bims-traimu 2023-01-08 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–01–08
eight papers selected by
Yantong Wan, Southern Medical University

[Epigenetic regulation of microglia-mediated innate immune memory and neurological diseases].
Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis.
Does the trained immune system play an important role in the extreme longevity that is seen in the Sardinian blue zone?
Oral supplementation with yeast β-glucans improves the resolution of Escherichia coli-associated inflammatory responses independently of monocyte/macrophage immune training.
New insights into β-glucan-enhanced immunity in largemouth bass Micropterus salmoides by transcriptome and intestinal microbial composition.
Low doses of diarrhoeagenic E. coli induce enhanced monocyte and mDC responses and prevent development of symptoms after homologous rechallenge.
Quantitatively Assessing the Respiratory Burst in Innate Immune Cells.
Neuroprotection by Preconditioning in Mice is Dependent on MyD88-Mediated CXCL10 Expression in Endothelial Cells.

Sheng Li Xue Bao. 2022 Dec 25. 74(6): 1031-1038

[Epigenetic regulation of microglia-mediated innate immune memory and neurological diseases].

Jin-Tao Zhou, Zhong-Wang Yu, Li Cao.

Microglia have the ability to mediate innate immune memory and can be reprogrammed by primary stimuli to enhance or inhibit the immune response of microglia to secondary stimuli. Inflammatory stimulation is an important factor for microglia to mediate innate immune memory. Single or repeated stimulation can induce microglia to form different phenotypes. Microglia-mediated innate immune response is involved in the regulation of immune memory. Enhancer modification is a key pathway of microglia epigenetic regulation, and the H3K27ac enhancer marker is closely related to immune training. TGF-β1 mediates the interaction between IL-10 and IL-1β, thereby influencing the microglial phenotype. Microglia glycolysis activity is increased after immune training, and oxidative phosphorylation is associated with immune tolerance. Innate immune memory is closely associated with neurodegenerative diseases, brain tumors, brain damage and psychosis. Further study on the mechanism of microglia-mediated innate immune memory is helpful to understand the occurrence and development of central nervous system diseases and provide new options for the treatment of central nervous system diseases.
Nat Immunol. 2023 Jan 05.

Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis.

Chuanlin Ding, Rejeena Shrestha, Xiaojuan Zhu, Anne E Geller, Shouzhen Wu, Matthew R Woeste, Wenqian Li, Haomin Wang, Fang Yuan, Raobo Xu, Julia H Chariker, Xiaoling Hu, Hong Li, David Tieri, Huang-Ge Zhang, Eric C Rouchka, Robert Mitchell, Leah J Siskind, Xiang Zhang, Xiaoji G Xu, Kelly M McMasters, Yan Yu, Jun Yan.

Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.

DOI: https://doi.org/10.1038/s41590-022-01388-8
Front Aging. 2022 ;3 1069415

Does the trained immune system play an important role in the extreme longevity that is seen in the Sardinian blue zone?

Mark J Soloski, Michel Poulain, Giovanni M Pes.

  Villages in the island of Sardinia in the Mediterranean that display exceptional longevity are clustered within a defined mountainous region. Because of their unique location we hypothesize that these villages had a unique infectious disease exposure relevant to the observed successful longevity. These highland villages had a significant exposure to malaria in the first half of the 20th century after which malaria was eliminated due to vector control mechanisms. In addition, there is likely a high incidence of Helicobacter pylori infections among shepherds in Sardinia, the primary occupation of many living in the LBZ, as well as helminth infections among children. This suggests that individuals living in the LBZ had a unique infectious disease exposure. Specifically, we hypothesize that the continued high exposure of residents in the LBZ to these infectious agents prior to the 1950s lead to the generation of a uniquely trained (or imprinted) immune system. Once some of these diseases were eliminated in the latter half of the century, individuals within the LBZ were equipped with a trained immune system that was uniquely capable of not only responding effectively to common infections but also responding in a manner that maximized maintaining tissue health. In addition, there are lifestyle factors that also favor such a trained immune system. This hypothesis may help explain the slow progression of chronic immune mediated diseases as well as other chronic non-transmissible age-related diseases seen in the Sardinian LBZ and serve as a template for future studies that support or refute this hypothesis.

Keywords:  Italy; Sardinia; infection; lifestyle; longevity blue zone; trained immunity

DOI:  https://doi.org/10.3389/fragi.2022.1069415
Front Immunol. 2022 ;13 1086413

Oral supplementation with yeast β-glucans improves the resolution of Escherichia coli-associated inflammatory responses independently of monocyte/macrophage immune training.

Sarah Walachowski, Koen Breyne, Thomas Secher, Céline Cougoule, Laurence Guzylack-Piriou, Evelyne Meyer, Gilles Foucras, Guillaume Tabouret.

   Introduction: Confronted with the emerging threat of antimicrobial resistance, the development of alternative strategies to limit the use of antibiotics or potentiate their effect through synergy with the immune system is urgently needed. Many natural or synthetic biological response modifiers have been investigated in this context. Among them, β-glucans, a type of soluble or insoluble polysaccharide composed of a linear or branched string of glucose molecules produced by various cereals, bacteria, algae, and inferior (yeast) and superior fungi (mushrooms) have garnered interest in the scientific community, with not less than 10,000 publications over the last two decades. Various biological activities of β-glucans have been reported, such as anticancer, antidiabetic and immune-modulating effects. In vitro, yeast β-glucans are known to markedly increase cytokine secretion of monocytes/macrophages during a secondary challenge, a phenomenon called immune training.
Methods: Here, we orally delivered β-glucans derived from the yeast S. cerevisiae to mice that were further challenged with Escherichia coli.
Results: β-glucan supplementation protected the mice from E. coli intraperitoneal and intra-mammary infections, as shown by a lower bacterial burden and greatly diminished tissue damage. Surprisingly, this was not associated with an increased local immune response. In addition, granulocyte recruitment was transient and limited, as well as local cytokine secretion, arguing for faster resolution of the inflammatory response. Furthermore, ex-vivo evaluation of monocytes/macrophages isolated or differentiated from β-glucan-supplemented mice showed these cells to lack a trained response versus those from control mice.
Conclusion: In conclusion, dietary β-glucans can improve the outcome of Escherichia coli infections and dampen tissue damages associated to excessive inflammatory response. The mechanisms associated with such protection are not necessarily linked to immune system hyper-activation or immune training.

Keywords:  escherichia coli; immune training; inflammation; innate immunity; macrophages; nutritional immuology; saccharomyces cerevisiae; β-glucans

DOI:  https://doi.org/10.3389/fimmu.2022.1086413
Front Immunol. 2022 ;13 1086103

New insights into β-glucan-enhanced immunity in largemouth bass Micropterus salmoides by transcriptome and intestinal microbial composition.

Yuexing Zhang, Mingyu Guo, Ning Li, Zhiyong Dong, Linwei Cai, Bowen Wu, Jianjun Xie, Liang Liu, Lina Ren, Bo Shi.

  β-glucan is widely used in aquaculture due to its immunostimulatory effects, but the specific effect and potential regulatory mechanism on largemouth bass (Micropterus salmoides) are still unclear. Here, we evaluated the effects of β-glucan on growth, resistance to Aeromonas schubertii, intestinal health, and transcriptome of largemouth bass to reveal the potential regulators, metabolic pathways, and altered differential microbiota. Four experimental diets were designed with β-glucan supplementation levels of 0 (control), 100 (LA-100), 200 (MA-200), and 300 (HA-300) mg kg-1, and each diet was fed to largemouth bass (79.30 ± 0.50 g) in triplicate for 70 days, followed by a 3-day challenge experiment. Results showed that different β-glucan supplementations had no significant effects on growth performance and whole-body composition. Fish fed a diet with 300 mg kg-1 β-glucan significantly increased the activity of lysozyme than those fed diets with 0 and 100 mg kg-1 β-glucan. In addition, the survival rate of largemouth bass in β-glucan supplementation groups was significantly higher than the control group at 12- and 24-h challenge by Aeromonas schubertii. Transcriptome analysis showed that a total of 1,245 genes were differentially expressed [|log2(fold change)| ≥1, q-value ≤0.05], including 109 immune-related differentially expressed genes (DEGs). Further analysis revealed that significantly upregulated and downregulated DEGs associated with immunity were mapped into 12 and 24 pathways, respectively. Results of intestinal microflora indicated that fish fed a diet with 300 mg kg-1 β-glucan had higher bacterial richness and diversity as evaluated by Sobs, Chao, Ace, and Simpson indices, but no significant differences were found in the comparison groups. Furthermore, 300 mg kg-1 β-glucan significantly increased the relative abundance of Mycoplasma and decreased Proteobacteria (mainly Escherichia-Shigella and Escherichia coli) and Bacillus anthracis in largemouth bass intestinal microflora. The findings of this study provided new insights that will be valuable in future studies to elucidate the mechanism of immunity enhancement by β-glucan.

Keywords:  Aeromonas schubertii; growth; immunity; largemouth bass; β-Glucan

DOI:  https://doi.org/10.3389/fimmu.2022.1086103
PLoS One. 2023 ;18(1): e0279626

Low doses of diarrhoeagenic E. coli induce enhanced monocyte and mDC responses and prevent development of symptoms after homologous rechallenge.

Mojtaba Porbahaie, Maartje van den Belt, Laurien Ulfman, Rianne M A J Ruijschop, Elly Lucas-van de Bos, Anita Hartog, Stefanie Lenz, Ingrid J van Alen-Boerrigter, Malgorzata Teodorowicz, Huub F J Savelkoul, Wim Calame, Els van Hoffen, R J Joost van Neerven, Alwine Kardinaal.

The experimental challenge with attenuated enterotoxigenic E. coli strain E1392/75-2A prevents diarrhea upon a secondary challenge with the same bacteria. A dose-response pilot study was performed to investigate which immunological factors are associated with this protection. Healthy subjects were inoculated with increasing E. coli doses of 1E6-1E10 CFU, and three weeks later, all participants were rechallenged with the highest dose (1E10 CFU). Gastrointestinal discomfort symptoms were recorded, and stool and blood samples were analyzed. After the primary challenge, stool frequency, diarrhea symptom scores, and E. coli-specific serum IgG (IgG-CFA/II) titer increased in a dose-dependent manner. Fecal calprotectin and serum IgG-CFA/II response after primary challenge were delayed in the lower dose groups. Even though stool frequency after the secondary challenge was inversely related to the primary inoculation dose, all E. coli doses protected against clinical symptoms upon rechallenge. Ex vivo stimulation of PBMCs with E. coli just before the second challenge resulted in increased numbers of IL-6+/TNF-α+ monocytes and mDCs than before the primary challenge, without dose-dependency. These data demonstrate that primary E. coli infection with as few as 1E6 CFU protects against a high-dose secondary challenge with a homologous attenuated strain. Increased serum IgG-CFA/II levels and E. coli-induced mDC and monocyte responses after primary challenge suggest that protection against secondary E. coli challenges is associated with adaptive as well as innate immune responses.

DOI: https://doi.org/10.1371/journal.pone.0279626
Methods Mol Biol. 2023 ;2614 47-70

Quantitatively Assessing the Respiratory Burst in Innate Immune Cells.

Ava L Sargent, Jordan A Leedberg, Jessica E Burress, Purva S Dalwadi, Kevin S O'Fallon, Erin Gaffney-Stomberg, Peter C W Gaines.

  The respiratory burst is a rapid cellular consumption of oxygen resulting in abundant production of reactive oxygen species (ROS), most often associated with primary mediators of innate immunity, neutrophils and macrophages. These myeloid cells convert ROS into potent antimicrobial oxidants that efficiently kill pathogens. The respiratory burst also can have destructive consequences, as ROS are well known to support chronic inflammation and aberrant autoimmune responses. Interestingly, ROS perform conflicting roles in the tumor microenvironment; ROS and derived cytotoxic products can destroy cancer cells but also suppress important tumor-fighting functions of T cells or natural killer cells, or yield mutagenized proteins that can promote tumorigenesis or support tumor cell growth. Moreover, high numbers of neutrophils or macrophages in tumors are associated with poor prognosis. Therefore, accurate and quantitative assays to assess the respiratory burst are an important tool for measuring ROS production by neutrophils or cells of the monocyte/macrophage system, each recently identified in the tumor microenvironment. Described are methods to derive mouse or human models of neutrophils or macrophages, which are then used in a detailed assay to quantitatively measure ROS produced by either cell type using luminescence-enhanced reagents and a multi-well platform along with different stimulants that cause rapid ROS production.

Keywords:  Human HL-60 myoblasts; Human U937 monocytes; Macrophages; Mouse bone marrow; Neutrophils; Opsonized zymosan; Phorbol myristate acetate; Reactive oxygen species

DOI:  https://doi.org/10.1007/978-1-0716-2914-7_4
ASN Neuro. 2023 Jan-Dec;15:15 17590914221146365

Neuroprotection by Preconditioning in Mice is Dependent on MyD88-Mediated CXCL10 Expression in Endothelial Cells.

Zhihong Chen, Weiwei Hu, Mynor J Mendez, Zachary C Gossman, Anthony Chomyk, Brendan T Boylan, Grahame J Kidd, Timothy W Phares, Cornelia C Bergmann, Bruce D Trapp.

  The central nervous system (CNS) can be preconditioned to resist damage by peripheral pretreatment with low-dose gram-negative bacterial endotoxin lipopolysaccharide (LPS). Underlying mechanisms associated with transient protection of the cerebral cortex against traumatic brain injury include increased neuronal production of antiapoptotic and neurotrophic molecules, microglial-mediated displacement of inhibitory presynaptic terminals innervating the soma of cortical projection neurons, and synchronized firing of cortical projection neurons. However, the cell types and signaling responsible for these neuronal and microglial changes are unknown. A fundamental question is whether LPS penetrates the CNS or acts on the luminal surface of brain endothelial cells, thereby triggering an indirect parenchymal neuroprotective response. The present study shows that a low-dose intraperitoneal LPS treatment increases brain endothelial cell activation markers CD54, but does not open the blood-brain barrier or alter brain endothelial cell tight junctions as assessed by electron microscopy. NanoString nCounter transcript analyses of CD31-positive brain endothelial cells further revealed significant upregulation of Cxcl10, C3, Ccl2, Il1β, Cxcl2, and Cxcl1, consistent with identification of myeloid differentiation primary response 88 (MyD88) as a regulator of these transcripts by pathway analysis. Conditional genetic endothelial cell gene ablation approaches demonstrated that both MyD88-dependent Toll-like receptor 4 (TLR4) signaling and Cxcl10 expression are essential for LPS-induced neuroprotection and microglial activation. These results suggest that C-X-C motif chemokine ligand 10 (CXCL10) production by endothelial cells in response to circulating TLR ligands may directly or indirectly signal to CXCR3 on neurons and/or microglia. Targeted activation of brain endothelial receptors may thus provide an attractive approach for inducing transient neuroprotection.

Keywords:  CXCL10; LPS; MyD88; TLR4; brain endothelial; microglia; neuroprotection

DOI:  https://doi.org/10.1177/17590914221146365