bims-traimu 2024-03-03 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–03–03
ten papers selected by
Yantong Wan, Southern Medical University

Potent induction of trained immunity by Saccharomyces cerevisiae β-glucans.
β-glucans from Agaricus bisporus mushroom products drive Trained Immunity.
I. IDC Key-note Lecture: Trained immunity: a memory for innate host defense.
Early life vaccination reprograms the metabolism and function of myeloid cells in neonates.
Hyperglycaemia amplifies TLR-mediated inflammatory response of M(IL4) macrophages to dyslipidemic ligands.
Addendum: USP3 plays a critical role in the induction of innate immune tolerance.
Protocol for localized macrophage stimulation with small-molecule TLR agonist via fluidic force microscopy.
The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis.
Single-Cell Analysis Reveals a Subset of High IL-12p40-Secreting Dendritic Cells within Mouse Bone Marrow-Derived Macrophages Differentiated with M-CSF.
Generation of Tolerogenic Dendritic Cells under the Persistent Inflammation Stimulation.

Front Immunol. 2024 ;15 1323333

Potent induction of trained immunity by Saccharomyces cerevisiae β-glucans.

Patricia Vuscan, Brenda Kischkel, Aikaterini Hatzioannou, Efrosyni Markaki, Andrei Sarlea, Maria Tintoré, Jordi Cuñé, Panayotis Verginis, Carlos de Lecea, Triantafyllos Chavakis, Leo A B Joosten, Mihai G Netea.

  Candida albicans cell wall component β-glucan has been extensively studied for its ability to induce epigenetic and functional reprogramming of innate immune cells, a process termed trained immunity. We show that a high-complexity blend of two individual β-glucans from Saccharomyces cerevisiae possesses strong bioactivity, resulting in an enhanced trained innate immune response by human primary monocytes. The training required the Dectin-1/CR3, TLR4, and MMR receptors, as well as the Raf-1, Syk, and PI3K downstream signaling molecules. By activating multiple receptors and downstream signaling pathways, the components of this β-glucan preparation are able to act synergistically, causing a robust secondary response upon an unrelated challenge. In in-vivo murine models of melanoma and bladder cell carcinoma, pre-treatment of mice with the β-glucan preparation led to a significant reduction in tumor growth. These insights may aid in the development of future therapies based on β-glucan structures that induce an effective trained immunity response.

Keywords:  bladder cell carcinoma; immunotherapy; innate immunity; melanoma; probiotics

DOI:  https://doi.org/10.3389/fimmu.2024.1323333
Front Nutr. 2024 ;11 1346706

β-glucans from Agaricus bisporus mushroom products drive Trained Immunity.

Sarah Case, Tara O'Brien, Anna E Ledwith, Shilong Chen, Cian J H Horneck Johnston, Emer E Hackett, Michele O'Sullivan, Hugo Charles-Messance, Elaine Dempsey, Supriya Yadav, Jude Wilson, Sinead C Corr, Shipra Nagar, Frederick J Sheedy.

   Introduction: Macrofungi, such as edible mushrooms, have been used as a valuable medical resource for millennia as a result of their antibacterial and immuno-modulatory components. Mushrooms contain dietary fibers known as β-glucans, a class of polysaccharides previously linked to the induction of Trained Immunity. However, little is known about the ability of mushroom-derived β-glucans to induce Trained Immunity.
Methods & results: Using various powdered forms of the white button mushroom (Agaricus bisporus), we found that mouse macrophages pre-treated with whole mushroom powder (WMP) displayed enhanced responses to restimulation with TLR ligands, being particularly sensitive to Toll-like receptor (TLR)-2 stimulation using synthetic lipopeptides. This trained response was modest compared to training observed with yeast-derived β-glucans and correlated with the amount of available β-glucans in the WMP. Enriching for β-glucans content using either a simulated in-vitro digestion or chemical fractionation retained and boosted the trained response with WMP, respectively. Importantly, both WMP and digested-WMP preparations retained β-glucans as identified by nuclear magnetic resonance analysis and both displayed the capacity to train human monocytes and enhanced responses to restimulation. To determine if dietary incorporation of mushroom products can lead to Trained Immunity in myeloid cells in vivo, mice were given a regimen of WMP by oral gavage prior to sacrifice. Flow cytometric analysis of bone-marrow progenitors indicated alterations in hematopoietic stem and progenitor cells population dynamics, with shift toward myeloid-committed multi-potent progenitor cells. Mature bone marrow-derived macrophages derived from these mice displayed enhanced responses to restimulation, again particularly sensitive to TLR2.
Discussion: Taken together, these data demonstrate that β-glucans from common macrofungi can train innate immune cells and could point to novel ways of delivering bio-available β-glucans for education of the innate immune system.

Keywords:  Trained Immunity; digestion; immunometabolism; mushroom; β-glucan

DOI:  https://doi.org/10.3389/fnut.2024.1346706
J Stem Cells Regen Med. 2023 ;19(2): 37-39

I. IDC Key-note Lecture: Trained immunity: a memory for innate host defense.

Prof Dr Mihai G Netea.

DOI: https://doi.org/10.46582/jsrm.1902009
Immunology. 2024 Feb 29.

Early life vaccination reprograms the metabolism and function of myeloid cells in neonates.

Yingying Chen, Hui Li, Jie Zhou.

  Vaccination after birth provides protection against pathogen infection and immune related disorders in healthy children. The detailed effects of vaccination on neonatal immunity, however, remain largely unknown. Here, we reported that vaccination using Bacillus Calmette-Guérin (BCG) diminished the immunosuppressive function of myeloid-derived suppressor cells in neonatal mice, an immature myeloid population. A combination of single-cell transcriptome, metabolite profiling, and functional analysis demonstrated that upregulation of mTOR/HIF1a signalling and the enhanced glycolysis explained the effects of BCG on neonatal myeloid cells. Pharmalogical inhibition of glycolysis or mTOR signalling efficiently rescued the effects of BCG on neonatal myeloid cells. These observations suggest that BCG facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life.

Keywords:  bacillus Calmette-Guérin; glycolysis; mTOR signalling; myeloid-derived suppressor cells

DOI:  https://doi.org/10.1111/imm.13772
J Leukoc Biol. 2024 Mar 01. pii: qiae050. [Epub ahead of print]

Hyperglycaemia amplifies TLR-mediated inflammatory response of M(IL4) macrophages to dyslipidemic ligands.

Luis Ernesto Badillo-Garcia, Quan Liu, Kim Ziebner, Michael Balduff, Tatyana Sevastyanova, Christina Schmuttermaier, Harald Klüter, Martin Harmsen, Julia Kzhyshkowska.

  Hyperglycaemia is critical for initiation of diabetic vascular complications. We systemically addressed the role of hyperglycaemia in the regulation of TLRs in primary human macrophages. Expression of TLRs (1-9) was examined in monocyte-derived M(NC), M(IFNγ) and M(IL4) differentiated in normoglycemic and hyperglycaemic conditions. Hyperglycaemia increased expression of TLR1 and TLR8 in M(NC), TLR 2 and 6 in M(IFNγ), and TLR4 and TLR5 in M(IL4). The strongest effect of hyperglycaemia in M(IL4) was the upregulation of TLR4 gene and protein expression. Hyperglycaemia amplified TLR4-mediated response of M(IL4) to LPS by significantly enhancing IL1beta and modestly supressing IL10 production. In M(IL4), hyperglycaemia in combination with synthetic triacylated lipopeptide (TLR1/TLR2 ligand), amplified expression of TLR4, and production of IL1beta. In summary, hyperglycaemia enhanced inflammatory potential of homeostatic, inflammatory and healing macrophages by increasing specific profiles of TLRs. In combination with dyslipidemic ligands, hyperglycaemia can stimulate low-grade inflammatory program in healing macrophages supporting vascular diabetic complications.

Keywords:  Innate immunity; Toll-like receptors; diabetes; hyperglycemia; immunometabolism; macrophages; monocytes

DOI:  https://doi.org/10.1093/jleuko/qiae050
EMBO Rep. 2024 Mar 01.

Addendum: USP3 plays a critical role in the induction of innate immune tolerance.

Tianhao Duan, Yanchun Feng, Yang Du, Changsheng Xing, Junjun Chu, Jiayu Ou, Xin Liu, Motao Zhu, Chen Qian, Bingnan Yin, Helen Y Wang, Jun Cui, Rong-Fu Wang.

DOI: https://doi.org/10.1038/s44319-024-00096-8
STAR Protoc. 2024 Feb 29. pii: S2666-1667(24)00038-8. [Epub ahead of print]5(1): 102873

Protocol for localized macrophage stimulation with small-molecule TLR agonist via fluidic force microscopy.

Elizabeth J Mulder, Brittany Moser, Jennifer Delgado, Rachel Steinhardt, Aaron P Esser-Kahn.

  Here, we present a protocol to deliver nanoliter volumes of Toll-like receptor (TLR) agonist onto a culture of nuclear factor κB (NF-κB) reporter macrophages using fluidic force microscopy and a micron-scale probe. We describe steps for quantifying the dose of agonist by modeling their diffusion with experimental inputs. We then detail procedures for quantifying and categorizing macrophage responses to individual and varied doses and combining agonist concentration and macrophage response to analyze the NF-κB response to localized TLR stimulation. For complete details on the use and execution of this protocol, please refer to Mulder et al. (2024).1.

Keywords:  AFM; Atomic Force Microscopy; Biophysics; Cell Biology; Cell culture; Cell-based Assays; Immunology; Microscopy; Single Cell

DOI:  https://doi.org/10.1016/j.xpro.2024.102873
Cell Discov. 2024 Feb 27. 10(1): 24

The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis.

Shuolin Liu, Yaguang Bi, Tianting Han, Yiran E Li, Qihang Wang, Ne Natalie Wu, Chenguo Xu, Junbo Ge, Ronggui Hu, Yingmei Zhang.

Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly understood. Here we report that expression levels of the E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse hearts upon I/R injury. Genetic ablation of MARCH2 aggravated myocardial infarction and cardiac dysfunction upon myocardial I/R injury. Single-cell RNA-seq analysis suggested that loss of MARCH2 prompted activation of NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found to act as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and fostering the recruitment of NLRP3. MARCH2 directly interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, resulting in reduced PGAM5-MAVS co-condensation, and consequently inhibition of NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 significantly ameliorated I/R-induced mouse heart dysfunction. Altogether, our findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury.

DOI: https://doi.org/10.1038/s41421-023-00622-3
J Immunol. 2024 Feb 28. pii: ji2300431. [Epub ahead of print]

Single-Cell Analysis Reveals a Subset of High IL-12p40-Secreting Dendritic Cells within Mouse Bone Marrow-Derived Macrophages Differentiated with M-CSF.

Kate Bridges, Gabriela A Pizzurro, Mihir Khunte, Meibin Chen, Erick Salvador Rocha, Amanda F Alexander, Victor Bass, Laura N Kellman, Janani Baskaran, Kathryn Miller-Jensen.

Macrophages and dendritic cells (DCs), although ontogenetically distinct, have overlapping functions and exhibit substantial cell-to-cell heterogeneity that can complicate their identification and obscure innate immune function. In this study, we report that M-CSF-differentiated murine bone marrow-derived macrophages (BMDMs) exhibit extreme heterogeneity in the production of IL-12, a key proinflammatory cytokine linking innate and adaptive immunity. A microwell secretion assay revealed that a small fraction of BMDMs stimulated with LPS secrete most IL-12p40, and we confirmed that this is due to extremely high expression of Il12b, the gene encoding IL-12p40, in a subset of cells. Using an Il12b-YFP reporter mouse, we isolated cells with high LPS-induced Il12b expression and found that this subset was enriched for genes associated with the DC lineage. Single-cell RNA sequencing data confirmed a DC-like subset that differentiates within BMDM cultures that is transcriptionally distinct but could not be isolated by surface marker expression. Although not readily apparent in the resting state, upon LPS stimulation, this subset exhibited a typical DC-associated activation program that is distinct from LPS-induced stochastic BMDM cell-to-cell heterogeneity. Overall, our findings underscore the difficulty in distinguishing macrophages and DCs even in widely used in vitro murine BMDM cultures and could affect the interpretation of some studies that use BMDMs to explore acute inflammatory responses.

DOI: https://doi.org/10.4049/jimmunol.2300431
Shock. 2024 Feb 27.

Generation of Tolerogenic Dendritic Cells under the Persistent Inflammation Stimulation.

Shumin Miao, Zenan Chang, Bin Gu, Jinlong Jiang, Fei Pei, Yishan Liu, Yu Zhou, Zimeng Liu, Xiang Si, Xiangdong Guan, Jianfeng Wu.

ABSTRACT: Immunosuppression, commonly accompanied by persistent inflammation, is a key feature in the later phase of sepsis. However, the pathophysiological mechanisms underlying this phenomenon remain unclear. Dendritic cells (DCs), specifically tolerogenic DCs (tolDCs), play a crucial role in this process by regulating immune responses through inducing T cell anergy and releasing anti-inflammatory cytokines. Nevertheless, the existing cell models are inadequate for investigating tolDCs during the immunosuppressive phase of sepsis. Therefore, this study aimed to develop a novel in vitro model to generate tolDCs under chronic inflammatory conditions. We have successfully generated tolDCs by exposing them to sublethal lipopolysaccharide (LPS) for 72 h while preserving cell viability. Considering that Interleukin-10-induced tolDCs (IL-10-tolDCs) are a well-established model, we compared the immunological tolerance between LPS-tolDCs and IL-10-tolDCs. Our findings indicated that both LPS-tolDCs and IL-10-tolDCs exhibited reduced expression of maturation markers, whereas their levels of inhibitory markers were elevated. Furthermore, the immunoregulatory activities of LPS-tolDCs and IL-10-tolDCs were found to be comparable. These dysfunctions include impaired antigen presenting capacity and suppression of T cell activation, proliferation, and differentiation. Notably, compared with IL-10-tolDCs, LPS-tolDCs showed a reduced response in maturation and cytokine production upon stimulation, indicating their potential as a better model for research. Overall, in comparison with IL-10-tolDCs, our data suggest that the immunological dysfunctions shown in LPS-tolDCs could more effectively elucidate the increased susceptibility to secondary infections during sepsis. Consequently, LPS-tolDCs have emerged as a promising therapeutic target for ameliorating the immunosuppressed state in septic patients.

DOI: https://doi.org/10.1097/SHK.0000000000002318