bims-traimu Biomed News
on Trained immunity
Issue of 2023‒07‒23
eight papers selected by
Yantong Wan
Southern Medical University
  1. Bacillus Calmette-Guérin-Trained Macrophages Elicit a Protective Inflammatory Response against the Pathogenic Bacteria Brucella abortus.
  2. Peripheral blood mononuclear cell hyperresponsiveness in patients with premature myocardial infarction without traditional risk factors.
  3. No evidence of durable trained immunity after two doses of adenovirus-vectored or mRNA COVID-19 vaccines.
  4. Comparative analyses of monocyte memory dynamics from mice to humans.
  5. Inheritance of associative memories and acquired cellular changes in C. elegans.
  6. Incorporation of a Toll-like receptor 2/6 agonist potentiates mRNA vaccines against cancer and infectious diseases.
  7. NLRP11 is a pattern recognition receptor for bacterial lipopolysaccharide in the cytosol of human macrophages.
  8. Yeast β-Glucan Modulates Macrophages and Improves Antitumor NK Cell Responses in Cancer.
  1. J Immunol. 2023 Jul 21. pii: ji2200642. [Epub ahead of print]
    Bacillus Calmette-Guérin-Trained Macrophages Elicit a Protective Inflammatory Response against the Pathogenic Bacteria Brucella abortus.
    Ana Carolina V S C de Araujo, Nina M G P de Queiroz, Fábio V Marinho, Sergio C Oliveira.
      The bacillus Calmette-Guérin (BCG) can elicit enhanced innate immune responses against a wide range of infections, known as trained immunity. Brucella abortus is the causative agent of brucellosis, a debilitating disease that affects humans and animals. In this study, we demonstrate that C57BL/6 mouse bone marrow-derived macrophages under BCG training enhance inflammatory responses against B. abortus. BCG-trained macrophages showed increased MHC class II and CD40 expression on the cell surface and higher IL-6, IL-12, and IL-1β production. The increase in IL-1β secretion was accompanied by enhanced activation of canonical and noncanonical inflammasome platforms. We observed elevated caspase-11 expression and caspase-1 processing in BCG-trained macrophages in response to B. abortus compared with untrained cells. In addition, these BCG-trained cells showed higher NLRP3 expression after B. abortus infection. From a metabolic point of view, signaling through the Akt/mammalian target of rapamycin/S6 kinase pathway was also enhanced. In addition, BCG training resulted in higher inducible NO synthase expression and nitrite production, culminating in an improved macrophage-killing capacity against intracellular B. abortus. In vivo, we monitored a significant reduction in the bacterial burden in organs from BCG-trained C57BL/6 mice when compared with the untrained group. In addition, previous BCG immunization of RAG-1-deficient mice partially protects against Brucella infection, suggesting the important role of the innate immune compartment in this scenario. Furthermore, naive recipient mice that received BM transfer from BCG-trained donors showed greater resistance to B. abortus when compared with their untrained counterparts. These results demonstrate that BCG-induced trained immunity in mice results in better control of intracellular B. abortus in vivo and in vitro.
    DOI:  https://doi.org/10.4049/jimmunol.2200642
  2. iScience. 2023 Jul 21. 26(7): 107183
    Peripheral blood mononuclear cell hyperresponsiveness in patients with premature myocardial infarction without traditional risk factors.
    Jan-Quinten Mol, Julia van Tuijl, Siroon Bekkering, Charlotte D C C van der Heijden, Sander A J Damen, Benjamin C Cossins, Liesbeth van Emst, Tim M Nielen, Laura Rodwell, Yang Li, Gheorghe A M Pop, Mihai G Netea, Niels van Royen, Niels P Riksen, Saloua El Messaoudi.
      An increasing number of patients develop an atherothrombotic myocardial infarction (MI) in the absence of standard modifiable risk factors (SMuRFs). Monocytes and macrophages regulate the development of atherosclerosis, and monocytes can adopt a long-term hyperinflammatory phenotype by epigenetic reprogramming, which can contribute to atherogenesis (called "trained immunity"). We assessed circulating monocyte phenotype and function and specific histone marks associated with trained immunity in SMuRFless patients with MI and matched healthy controls. Even in the absence of systemic inflammation, monocytes from SMuRFless patients with MI had an increased overall cytokine production capacity, with the strongest difference for LPS-induced interleukin-10 production, which was associated with an enrichment of the permissive histone marker H3K4me3 at the promoter region. Considering the lack of intervenable risk factors in these patients, trained immunity could be a promising target for future therapy.
    Keywords:  Cardiovascular medicine; Components of the immune system; Molecular mechanism of gene regulation; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2023.107183
  3. J Clin Invest. 2023 Jul 20. pii: e171742. [Epub ahead of print]
    No evidence of durable trained immunity after two doses of adenovirus-vectored or mRNA COVID-19 vaccines.
    Natalie E Stevens, Feargal J Ryan, Nicole L Messina, Stephen J Blake, Todd S Norton, Susie Germano, Jane James, Georgina L Eden, Yee C Tee, Miriam A Lynn, Rochelle Botten, Simone E Barry, Nigel Curtis, David J Lynn.
      
    Keywords:  COVID-19; Epigenetics; Innate immunity; Monocytes; Vaccines
    DOI:  https://doi.org/10.1172/JCI171742
  4. Inflamm Res. 2023 Jul 15.
    Comparative analyses of monocyte memory dynamics from mice to humans.
    Ziyue Yi, Shuo Geng, Liwu Li.
      BACKGROUND: Innate monocytes can adopt dynamic "memory" states ranging from low-grade inflammation to pathogenic exhaustion, dependent upon signal strength and history of challenges. Low-grade inflammatory monocytes facilitate the pathogenesis of chronic inflammatory diseases, while exhausted monocytes drive the pathogenesis of severe sepsis. Although clinical and basic studies suggest the conservation of key features of exhausted monocytes from human and murine sepsis, systems analyses of monocyte exhaustion among human and murine monocytes are lacking.METHODS: We performed cross examination of septic monocytes scRNAseq data recently collected from human sepsis patients as well as experimental septic mice, in reference to monocytes experimentally exhausted in vitro. Furthermore, we performed pseudo-time analyses of in vitro programmed monocytes following prolonged challenges causing either low-grade inflammation or exhaustion. Additional comparative analyses of low-grade inflammatory monocytes were performed with scRNAseq data from selected human patients with chronic low-grade inflammatory diseases.
    RESULTS: Our systems analyses reveal key features of monocyte exhaustion including reduced differentiation, pathogenic inflammation and immune suppression that are highly conserved in human and murine septic monocytes, and captured by in vitro experimental exhaustion. Pseudo-time analyses reveal that monocytes initially transition into a less-differentiated state with proliferative potential. The expansion of proliferative monocytes can be observed not only in experimentally challenged monocytes, but also in tissues of murine sepsis and human septic blood. We observed that monocytes similarly transition into the less-differentiated state when challenged with a subclinical dose endotoxin under chronic inflammatory conditions. Instead of being exhausted, monocytes with prolonged challenges with super-low dose endotoxin bifurcate into the low-grade inflammatory immune-enhancing or the chemotactic/adhesive state, often see in atherosclerosis or auto-immune diseases.
    CONCLUSIONS: Key features of monocyte memory dynamics are identified and conserved in human and murine monocytes, which can be captured by prolonged challenges of innate signals with varying signal strength.
    Keywords:  Chronic and acute inflammatory diseases; Comparative analyses; Comparative single cell analyses; Exhaustion; Innate immune memory; Leukocyte therapeutics; Monocyte memory dynamics; Monocyte subsets; Sepsis; Trajectory
    DOI:  https://doi.org/10.1007/s00011-023-01762-8
  5. Nat Commun. 2023 Jul 15. 14(1): 4232
    Inheritance of associative memories and acquired cellular changes in C. elegans.
    Noa Deshe, Yifat Eliezer, Lihi Hoch, Eyal Itskovits, Eduard Bokman, Shachaf Ben-Ezra, Alon Zaslaver.
      Experiences have been shown to modulate behavior and physiology of future generations in some contexts, but there is limited evidence for inheritance of associative memory in different species. Here, we trained C. elegans nematodes to associate an attractive odorant with stressful starvation conditions and revealed that this associative memory was transmitted to the F1 progeny who showed odor-evoked avoidance behavior. Moreover, the F1 and the F2 descendants of trained animals exhibited odor-evoked cellular stress responses, manifested by the translocation of DAF-16/FOXO to cells' nuclei. Sperm, but not oocytes, transmitted these odor-evoked cellular stress responses which involved H3K9 and H3K36 methylations, the small RNA pathway machinery, and intact neuropeptide secretion. Activation of a single chemosensory neuron sufficed to induce a serotonin-mediated systemic stress response in both the parental trained generation and in its progeny. Moreover, inheritance of the cellular stress responses increased survival chances of the progeny as exposure to the training odorant allowed the animals to prepare in advance for an impending adversity. These findings suggest that in C. elegans associative memories and cellular changes may be transferred across generations.
    DOI:  https://doi.org/10.1038/s41467-023-39804-8
  6. Signal Transduct Target Ther. 2023 07 17. 8(1): 273
    Incorporation of a Toll-like receptor 2/6 agonist potentiates mRNA vaccines against cancer and infectious diseases.
    Yangzhuo Gu, Jingyun Yang, Cai He, Tingmei Zhao, Ran Lu, Jian Liu, Xianming Mo, Fuqiang Wen, Huashan Shi.
      mRNA vaccines have emerged rapidly in recent years as a prophylactic and therapeutic agent against various diseases including cancer and infectious diseases. Improvements of mRNA vaccines have been underway, among which boosting of efficacy is of great importance. Pam2Cys, a simple synthetic metabolizable lipoamino acid that signals through Toll-like receptor (TLR) 2/6 pathway, eliciting both humoral and cellular adaptive immune responses, is an interesting candidate adjuvant. To investigate the enhancement of the efficacies of mRNA vaccines by Pam2Cys, the adjuvant was incorporated into mRNA-lipid nanoparticles (LNPs) to achieve co-delivery with mRNA. Immunization with the resulting mRNA-LNPs (Pam2Cys) shaped up the immune milieu in the draining lymph nodes (dLNs) through the induction of IL-12 and IL-17, among other cytokines. Antigen presentation was carried out mainly by migratory and dLN-resident conventional type 2 DCs (cDC2s) and significantly more potent antitumor responses were triggered in both prophylactic and therapeutic tumor models in a CD4+ and CD8+ T cell-dependent fashion. Accompanying memory antitumor immunity was also established. Moreover, the vaccine also stimulated much more robust humoral and cellular immunity in a surrogate COVID-19 prophylactic model. Last but not the least, the new vaccines exhibited good preliminary safety profiles in murine models. These facts warrant future development of Pam2Cys-incorporated mRNA vaccines or relevant mRNA therapeutics for clinical application.
    DOI:  https://doi.org/10.1038/s41392-023-01479-4
  7. Sci Immunol. 2023 Jul 21. 8(85): eabo4767
    NLRP11 is a pattern recognition receptor for bacterial lipopolysaccharide in the cytosol of human macrophages.
    Maricarmen Rojas-Lopez, María Luisa Gil-Marqués, Vritti Kharbanda, Amanda S Zajac, Kelly A Miller, Thomas E Wood, Austin C Hachey, Keith T Egger, Marcia B Goldberg.
      Endotoxin-bacterial lipopolysaccharide (LPS)-is a driver of lethal infection sepsis through excessive activation of innate immune responses. When delivered to the cytosol of macrophages, cytosolic LPS (cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice. Whereas activation of all other inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic pattern recognition receptor protein, whether pattern recognition receptors for cLPS exist has remained unclear, because caspase-4, caspase-5, and caspase-11 bind and activate LPS directly in vitro. Here, we show that the primate-specific protein NLRP11 is a pattern recognition receptor for cLPS that is required for efficient activation of the caspase-4 inflammasome in human macrophages. In human macrophages, NLRP11 is required for efficient activation of caspase-4 during infection with intracellular Gram-negative bacteria or upon electroporation of LPS. NLRP11 could bind LPS and separately caspase-4, forming a high-molecular weight complex with caspase-4 in HEK293T cells. NLRP11 is present in humans and other primates but absent in mice, likely explaining why it has been overlooked in screens looking for innate immune signaling molecules, most of which have been carried out in mice. Our results demonstrate that NLRP11 is a component of the caspase-4 inflammasome activation pathway in human macrophages.
    DOI:  https://doi.org/10.1126/sciimmunol.abo4767
  8. Clin Exp Immunol. 2023 Jul 17. pii: uxad080. [Epub ahead of print]
    Yeast β-Glucan Modulates Macrophages and Improves Antitumor NK Cell Responses in Cancer.
    Zhichao Zhu, Liuyang He, Yu Bai, Lei Xia, Xiao Sun, Chunjian Qi.
      As the largest proportion of myeloid immune cells in tumors, macrophages play an important role in tumor growth and regression according to their different phenotypes, thus reprogramming macrophages has become a new research direction for cancer immunotherapy. Yeast-derived whole β-glucan particles (WGPs) can induce M0 macrophages to differentiate into M1 macrophages and convert M2 macrophages and tumor-associated macrophages (TAMs) into M1 macrophages. In vitro, studies have confirmed that WGP-treated macrophages increase the activating receptors in natural killer cells (NK cells) and enhance the cytotoxicity of NK cells. The extracellular regulated protein kinases (ERK) signaling pathway is involved in WGP-mediated regulation of the macrophage phenotype. Further in vivo studies show that oral WGP can significantly delay tumor growth, which is related to the increased proportion of macrophages and NK cells, the macrophage phenotype reversal and the enhancement of NK cell immune function. NK cell depletion reduces the therapeutic efficacy of WGP in tumor-bearing mice. These findings revealed that in addition to T cells, NK cells also participate in the antitumor process of WGP. It was confirmed that WGP regulates the macrophage phenotype to regulate NK cell function.
    Keywords:  Antitumor immunity; Macrophages; NK cells; Whole glucan particle (WGP)
    DOI:  https://doi.org/10.1093/cei/uxad080
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