunity typically involves innate and adaptive immune cells, while the cellular mechanism of teleost's intestinal immune cells that engages gut homeostasis against bacterial infection remains largely unknown. Taking advantage of the enteric fish pathogen (Edwardsiella piscicida) infection-induced intestinal inflammation in turbot (Scophthalmus maximus), we find that β-glucan training could mitigate the bacterial infection-induced intestinal inflammation. Through single-cell transcriptome profiling and cellular function analysis, we identify that E. piscicida infection could tune down the activation of intestinal Th17 cells, while β-glucan-training could preserve the potential to amplify and restore the function of intestinal Th17 cells. Moreover, through pharmacological inhibitor treatment, we identify that Th17 cells are essential for ameliorating bacterial infection-induced intestinal inflammation in teleost. Taken together, these results suggest a new concept of trained immunity activation to regulate the intestinal Th17 cells' function, which might contribute to better developing strategies for maintaining gut homeostasis against bacterial infection.
    Keywords:  Edwardsiella piscicida; Intestinal inflammation; Teleost; Th17 cells; β-Glucan
    DOI:  https://doi.org/10.1016/j.micres.2024.127912
  8. Trends Immunol. 2024 Sep 20. pii: S1471-4906(24)00209-6. [Epub ahead of print]
    Myeloid cells take ischemic insult to heart.
    Leo Nicolai, Steffen Massberg.
      Morbidity and mortality associated with stroke cannot be attributed solely to the acute ischemic event, but are also rooted in long-term complications, including heart disease. Simats, Zhang, and colleagues now demonstrate that interleukin (IL)-1ß-mediated innate immune memory after brain ischemic stroke leads to proinflammatory changes in the heart causing myocardial fibrosis.
    DOI:  https://doi.org/10.1016/j.it.2024.09.001
  9. Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2415648121
    Hunting down the elusive cytosolic-DNA sensor.
    Diane Mathis.
      The 2024 Albert Lasker Basic Medical Research Award was attributed to Zhijian (James) Chen for "the discovery of the cGAS enzyme that senses foreign and self DNA, solving the mystery of how DNA stimulates immune and inflammatory responses." Bringing to bear an ingenious in vitro complementation system, an astute insight, and superlative biochemistry, Chen and colleagues identified cGAS (cGAMP synthase) as both the molecule that perceives cytosolic DNA in infected, stressed, or dying cells and the enzyme that catalyzes the synthesis of cGAMP (cyclic GMP-AMP), a critical second messenger along the route to inflammatory cytokine production. These findings cleared up the reigning confusion surrounding a major mechanism of inciting the innate immune system, with therapeutic implications for fighting infections, containing tumors, and extinguishing autoimmune and inflammatory diseases.
    DOI:  https://doi.org/10.1073/pnas.2415648121
  10. Cell Rep. 2024 Sep 25. pii: S2211-1247(24)01131-8. [Epub ahead of print]43(10): 114780
    Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
    Jiawei Yan, Xin Zhang, Huiying Wang, Xinglong Jia, Ruohong Wang, Shuangyang Wu, Zheng-Jiang Zhu, Minjia Tan, Tiffany Horng.
      Macrophage elaboration of inflammatory responses is dynamically regulated, shifting from acute induction to delayed suppression during the course of infection. Here, we show that such regulation of inflammation is modulated by dynamic shifts in metabolism. In macrophages exposed to the bacterial product lipopolysaccharide (LPS), an initial induction of protein biosynthesis is followed by compensatory induction of the transcription factor nuclear factor erythroid 2-like 1 (NRF1), leading to increased flux through the ubiquitin proteasome system (UPS). A major target of NRF1-mediated UPS flux is the mitochondrial proteome, and in the absence of NRF1, ubiquitinated mitochondrial proteins accumulate to trigger severe mitochondrial stress. Such mitochondrial stress engages the integrated stress response-ATF4 axis, which limits mitochondrial translation to attenuate mitochondrial stress but amplifies inflammatory responses to augment susceptibility to septic shock. Therefore, NRF1 mediates a dynamic regulation of mitochondrial proteostasis in inflammatory macrophages that contributes to curbing inflammatory responses.
    Keywords:  CP: Metabolism; CP: Molecular biology; NRF1; immunometabolism; inflammation; integrated stress response; macrophage; mitochondria; proteostasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114780
  11. Eur Urol Focus. 2024 Sep 20. pii: S2405-4569(24)00173-1. [Epub ahead of print]
    Comparative Effectiveness of Bacillus Calmette-Guérin and Sequential Intravesical Gemcitabine and Docetaxel for Treatment-naïve Intermediate-risk Non-muscle-invasive Bladder Cancer.
    Kaushik P Kolanukuduru, Reuben Ben-David, Sarah Lidagoster, Mohammed Almoflihi, Neeraja Tillu, Ahmed Eraky, Parissa Alerasool, Nikhil Waigankar, Kyrollis Attalla, Reza Mehrazin, Peter Wiklund, John P Sfakianos.
       BACKGROUND AND OBJECTIVE: Sequential intravesical gemcitabine/docetaxel (Gem/Doce) has emerged as a potential alternative to bacillus Calmette-Guérin (BCG) for the treatment of non-muscle-invasive bladder cancer (NMIBC). Our aim was to determine the comparative effectiveness of BCG and Gem/Doce for patients with intermediate-risk (IR) NMIBC, composed mainly of high-grade (HG) Ta disease.
    METHODS: Patients with IR-NMIBC who received either BCG or Gem/Doce during 2013-2023 were included. Maintenance BCG (as per the Southwest Oncology Group protocol) and monthly Gem/Doce maintenance for 1 yr were offered to patients with no evidence of recurrence after induction. Routine surveillance with cystoscopy was performed according to the American Urological Association guidelines. The Kaplan-Meier method was used to assess high-grade and any-grade recurrence-free survival (RFS). Cox regression analysis was performed to find predictors of recurrence.
    KEY FINDINGS AND LIMITATIONS: Of 483 patients, 127 had IR-NMIBC; 66 patients received BCG and 61 received Gem/Doce. Median age was 69 yr (interquartile range [IQR] 61-76) for the BCG group and 72 yr (IQR 62-76) for the Gem/Doce group. Median follow-up was 53.1 mo (IQR 25.3-71.2) for the BCG group and 20.2 mo (IQR 8.28-33.1) for the Gem/Doce group. The 2-yr high-grade RFS rates for primary high-grade tumors for BCG versus Gem/Doce groups were 81% versus 61%, with corresponding any-grade RFS rates of 60% versus 41%. Induction with Gem/Doce predicted any-grade recurrence (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.1-3.2) and high-grade recurrence for primary high-grade tumors (HR 3.4 95% CI 1.27-9.13), while receipt of maintenance therapy decreased the risk of any-grade recurrence (HR 0.4, 95% CI 0.22-0.72). This study is limited by its retrospective design.
    CONCLUSIONS AND CLINICAL IMPLICATIONS: For patients with IR-NMIBC, BCG was associated with superior any-grade RFS and high-grade RFS for primary high-grade tumors. Maintenance therapy was associated with better RFS when receiving Gem/Doce. Standardization and longer maintenance therapy protocols should be considered for Gem/Doce treatment.
    PATIENT SUMMARY: We compared outcomes for patients who received two different in-bladder treatments for intermediate-risk bladder cancer. Bacillus Calmette-Guérin (BCG) led to better outcomes than gemcitabine + docetaxel (Gem/Doce). Monthly maintenance therapy improved recurrence-free survival for patients who received Gem/Doce. We conclude that maintenance therapy is essential for patients receiving Gem/Doce to avoid bladder cancer recurrence after treatment.
    Keywords:  Docetaxel; Gemcitabine; Intravesical drug administration; Non–muscle-invasive bladder neoplasms; Urinary bladder neoplasms
    DOI:  https://doi.org/10.1016/j.euf.2024.09.006
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