bims-traimu Biomed News
on Trained immunity
Issue of 2024–12–15
six papers selected by
Yantong Wan, Southern Medical University
  1. Induction of Innate Immune Memory in LPS-Primed Microglial Cells by Water-Soluble Chitosan.
  2. Infection-induced trained immunity: a twist in paradigm of innate host defense and generation of immunological memory.
  3. Porphyromonas gingivalis-Lipopolysaccharide Induced Gingival Fibroblasts Trained Immunity Sustains Inflammation in Periodontitis.
  4. BCG's role in strengthening immune responses: Implications for tuberculosis and comorbid diseases.
  5. Inflammation-driven NFκB signaling represses Ferroportin transcription in macrophages via HDAC 1 and 3.
  6. Red Blood Cells Capture and Deliver Bacterial DNA to Drive Host Responses During Polymicrobial Sepsis.
  1. Biomed Res Int. 2024 ;2024 8027006
    Induction of Innate Immune Memory in LPS-Primed Microglial Cells by Water-Soluble Chitosan.
    Vo Thuy Anh Thu, Thi Xoan Hoang, Jae Kweon Park, Jae Young Kim.
      Innate immune memory or trained immunity refers to a long-lasting response of the innate immune cells against repeated exposure to the homogenous or heterogenous infectious agent. The trained immunity is induced through epigenetic modification and is characterized by the change of both intracellular immunological signaling and cellular metabolism. Recently, different groups have tried to establish protocols to generate trained innate immune cells. However, the molecular basis of innate memory induction remains poorly understood. Here, we evaluated the impact of water-soluble chitosan on the innate immune memory induction in microglial cells primed with LPS. The trained-immune response was accessed by measuring proinflammatory markers, metabolic change, and epigenetic modification. We showed that the stimulation/restimulation with LPS only caused a robust reduction of iNOS, and proinflammatory cytokines, indicating induced immune tolerance. In contrast, the treatment of chitosan induces long-lasting memory microglial cells accompanied by a high level of iNOS, increased lactate production, induced epigenetic modification, and the upregulation of proinflammatory cytokines upon further exposure to the same stimulus. These findings suggest that chitosan induces microglial-trained immunity by targeting distinct epigenetic and metabolic pathways; therefore, chitosan treatment may provide a novel approach for targeting innate immunity towards a memory-like response in an in vitro model.
    Keywords:  microglia; trained immunity; water-soluble chitosan
    DOI:  https://doi.org/10.1155/bmri/8027006
  2. Infect Immun. 2024 Dec 10. e0047224
    Infection-induced trained immunity: a twist in paradigm of innate host defense and generation of immunological memory.
    Aayush Bahl, Saurabh Pandey, Roopshali Rakshit, Sashi Kant, Deeksha Tripathi.
      In contrast to adaptive immunity, which relies on memory T and B cells for long-term pathogen-specific responses, trained immunity involves the enhancement of innate immune responses through cellular reprogramming. Experimental evidence from animal models and human studies supports the concept of trained immunity and its potential therapeutic applications in the development of personalized medicine. However, there remains a huge gap in understanding the mechanisms, identifying specific microbial triggers responsible for the induction of trained immunity. This underscores the importance of investigating the potential role of trained immunity in redefining host defense and highlights future research directions. This minireview will provide a comprehensive summary of the new paradigm of trained immunity or innate memory pathways. It will shed light on infection-induced pathways through non-specific stimulation within macrophages and natural killer cells, which will be further elaborated in multiple disease perspectives caused by infectious agents such as bacteria, fungi, and viruses. The article further elaborates on the biochemical and cellular basis of trained immunity and its impact on disease status during recurrent exposures. The review concludes with a perspective segment discussing potential therapeutic benefits, limitations, and future challenges in this area of study. The review also sheds light upon potential risks involved in the induction of trained immunity.
    Keywords:  adaptive immunity; epigenetic reprogramming; infection; innate immunity; microbial triggers; trained immunity
    DOI:  https://doi.org/10.1128/iai.00472-24
  3. J Periodontal Res. 2024 Dec 12.
    Porphyromonas gingivalis-Lipopolysaccharide Induced Gingival Fibroblasts Trained Immunity Sustains Inflammation in Periodontitis.
    Jiayi Liu, Haoyang Tian, Jinhong Ju, Fujiao Nie, Qiuyue Yin, Jingjing Zhao, Suli Wang, Hongmei Guo, Pishan Yang.
       AIM: To investigate whether trained immunity occurs in gingival fibroblasts (GFs) and its relationship to the persistence of inflammation in periodontitis.
    METHODS: Periodontally healthy and inflammatory gingival fibroblasts (HGFs and IGFs) were cultured through continuous adherence subculture of tissue blocks. Trained immunity in HGFs was evaluated via a classic in vitro model, with relevant markers assessed via enzyme-linked immunosorbent assay, lactate content assay, glycolytic rate assay, and chromatin immunoprecipitation. A histone methyltransferase blocker and a PI3K inhibitor were added to investigate the mechanisms underlying trained immunity. The relationship between trained immunity and periodontitis was further examined via immunofluorescence staining and chromatin immunoprecipitation on IGFs.
    RESULTS: Compared with untrained cells, GFs trained with Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS) exhibited a significant increase in IL-6 and TNF-α secretion, enhanced glycolytic metabolism, and enriched mono-methylation of lysine 4 on histone H3 (H3K4me1) at the enhancer regions of TNF-α and IL-6. The addition of a histone methyltransferase blocker and a PI3K inhibitor greatly reduced trained immunity. Additionally, the response of IGFs to P. gingivalis-LPS stimulation and their epigenetic modifications were similar to those observed in trained HGFs.
    CONCLUSION: This study novelly discovered that both P. gingivalis-LPS-stimulated HGFs and IGFs in periodontitis acquired trained immunity. Following P. gingivalis-LPS stimulation, HGFs underwent metabolic and epigenetic changes via the PI3K/AKT pathway, with these epigenetic changes also observed in IGFs. This finding suggests that trained immunity in GFs may be a key mechanism underlying the recurrence and persistence of periodontitis.
    Keywords:  PI3K/AKT pathway; gingival fibroblast; inflammation; metabolic and epigenetic reprogramming; trained immunity
    DOI:  https://doi.org/10.1111/jre.13372
  4. Infect Genet Evol. 2024 Dec 10. pii: S1567-1348(24)00155-2. [Epub ahead of print] 105703
    BCG's role in strengthening immune responses: Implications for tuberculosis and comorbid diseases.
    Nilofer Naqvi, Yashika Ahuja, Sheeba Zarin, Anwar Alam, Waseem Ali, Mohd Shariq, Seyed E Hasnain, Nasreen Z Ehtesham.
      The BCG vaccine represents a significant milestone in the prevention of tuberculosis (TB), particularly in children. Researchers have been developing recombinant BCG (rBCG) variants that can trigger lasting memory responses, thereby enhancing protection against TB in adults. The breakdown of immune surveillance is a key link between TB and other communicable and non-communicable diseases. Notably, TB is more prevalent among people with comorbidities such as HIV, diabetes, cancer, influenza, COVID-19, and autoimmune disorders. rBCG formulations have the potential to address both TB and HIV co-pandemics. TB increases the risk of lung cancer and immunosuppression caused by cancer can reactivate latent TB infections. Moreover, BCG's efficacy extends to bladder cancer treatment and blood glucose regulation in patients with diabetes and TB. Additionally, BCG provides cross-protection against unrelated pathogens, emphasizing the importance of BCG-induced trained immunity in COVID-19 and other respiratory diseases. Furthermore, BCG reduced the severity of pulmonary TB-induced influenza virus infections. Recent studies have proposed innovations in BCG delivery, revaccination, and attenuation techniques. Disease-centered research has highlighted the immunomodulatory effects of BCG on TB, HIV, cancer, diabetes, COVID-19, and autoimmune diseases. The complex relationship between TB and comorbidities requires a nuanced re-evaluation to understand the shared attributes regulated by BCG. This review assessed the interconnected relationships influenced by BCG administration in TB and related disorders, recommending the expanded use of rBCG in healthcare. Collaboration among vaccine research stakeholders is vital to enhance BCG's efficacy against global health challenges.
    Keywords:  Adaptive immunity; Bladder cancer; Comorbidity; Heterologous protection; Innate immunity; Trained-immunity
    DOI:  https://doi.org/10.1016/j.meegid.2024.105703
  5. Blood. 2024 Dec 10. pii: blood.2023023417. [Epub ahead of print]
    Inflammation-driven NFκB signaling represses Ferroportin transcription in macrophages via HDAC 1 and 3.
    Oriana Marques, Natalie K Horvat, Laura Zechner, Silvia Colucci, Richard Sparla, Stefan Zimmermann, Christopher J Neufeldt, Sandro Altamura, Ruiyue Qiu, Katja Müdder, Günter Weiss, Matthias W Hentze, Martina U Muckenthaler.
      Anemia of Inflammation is a prevalent co-morbidity in patients with chronic inflammatory disorders. Inflammation causes hypoferremia and iron-restricted erythropoiesis by limiting Ferroportin (FPN)-mediated iron export from macrophages that recycle senescent erythrocytes. Macrophage cell surface expression of FPN is reduced by hepcidin-induced degradation and/or by repression of FPN (Slc40a1) transcription via cytokine and Toll-like receptor (TLR) stimulation. While the mechanisms underlying hepcidin-mediated control of FPN have been extensively studied, those inhibiting Slc40a1 mRNA expression remain unknown. We applied targeted RNA interference and pharmacological screens in macrophages stimulated with the TLR2/6 ligand FSL1 and identified critical signalling regulators of Slc40a1 mRNA repression downstream of TLRs and NFкB signaling. Interestingly, the NFкB regulatory hub is equally relevant for Slc40a1 mRNA repression driven by the TLR4 ligand LPS, the cytokine TNFβ/LTA and heat-killed bacteria. Mechanistically, macrophage stimulation with heat-killed Staphylococcus aureus recruits the Histone deacetylases (HDAC) 1 and 3 to the antioxidant response element (ARE) located in the Slc40a1 promoter. Accordingly, pre-treatment with a pan-HDAC inhibitor abrogates Slc40a1 mRNA repression in response to inflammatory cues, suggesting that HDACs act downstream of NFкB to repress Slc40a1 transcription. Consistently, recruitment of HDAC 1 and 3 to the Slc40a1 ARE following stimulation with heat-killed Staphylococcus aureus is dependent on NFκB signaling. These results support a model in which the ARE integrates the transcriptional responses of Slc40a1 triggered by signals from redox, metabolic and inflammatory pathways. This work identifies the long-sought mechanism of Slc40a1 transcriptional downregulation upon inflammation, paving the way for therapeutic interventions at this critical juncture.
    DOI:  https://doi.org/10.1182/blood.2023023417
  6. J Clin Invest. 2024 Dec 12. pii: e182127. [Epub ahead of print]
    Red Blood Cells Capture and Deliver Bacterial DNA to Drive Host Responses During Polymicrobial Sepsis.
    L K Metthew Lam, Nathan J Klingensmith, Layal Sayegh, Emily Oatman, Joshua S Jose, Christopher V Cosgriff, Kaitlyn A Eckart, John McGinnis, Piyush Ranjan, Matthew Lanza, Nadir Yehya, Nuala J Meyer, Robert P Dickson, Nilam S Mangalmurti.
      Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not Tlr9-deleted RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid Tlr9-deleted mice. Plasma cytokine analysis in these mice revealed distinct sepsis clusters characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-Tlr9 deletion attenuated plasma and tissue IL-6 production in the most severe group. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.
    Keywords:  Cytokines; Inflammation; Innate immunity; Pulmonology
    DOI:  https://doi.org/10.1172/JCI182127
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