bims-traimu 2024-02-04 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024‒02‒04
ten papers selected by
Yantong Wan, Southern Medical University

The impact of trained immunity in respiratory viral infections.
MMR vaccination induces trained immunity via functional and metabolic reprogramming of γδ T cells.
Skin innate immune response against fungal infections and the potential role of trained immunity.
BCG as an Innovative Option for HCC Treatment: Repurposing and Mechanistic Insights.
Epigenetic regulation of innate immune dynamics during inflammation.
Author Correction: BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity.
Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation.
Angiotensin-(1-7) Modulates the Warburg Effect to Alleviate Inflammation in LPS-Induced Macrophages and Septic Mice.
Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation.
Macrophage subpopulation identity in Drosophila is modulated by apoptotic cell clearance and related signalling pathways.

Rev Med Virol. 2024 Jan;34(1): e2510

The impact of trained immunity in respiratory viral infections.

Jocelyne Piret, Guy Boivin.

  Epidemic peaks of respiratory viruses that co-circulate during the winter-spring seasons can be synchronous or asynchronous. The occurrence of temporal patterns in epidemics caused by some respiratory viruses suggests that they could negatively interact with each other. These negative interactions may result from a programme of innate immune memory, known as trained immunity, which may confer broad protective effects against respiratory viruses. It is suggested that stimulation of innate immune cells by a vaccine or a pathogen could induce their long-term functional reprogramming through an interplay between metabolic and epigenetic changes, which influence the transcriptional response to a secondary challenge. During the coronavirus disease 2019 pandemic, the circulation of most respiratory viruses was prevented by non-pharmacological interventions and then resumed at unusual periods once sanitary measures were lifted. With time, respiratory viruses should find again their own ecological niches. This transition period provides an opportunity to study the interactions between respiratory viruses at the population level.

Keywords:  epidemiology; epigenetic reprogramming; innate immune memory; respiratory viruses; trained immunity; vaccines

DOI:  https://doi.org/10.1002/rmv.2510
J Clin Invest. 2024 Jan 30. pii: e170848. [Epub ahead of print]

MMR vaccination induces trained immunity via functional and metabolic reprogramming of γδ T cells.

Rutger J Röring, Priya A Debisarun, Javier Botey-Bataller, Tsz Kin Suen, Ozlem Bulut, Gizem Kilic, Valerie Acm Koeken, Andrei Sarlea, Harsh Bahrar, Helga Dijkstra, Heidi Lemmers, Katharina L Gössling, Nadine Rüchel, Philipp N Ostermann, Lisa Müller, Heiner Schaal, Ortwin Adams, Arndt Borkhardt, Yavuz Ariyurek, Emile J de Meijer, Susan L Kloet, Jaap Ten Oever, Katarzyna Placek, Yang Li, Mihai G Netea.

  The measles, mumps and rubella (MMR) vaccine protects against all-cause mortality in children, but the immunological mechanisms mediating these effects are poorly known. We systematically investigated whether MMR can induce long-term functional changes in innate immune cells, a process termed trained immunity, that could at least partially mediate this heterologous protection. In a randomized placebo-controlled trial, 39 healthy adults received either the MMR vaccine or a placebo. By using single-cell RNA-sequencing, we found that MMR caused transcriptomic changes in CD14-positive monocytes and NK cells, but most profoundly in γδ T cells. Monocyte function was not altered by MMR vaccination. In contrast, the function of γδ T cells was markedly enhanced by MMR vaccination, with higher production of TNF and IFNγ, as well as upregulation of cellular metabolic pathways. In conclusion, we describe a trained immunity program characterized by modulation of γδ T cell function induced by MMR vaccination.

Keywords:  Cellular immune response; Immunology; Innate immunity

DOI:  https://doi.org/10.1172/JCI170848
Mycoses. 2024 Jan;67(1):

Skin innate immune response against fungal infections and the potential role of trained immunity.

Amanda Bombassaro, Julia Marcondes Figueiredo, Carlos P Taborda, Leo A B Joosten, Vania A Vicente, Flavio Queiroz-Telles, Jacques F Meis, Brenda Kischkel.

  Fungal skin infections are distributed worldwide and can be associated with economic and social traits. The immune response related to skin cells is complex and its understanding is essential to the comprehension of each cell's role and the discovery of treatment alternatives. The first studies of trained immunity (TI) described the ability of monocytes, macrophages and natural killer (NK) cells to develop a memory-like response. However, the duration of TI does not reflect the shorter lifespan of these cells. These conclusions supported later studies showing that TI can be observed in stem and haematopoietic cells and, more recently, also in non-immune skin cells such as fibroblasts, highlighting the importance of resident cells in response to skin disorders. Besides, the participation of less studied proinflammatory cytokines in the skin immune response, such as IL-36γ, shed light into a new possibility of inflammatory pathway blockade by drugs. In this review, we will discuss the skin immune response associated with fungal infections, the role of TI in skin and clinical evidence supporting opportunities and challenges of TI and other inflammatory responses in the pathogenesis of fungal skin infections.

Keywords:  fungal skin infections; immune response; proinflammatory cytokines; tissue inflammation; trained immunity

DOI:  https://doi.org/10.1111/myc.13682
Adv Sci (Weinh). 2024 Feb 02. e2308242

BCG as an Innovative Option for HCC Treatment: Repurposing and Mechanistic Insights.

Farzam Vaziri, Tahereh Setayesh, Ying Hu, Resmi Ravindran, Dongguang Wei, Yu-Jui Yvonne Wan.

  This study investigates Bacillus Calmette-Guérin (BCG) as a potential treatment for hepatocellular carcinoma (HCC), a condition often associated with unfavorable treatment outcomes. Exploiting BCG's recognized immune-boosting properties, preclinical trials are conducted using HCC mice, with a single subcutaneous dose of BCG administered post-tumor formation. Results indicate that BCG treatment effectively diminishes tumor burden and extends survival in both male and female HCC mice. Positive influences on hepatic fibrosis and metabolism are observed, leading to a reduction in lipid levels. Spatial analysis underscores BCG's tumor-specific effects, inducing the enrichment of metabolic pathways and inhibiting various cancer-related pathways. Furthermore, BCG promotes immune cell infiltration, including CD4+, CD8+ T cells, and M1 macrophages, in both v-akt murine thymoma viral oncogene homolog 1(AKT)/neutoblastoma RAS viral oncogene homolog (RAS) and β-catenin positive HCC models. Interestingly, blocking T cells, trained immunity, and Interferon-γ (IFN-γ) function reverses BCG's anti-HCC effects. In conclusion, BCG emerges as a promising treatment option for HCC, characterized by a favorable safety profile and efficacy in inhibiting fibrosis, improving metabolism, and engaging both trained immunity and T cells in therapeutic mechanisms.

Keywords:  bacterial immunotherapy; fibrosis; interferon; liver; trained immunity

DOI:  https://doi.org/10.1002/advs.202308242
J Leukoc Biol. 2024 Feb 01. pii: qiae026. [Epub ahead of print]

Epigenetic regulation of innate immune dynamics during inflammation.

Blake A Caldwell, Liwu Li.

  Innate immune cells play essential roles in modulating both immune defense and inflammation by expressing a diverse array of cytokines and inflammatory mediators, phagocytizing pathogens to promote immune clearance, and assisting with the adaptive immune processes through antigen presentation. Rudimentary innate immune "memory" states such as training, tolerance, and exhaustion develop based on the nature, strength, and duration of immune challenge, thereby enabling dynamic transcriptional reprogramming to alter present and future cell behavior. Underlying transcriptional reprogramming are broad changes to the epigenome, or chromatin alterations above the level of DNA sequence. These changes include direct modification of DNA through cytosine methylation as well as indirect modifications through alterations to histones that comprise the protein core of nucleosomes. In this review, we will discuss recent advances in our understanding of how these epigenetic changes influence the dynamic behavior of the innate immune system during both acute and chronic inflammation, as well as how stable changes to the epigenome result in long-term alterations of innate cell behavior related to pathophysiology.

Keywords:  DNA methylation; Inflammation; epigenetics; histones; innate immune memory; innate immune system

DOI:  https://doi.org/10.1093/jleuko/qiae026
Nat Immunol. 2024 Feb 01.

Author Correction: BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity.

Kim A Tran, Erwan Pernet, Mina Sadeghi, Jeffrey Downey, Julia Chronopoulos, Elizabeth Lapshina, Oscar Tsai, Eva Kaufmann, Jun Ding, Maziar Divangahi.

DOI: https://doi.org/10.1038/s41590-024-01773-5
Elife. 2024 Feb 02. pii: RP92420. [Epub ahead of print]12

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation.

Rabina Mainali, Nancy Buechler, Cristian Otero, Laken Edwards, Chia-Chi Key, Cristina Furdui, Matthew A Quinn.

  One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Acod1 knockout mice that are deficient in synthesizing itaconate, we aimed to understand the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Acod1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveals enhanced expression of enzymes involved in fatty acid oxidation in following 4-octyl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Acod1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.

Keywords:  fatty acid oxidation; immunology; inflammation; itaconate; mouse

DOI:  https://doi.org/10.7554/eLife.92420
J Inflamm Res. 2024 ;17 469-485

Angiotensin-(1-7) Modulates the Warburg Effect to Alleviate Inflammation in LPS-Induced Macrophages and Septic Mice.

Dan Yu, Wenhan Huang, Min Sheng, Shan Zhang, Hang Pan, Feifeng Ren, Lei Luo, Jun Zhou, Dongmei Huang, Lin Tang.

  Purpose: Inflammation triggers a metabolic shift in macrophages from oxidative phosphorylation to glycolysis, a phenomenon known as the Warburg effect. This metabolic reprogramming worsens inflammation and cascades into organ damage. Angiotensin-(1-7) [Ang-(1-7)], a small molecule, has demonstrated anti-inflammatory properties. This study investigates whether Ang-(1-7) mitigates inflammation in LPS-induced macrophages and septic mice by regulating the Warburg effect in immune metabolism.Methods: The study induced macrophages with LPS in vitro and measured inflammatory factors using ELISA and Western blot. Key enzymes in glycolysis, mitochondrial respiratory complexes, and citrate pathway key molecules were assessed using Western blot and qRT-PCR. Mitochondrial membrane potential (MMP), lactate, and ATP were measured using assay kits. In vivo, a mouse model of sepsis induced by LPS was used. Kidney tissues were examined for pathological and mitochondrial ultrastructural alterations. The levels of inflammatory factors in mouse serum, glycolysis and citrate pathway-related molecules in the kidney were assessed using qRT-PCR, Western blot, and immunofluorescence techniques. Additionally, MMP, lactate, and ATP in the kidney were measured using assay kits.
Results: In vitro experiments demonstrated that Ang-(1-7) inhibited the levels of inflammatory factors in LPS-treated RAW264.7 cells. It also reduced the expression of key glycolytic enzymes HK2, PFKFB3, and PKM2, as well as lactate levels. Additionally, it decreased intracellular citrate accumulation, enhanced mitochondrial respiratory complexes I and III, and ATP levels. Ang-(1-7) alleviated MMP damage, modulated citrate pathway-related molecules, including SLC25A1, ACLY, and HIF-1α. In vivo experiments showed that Ang-(1-7) lowered glycolysis levels in septic mice, improved mitochondrial ultrastructure and function, mitigated inflammation and renal tissues damage in septic mice, and suppressed the expression of key molecules in the citrate pathway.
Conclusion: In conclusion, Ang-(1-7) can regulate the Warburg effect through the citrate pathway, thereby alleviating inflammation in LPS-induced macrophages and septic mice.

Keywords:  Ang-(1-7); Warburg effect; citrate; glycolysis; macrophage; sepsis

DOI:  https://doi.org/10.2147/JIR.S446013
Mol Metab. 2024 Jan 31. pii: S2212-8778(24)00019-X. [Epub ahead of print] 101888

Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation.

Marissa N Trujillo, Erin Q Jennings, Emely A Hoffman, Hao Zhang, Aiden M Phoebe, Grace E Mastin, Naoya Kitamura, Julie A Reisz, Emily Megill, Daniel Kantner, Mariola M Marcinkiewicz, Shannon M Twardy, Felicidad Lebario, Eli Chapman, Rebecca L McCullough, Angelo D'Alessandro, Nathaniel W Snyder, Darren A Cusanovich, James J Galligan.

  Chronic, systemic inflammation is a pathophysiological manifestation of metabolic disorders. Inflammatory signaling leads to elevated glycolytic flux and a metabolic shift towards aerobic glycolysis and lactate generation. This rise in lactate corresponds with increased generation of lactoylLys modifications on histones, mediating transcriptional responses to inflammatory stimuli. Lactoylation is also generated through a non-enzymatic S-to-N acyltransfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Here, we report a regulatory role for LGSH in mediating histone lactoylation and inflammatory signaling. In the absence of the primary LGSH hydrolase, glyoxalase 2 (GLO2), RAW264.7 macrophages display significant elevations in LGSH and histone lactoylation with a corresponding potentiation of the inflammatory response when exposed to lipopolysaccharides. An analysis of chromatin accessibility shows that lactoylation is associated with more compacted chromatin than acetylation in an unstimulated state; upon stimulation, however, regions of the genome associated with lactoylation become markedly more accessible. Lastly, we demonstrate a spontaneous S-to-S acyltransfer of lactate from LGSH to CoA, yielding lactoyl-CoA. This represents the first known mechanism for the generation of this metabolite. Collectively, these data suggest that LGSH, and not intracellular lactate, is the primary driving factor facilitating histone lactoylation and a major contributor to inflammatory signaling.

Keywords:  Metabolism; glyoxalase; inflammation; lactate; post-translational modification

DOI:  https://doi.org/10.1016/j.molmet.2024.101888
Front Immunol. 2023 ;14 1310117

Macrophage subpopulation identity in Drosophila is modulated by apoptotic cell clearance and related signalling pathways.

Elliot C Brooks, Martin P Zeidler, Albert C M Ong, Iwan R Evans.

  In Drosophila blood, plasmatocytes of the haemocyte lineage represent the functional equivalent of vertebrate macrophages and have become an established in vivo model with which to study macrophage function and behaviour. However, the use of plasmatocytes as a macrophage model has been limited by a historical perspective that plasmatocytes represent a homogenous population of cells, in contrast to the high levels of heterogeneity of vertebrate macrophages. Recently, a number of groups have reported transcriptomic approaches which suggest the existence of plasmatocyte heterogeneity, while we identified enhancer elements that identify subpopulations of plasmatocytes which exhibit potentially pro-inflammatory behaviours, suggesting conservation of plasmatocyte heterogeneity in Drosophila. These plasmatocyte subpopulations exhibit enhanced responses to wounds and decreased rates of efferocytosis when compared to the overall plasmatocyte population. Interestingly, increasing the phagocytic requirement placed upon plasmatocytes is sufficient to decrease the size of these plasmatocyte subpopulations in the embryo. However, the mechanistic basis for this response was unclear. Here, we examine how plasmatocyte subpopulations are modulated by apoptotic cell clearance (efferocytosis) demands and associated signalling pathways. We show that loss of the phosphatidylserine receptor Simu prevents an increased phagocytic burden from modulating specific subpopulation cells, while blocking other apoptotic cell receptors revealed no such rescue. This suggests that Simu-dependent efferocytosis is specifically involved in determining fate of particular subpopulations. Supportive of our original finding, mutations in amo (the Drosophila homolog of PKD2), a calcium-permeable channel which operates downstream of Simu, phenocopy simu mutants. Furthermore, we show that Amo is involved in the acidification of the apoptotic cell-containing phagosomes, suggesting that this reduction in pH may be associated with macrophage reprogramming. Additionally, our results also identify Ecdysone receptor signalling, a pathway related to control of cell death during developmental transitions, as a controller of plasmatocyte subpopulation identity. Overall, these results identify fundamental pathways involved in the specification of plasmatocyte subpopulations and so further validate Drosophila plasmatocytes as a heterogeneous population of macrophage-like cells within this important developmental and immune model.

Keywords:  Drosophila; apoptosis; apoptotic cell clearance; ecdysone; haemocyte; macrophage

DOI:  https://doi.org/10.3389/fimmu.2023.1310117