bims-traimu Biomed News
on Trained immunity
Issue of 2024–03–31
nine papers selected by
Yantong Wan, Southern Medical University
  1. Trained immunity: General and emerging concepts.
  2. Non-specific effects of inactivated Mycobacterium bovis oral and parenteral treatment in a rabbit scabies model.
  3. The human MIF polymorphism CATT7 enhances pro-inflammatory macrophage polarization in a clinically relevant model of allergic airway inflammation.
  4. Persistent epigenetic signals propel a senescence-associated secretory phenotype and trained innate immunity in CD34+ hematopoietic stem cells from diabetic patients.
  5. [Trained immunity : emerging strategies against antibiotic resistance].
  6. [BCG instillation sepsis in bladder carcinoma].
  7. Propofol improves survival in a murine model of sepsis via inhibiting Rab5a-mediated intracellular trafficking of TLR4.
  8. Reprogramming of the LXRα Transcriptome Sustains Macrophage Secondary Inflammatory Responses.
  9. Innate immunity in neurons makes memories persist.
  1. Immunol Rev. 2024 Mar 29.
    Trained immunity: General and emerging concepts.
    Patricia Vuscan, Brenda Kischkel, Leo A B Joosten, Mihai G Netea.
      Over the past decade, compelling evidence has unveiled previously overlooked adaptive characteristics of innate immune cells. Beyond their traditional role in providing short, non-specific protection against pathogens, innate immune cells can acquire antigen-agnostic memory, exhibiting increased responsiveness to secondary stimulation. This long-term de-facto innate immune memory, also termed trained immunity, is mediated through extensive metabolic rewiring and epigenetic modifications. While the upregulation of trained immunity proves advantageous in countering immune paralysis, its overactivation contributes to the pathogenesis of autoinflammatory and autoimmune disorders. In this review, we present the latest advancements in the field of innate immune memory followed by a description of the fundamental mechanisms underpinning trained immunity generation and different cell types that mediate it. Furthermore, we explore its implications for various diseases and examine current limitations and its potential therapeutic targeting in immune-related disorders.
    Keywords:  epigenetics; inflammation; innate immune memory; vaccines
    DOI:  https://doi.org/10.1111/imr.13326
  2. Vet Res. 2024 Mar 26. 55(1): 41
    Non-specific effects of inactivated Mycobacterium bovis oral and parenteral treatment in a rabbit scabies model.
    Rosa Casais, Natalia Iglesias, Iker A Sevilla, Joseba M Garrido, Ana Balseiro, Mercedes Dominguez, Ramon A Juste.
      Tuberculosis BCG vaccination induced non-specific protective effects in humans led to postulate the concept of trained immunity (TRAIM) as an innate type of immune mechanism that triggered by a pathogen, protects against others. Killed vaccines have been considered not to be effective. However, field efficacy of a commercial vaccine against paratuberculosis, as well as of a recently developed M. bovis heat-inactivated vaccine (HIMB) prompted to test whether it could also induce TRAIM. To this, we used a sarcoptic mange rabbit model. Twenty-four weaned rabbits were treated orally or subcutaneously with a suspension of either HIMB (107 UFC) or placebo. Eighty-four days later the animals were challenged with approximately 5000 S. scabiei mites on the left hind limb. Skin lesion extension was measured every 2 weeks until 92 days post-infection (dpi). Two animals were killed at 77 dpi because of extensive skin damage. The rest were euthanized and necropsied and the lesion area and the mite burden per squared cm were estimated. Specific humoral immune responses to S. scabiei and to M. bovis were investigated with the corresponding specific ELISA tests. Subcutaneously and orally HIMB vaccinated animals compared with placebo showed reduced lesion scores (up to 74% and 62%, respectively) and mite counts (-170% and 39%, respectively). This, together with a significant positive correlation (r = 0.6276, p = 0.0031) between tuberculosis-specific antibodies and mite count at 92 dpi supported the hypothesis of non-specific effects of killed mycobacterial vaccination. Further research is needed to better understand this mechanism to maximize cross protection.
    Keywords:   Mycobacterium bovis ; Sarcoptes scabiei ; killed vaccine; scabies; serology; trained immunity; tuberculosis
    DOI:  https://doi.org/10.1186/s13567-024-01293-y
  3. FASEB J. 2024 Mar 31. 38(6): e23576
    The human MIF polymorphism CATT7 enhances pro-inflammatory macrophage polarization in a clinically relevant model of allergic airway inflammation.
    Hazel Dunbar, Ian J Hawthorne, Eóin N McNamee, Michelle E Armstrong, Seamas C Donnelly, Karen English.
      High level expression of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been associated with severe asthma. The role of MIF and its functional promotor polymorphism in innate immune training is currently unknown. Using novel humanized CATT7 MIF mice, this study is the first to investigate the effect of MIF on bone marrow-derived macrophage (BMDM) memory after house dust mite (HDM) challenge. CATT7 BMDMs demonstrated a significant primed increase in M1 markers following HDM and LPS stimulation, compared to naive mice. This M1 signature was found to be MIF-dependent, as administration of a small molecule MIF inhibitor, SCD-19, blocked the induction of this pro-inflammatory M1-like phenotype in BMDMs from CATT7 mice challenged with HDM. Training naive BMDMs in vitro with HDM for 24 h followed by a rest period and subsequent stimulation with LPS led to significantly increased production of the pro-inflammatory cytokine TNFα in BMDMs from CATT7 mice but not WT mice. Addition of the pan methyltransferase inhibitor MTA before HDM training significantly abrogated this effect in BMDMs from CATT7 mice, suggesting that HDM-induced training is associated with epigenetic remodelling. These findings suggest that trained immunity induced by HDM is under genetic control, playing an important role in asthma patients with the high MIF genotypes (CATT6/7/8).
    Keywords:  bone marrow‐derived macrophages; house dust mite; innate immunity; innate priming; innate training; macrophage migration inhibitory factor; polarization
    DOI:  https://doi.org/10.1096/fj.202400207R
  4. Cardiovasc Diabetol. 2024 Mar 29. 23(1): 107
    Persistent epigenetic signals propel a senescence-associated secretory phenotype and trained innate immunity in CD34+ hematopoietic stem cells from diabetic patients.
    Maria Cristina Vinci, Sarah Costantino, Giulia Damiano, Erica Rurali, Raffaella Rinaldi, Vera Vigorelli, Annalisa Sforza, Ermes Carulli, Sergio Pirola, Giorgio Mastroiacovo, Angela Raucci, Assam El-Osta, Francesco Paneni, Giulio Pompilio.
       BACKGROUND: Diabetes-induced trained immunity contributes to the development of atherosclerosis and its complications. This study aimed to investigate in humans whether epigenetic signals involved in immune cell activation and inflammation are initiated in hematopoietic stem/progenitor cells (HSPCs) and transferred to differentiated progeny.
    METHODS AND RESULTS: High glucose (HG)-exposure of cord blood (CB)-derived HSPCs induced a senescent-associated secretory phenotype (SASP) characterized by cell proliferation lowering, ROS production, telomere shortening, up-regulation of p21 and p27genes, upregulation of NFkB-p65 transcription factor and increased secretion of the inflammatory cytokines TNFα and IL6. Chromatin immunoprecipitation assay (ChIP) of p65 promoter revealed that H3K4me1 histone mark accumulation and methyltransferase SetD7 recruitment, along with the reduction of repressive H3K9me3 histone modification, were involved in NFkB-p65 upregulation of HG-HSPCs, as confirmed by increased RNA polymerase II engagement at gene level. The differentiation of HG-HSPCs into myeloid cells generated highly responsive monocytes, mainly composed of intermediate subsets (CD14hiCD16+), that like the cells from which they derive, were characterized by SASP features and similar epigenetic patterns at the p65 promoter. The clinical relevance of our findings was confirmed in sternal BM-derived HSPCs of T2DM patients. In line with our in vitro model, T2DM HSPCs were characterized by SASP profile and SETD7 upregulation. Additionally, they generated, after myeloid differentiation, senescent monocytes mainly composed of proinflammatory intermediates (CD14hiCD16+) characterized by H3K4me1 accumulation at NFkB-p65 promoter.
    CONCLUSIONS: Hyperglycemia induces marked chromatin modifications in HSPCs, which, once transmitted to the cell progeny, contributes to persistent and pathogenic changes in immune cell function and composition.
    Keywords:  Cardiovascular disease; Diabetes mellitus; Epigenetics; Hematopoietic stem cells; Trained immunity
    DOI:  https://doi.org/10.1186/s12933-024-02195-1
  5. Med Sci (Paris). 2024 Mar;40(3): 301-304
    [Trained immunity : emerging strategies against antibiotic resistance].
    Lea Badin, Celya Franc, Paul Gilbert, Jean-Jacques Magdeleine, Lisa Martin, Rudy Vernaz, Nicole Arrighi, Juan A Garcia-Sanchez.
      
    DOI:  https://doi.org/10.1051/medsci/2024019
  6. Praxis (Bern 1994). 2024 Feb;113(2): 44
    [BCG instillation sepsis in bladder carcinoma].
    Hubert John.
       INTRODUCTION:
  7. J Transl Med. 2024 Mar 28. 22(1): 316
    Propofol improves survival in a murine model of sepsis via inhibiting Rab5a-mediated intracellular trafficking of TLR4.
    Bo-Wei Zhou, Wen-Juan Zhang, Fang-Ling Zhang, Xiao Yang, Yu-Qi Ding, Zhi-Wen Yao, Zheng-Zheng Yan, Bing-Cheng Zhao, Xiao-Dong Chen, Cai Li, Ke-Xuan Liu.
       BACKGROUND: Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol.
    METHODS: The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a-/- and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers.
    RESULTS: We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells.
    CONCLUSIONS: We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.
    Keywords:  Propofol; Rab5a; Sepsis; TLR4
    DOI:  https://doi.org/10.1186/s12967-024-05107-9
  8. Adv Sci (Weinh). 2024 Mar 28. e2307201
    Reprogramming of the LXRα Transcriptome Sustains Macrophage Secondary Inflammatory Responses.
    Juan Vladimir de la Rosa, Carlos Tabraue, Zhiqiang Huang, Marta C Orizaola, Patricia Martin-Rodríguez, Knut R Steffensen, Juan Manuel Zapata, Lisardo Boscá, Peter Tontonoz, Susana Alemany, Eckardt Treuter, Antonio Castrillo.
      Macrophages regulate essential aspects of innate immunity against pathogens. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXRα, LXRβ) are ligand-dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXRα and LXRβ in antimicrobial responses. Here, the author demonstrate that induction of LXRα transcription by prolonged exposure to lipopolysaccharide (LPS) supports inflammatory gene expression in macrophages. LXRα transcription is induced by NF-κB and type-I interferon downstream of TLR4 activation. Moreover, LPS triggers a reprogramming of the LXRα cistrome that promotes cytokine and chemokine gene expression through direct LXRα binding to DNA consensus sequences within cis-regulatory regions including enhancers. LXRα-deficient macrophages present fewer binding of p65 NF-κB and reduced histone H3K27 acetylation at enhancers of secondary inflammatory response genes. Mice lacking LXRα in the hematopoietic compartment show impaired responses to bacterial endotoxin in peritonitis models, exhibiting reduced neutrophil infiltration and decreased expansion and inflammatory activation of recruited F4/80lo-MHC-IIhi peritoneal macrophages. Together, these results uncover a previously unrecognized function for LXRα-dependent transcriptional cis-activation of secondary inflammatory gene expression in macrophages and the host response to microbial ligands.
    Keywords:  gene expression; inflammation; macrophage; nuclear receptor LXR
    DOI:  https://doi.org/10.1002/advs.202307201
  9. Nature. 2024 Apr;628(8006): 40-42
    Innate immunity in neurons makes memories persist.
    Benjamin A Kelvington, Ted Abel.
      
    Keywords:  Brain; Immunology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00679-4
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