bims-traimu 2023-10-15 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–10–15
eight papers selected by
Yantong Wan, Southern Medical University

BCG revaccination in adults enhances pro-inflammatory markers of trained immunity along with anti-inflammatory pathways.
Innate Immune Pathways in Atherosclerosis-From Signaling to Long-Term Epigenetic Reprogramming.
Prolonged Inhibition of the MEK1/2-ERK Signaling Axis Primes Interleukin-1 Beta Expression through Histone 3 Lysine 9 Demethylation in Murine Macrophages.
Cardinal features of immune memory in innate lymphocytes.
Mapping the epigenomic landscape of human monocytes following innate immune activation reveals context-specific mechanisms driving endotoxin tolerance.
Macrophage-derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection.
BRD4 regulates glycolysis-dependent Nos2 expression in macrophages upon H. pylori infection.
Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.

iScience. 2023 Oct 20. 26(10): 107889

BCG revaccination in adults enhances pro-inflammatory markers of trained immunity along with anti-inflammatory pathways.

Asma Ahmed, Himanshu Tripathi, Krista E van Meijgaarden, Nirutha Chetan Kumar, Vasista Adiga, Srabanti Rakshit, Chaitra Parthiban, Sharon Eveline J, George D'Souza, Mary Dias, Tom H M Ottenhoff, Mihai G Netea, Simone A Joosten, Annapurna Vyakarnam.

  This study characterized mechanisms of Bacille Calmette-Guérin (BCG) revaccination-induced trained immunity (TI) in India. Adults, BCG vaccinated at birth, were sampled longitudinally before and after a second BCG dose. BCG revaccination significantly elevated tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 in HLA-DR+CD16-CD14hi monocytes, demonstrating induction of TI. Mycobacteria-specific CD4+ T cell interferon (IFN) γ, IL-2, and TNF-α were significantly higher in re-vaccinees and correlated positively with HLA-DR+CD16-CD14hi TI responses. This, however, did not translate into increased mycobacterial growth control, measured by mycobacterial growth inhibition assay (MGIA). Post revaccination, elevated secreted TNF-α, IL-1β, and IL-6 to "heterologous" fungal, bacterial, and enhanced CXCL-10 and IFNα to viral stimuli were also observed concomitant with increased anti-inflammatory cytokine, IL-1RA. RNA sequencing after revaccination highlighted a BCG and LPS induced signature which included upregulated IL17 and TNF pathway genes and downregulated key inflammatory genes: CXCL11, CCL24, HLADRA, CTSS, CTSC. Our data highlight a balanced immune response comprising pro- and anti-inflammatory mediators to be a feature of BCG revaccination-induced immunity.

Keywords:  Immune response; Immunity; Immunology; Molecular biology; Omics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2023.107889
Cells. 2023 Sep 26. pii: 2359. [Epub ahead of print]12(19):

Innate Immune Pathways in Atherosclerosis-From Signaling to Long-Term Epigenetic Reprogramming.

Arailym Aronova, Federica Tosato, Nawraa Naser, Yaw Asare.

  Innate immune pathways play a crucial role in the development of atherosclerosis, from sensing initial danger signals to the long-term reprogramming of immune cells. Despite the success of lipid-lowering therapy, anti-hypertensive medications, and other measures in reducing complications associated with atherosclerosis, cardiovascular disease (CVD) remains the leading cause of death worldwide. Consequently, there is an urgent need to devise novel preventive and therapeutic strategies to alleviate the global burden of CVD. Extensive experimental research and epidemiological studies have demonstrated the dominant role of innate immune mechanisms in the progression of atherosclerosis. Recently, landmark trials including CANTOS, COLCOT, and LoDoCo2 have provided solid evidence demonstrating that targeting innate immune pathways can effectively reduce the risk of CVD. These groundbreaking trials mark a significant paradigm shift in the field and open new avenues for atheroprotective treatments. It is therefore crucial to comprehend the intricate interplay between innate immune pathways and atherosclerosis for the development of targeted therapeutic interventions. Additionally, unraveling the mechanisms underlying long-term reprogramming may offer novel strategies to reverse the pro-inflammatory phenotype of immune cells and restore immune homeostasis in atherosclerosis. In this review, we present an overview of the innate immune pathways implicated in atherosclerosis, with a specific focus on the signaling pathways driving chronic inflammation in atherosclerosis and the long-term reprogramming of immune cells within atherosclerotic plaque. Elucidating the molecular mechanisms governing these processes presents exciting opportunities for the development of a new class of immunotherapeutic approaches aimed at reducing inflammation and promoting plaque stability. By addressing these aspects, we can potentially revolutionize the management of atherosclerosis and its associated cardiovascular complications.

Keywords:  atherosclerosis; innate immunity; signaling pathways; trained immunity

DOI:  https://doi.org/10.3390/cells12192359
Int J Mol Sci. 2023 Sep 22. pii: 14428. [Epub ahead of print]24(19):

Prolonged Inhibition of the MEK1/2-ERK Signaling Axis Primes Interleukin-1 Beta Expression through Histone 3 Lysine 9 Demethylation in Murine Macrophages.

Rachel Low, Soon-Duck Ha, Nichita Sleapnicov, Parthiv Maneesh, Sung Ouk Kim.

  Macrophages undergo different cellular states upon activation that can be hyporesponsive (tolerated) or hyperresponsive (primed or trained) to subsequent stimuli. Epigenetic modifications are known to play key roles in determining these cellular states. However, little is known about the role of signaling pathways that lead to these epigenetic modifications. Here, we examined the effects of various inhibitors targeting key signaling pathways induced by lipopolysaccharide (LPS) on tolerance and priming in murine macrophages. We found that a prolonged inhibition (>18 h) of the mitogen-activated protein kinase (MEK)1/2-extracellular signal-regulated kinase (ERK)1/2 signaling axis reversed tolerance and primed cells in expressing interleukin (IL)-1β and other inflammatory cytokines such as IL-6, tumor necrosis factor (TNF)α, and CXCL10. The ectopic expression of catalytically active and inactive MEK1 mutants suppressed and enhanced IL-1β expression, respectively. A transcriptomic analysis showed that cells primed by the MEK1/2 inhibitor U0126 expressed higher levels of gene sets associated with immune responses and cytokine/chemokine production, but expressed lower levels of genes with cell cycle progression, chromosome organization, and heterochromatin formation than non-primed cells. Of interest, the mRNA expressions of the histone 3 lysine 9 (H3K9) methyltransferase Suv39h1 and the H3K9 methylation reader Cbx5 were substantially suppressed, whereas the H3K9 demethylase Kdm7a was enhanced, suggesting a role of the MEK1/2-ERK signaling axis in H3K9 demethylation. The H3K9 trimethylation levels in the genomic regions of IL-1β, TNFα, and CXCL10 were decreased by U0126. Also, the H3K9 methyltransferase inhibitor BIX01294 mimicked the U0126 training effects and the overexpression of chromobox homolog (CBX)5 prevented the U0126 training effects in both RAW264.7 cells and bone-marrow-derived macrophages. Collectively, these data suggest that the prolonged inhibition of the MEK1/2-ERK signaling axis reverses tolerance and primed macrophages likely through decreasing the H3K9 methylation levels.

Keywords:  CBX5; ERK; H3K9 methylation; IL-1β; LPS; MEK1/2; innate immune memory; macrophages; priming; tolerance; training

DOI:  https://doi.org/10.3390/ijms241914428
Nat Immunol. 2023 Oct 12.

Cardinal features of immune memory in innate lymphocytes.

Endi K Santosa, Joseph C Sun.

The ability of vertebrates to 'remember' previous infections had once been attributed exclusively to adaptive immunity. We now appreciate that innate lymphocytes also possess memory properties akin to those of adaptive immune cells. In this Review, we draw parallels from T cell biology to explore the key features of immune memory in innate lymphocytes, including quantity, quality, and location. We discuss the signals that trigger clonal or clonal-like expansion in innate lymphocytes, and highlight recent studies that shed light on the complex cellular and molecular crosstalk between metabolism, epigenetics, and transcription responsible for differentiating innate lymphocyte responses towards a memory fate. Additionally, we explore emerging evidence that activated innate lymphocytes relocate and establish themselves in specific peripheral tissues during infection, which may facilitate an accelerated response program akin to those of tissue-resident memory T cells.

DOI: https://doi.org/10.1038/s41590-023-01607-w
BMC Genomics. 2023 Oct 07. 24(1): 595

Mapping the epigenomic landscape of human monocytes following innate immune activation reveals context-specific mechanisms driving endotoxin tolerance.

Harindra E Amarasinghe, Ping Zhang, Justin P Whalley, Alice Allcock, Gabriele Migliorini, Andrew C Brown, Giuseppe Scozzafava, Julian C Knight.

   BACKGROUND: Monocytes are key mediators of innate immunity to infection, undergoing profound and dynamic changes in epigenetic state and immune function which are broadly protective but may be dysregulated in disease. Here, we aimed to advance understanding of epigenetic regulation following innate immune activation, acutely and in endotoxin tolerant states.
METHODS: We exposed human primary monocytes from healthy donors (n = 6) to interferon-γ or differing combinations of endotoxin (lipopolysaccharide), including acute response (2 h) and two models of endotoxin tolerance: repeated stimulations (6 + 6 h) and prolonged exposure to endotoxin (24 h). Another subset of monocytes was left untreated (naïve). We identified context-specific regulatory elements based on epigenetic signatures for chromatin accessibility (ATAC-seq) and regulatory non-coding RNAs from total RNA sequencing.
RESULTS: We present an atlas of differential gene expression for endotoxin and interferon response, identifying widespread context specific changes. Across assayed states, only 24-29% of genes showing differential exon usage are also differential at the gene level. Overall, 19.9% (6,884 of 34,616) of repeatedly observed ATAC peaks were differential in at least one condition, the majority upregulated on stimulation and located in distal regions (64.1% vs 45.9% of non-differential peaks) within which sequences were less conserved than non-differential peaks. We identified enhancer-derived RNA signatures specific to different monocyte states that correlated with chromatin accessibility changes. The endotoxin tolerance models showed distinct chromatin accessibility and transcriptomic signatures, with integrated analysis identifying genes and pathways involved in the inflammatory response, detoxification, metabolism and wound healing. We leveraged eQTL mapping for the same monocyte activation states to link potential enhancers with specific genes, identifying 1,946 unique differential ATAC peaks with 1,340 expression associated genes. We further use this to inform understanding of reported GWAS, for example involving FCHO1 and coronary artery disease.
CONCLUSION: This study reports context-specific regulatory elements based on transcriptomic profiling and epigenetic signatures for enhancer-derived RNAs and chromatin accessibility in immune tolerant monocyte states, and demonstrates the informativeness of linking such elements and eQTL to inform future mechanistic studies aimed at defining therapeutic targets of immunosuppression and diseases.

Keywords:  Chromatin accessibility; Context-specificity; Endotoxin tolerance; Enhancer RNA; Expression quantitative trait loci; Human monocytes

DOI:  https://doi.org/10.1186/s12864-023-09663-0
EMBO J. 2023 Oct 09. e114086

Macrophage-derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection.

Gabriela Krejčová, Cecilia Morgantini, Helena Zemanová, Volker M Lauschke, Julie Kovářová, Jiří Kubásek, Pavla Nedbalová, Nick Kamps-Hughes, Martin Moos, Myriam Aouadi, Tomáš Doležal, Adam Bajgar.

  The immune response is an energy-demanding process that must be coordinated with systemic metabolic changes redirecting nutrients from stores to the immune system. Although this interplay is fundamental for the function of the immune system, the underlying mechanisms remain elusive. Our data show that the pro-inflammatory polarization of Drosophila macrophages is coupled to the production of the insulin antagonist ImpL2 through the activity of the transcription factor HIF1α. ImpL2 production, reflecting nutritional demands of activated macrophages, subsequently impairs insulin signaling in the fat body, thereby triggering FOXO-driven mobilization of lipoproteins. This metabolic adaptation is fundamental for the function of the immune system and an individual's resistance to infection. We demonstrated that analogically to Drosophila, mammalian immune-activated macrophages produce ImpL2 homolog IGFBP7 in a HIF1α-dependent manner and that enhanced IGFBP7 production by these cells induces mobilization of lipoproteins from hepatocytes. Hence, the production of ImpL2/IGFBP7 by macrophages represents an evolutionarily conserved mechanism by which macrophages alleviate insulin signaling in the central metabolic organ to secure nutrients necessary for their function upon bacterial infection.

Keywords:  Drosophila; ImpL2; insulin resistance; lipoproteins; macrophage polarization

DOI:  https://doi.org/10.15252/embj.2023114086
Cell Mol Gastroenterol Hepatol. 2023 Oct 09. pii: S2352-345X(23)00180-7. [Epub ahead of print]

BRD4 regulates glycolysis-dependent Nos2 expression in macrophages upon H. pylori infection.

Nikita Modi, Yanheng Chen, Xingchen Dong, Xiangming Hu, Gee W Lau, Keith T Wilson, Richard M Peek, Lin-Feng Chen.

   BACKGROUND & AIMS: Metabolic reprogramming is essential for the activation and functions of macrophages, including bacterial killing and cytokine production. Bromodomain-containing protein 4 (BRD4) has emerged as a critical regulator of innate immune response. However, the potential role of BRD4 in metabolic reprogramming of macrophage activation upon H. pylori infection remains unclear.
METHODS: Bone marrow-derived macrophages (BMDMs) from WT and Brd4-myeloid deletion conditional knockout mice (Brd4-CKO) were infected with H. pylori. RNA sequencing was performed to evaluate the differential gene expression between WT and Brd4-deficient BMDMs upon infection. An in vivo model of WT and Brd4-CKO mice was used to confirm the role of BRD4 in innate immune response to H. pylori infection.
RESULTS: Depletion of Brd4 in BMDMs impaired H. pylori-induced glycolysis. Additionally, H. pylori-induced expression of glycolytic genes, including Glucose transporter type 1 (Glut1) and Hexokinase 2 (Hk2), was decreased in Brd4-deficient BMDMs. BRD4 was recruited to promoters of Glut1 and Hk2 via Hypoxia-inducible factor 1 alpha (HIF-1α), facilitating their expression. BRD4-mediated glycolysis stabilized H. pylori-induced nitric oxide synthase (Nos2) mRNA to produce nitric oxide (NO). The NO-mediated killing of H. pylori decreased in Brd4-deficient BMDMs, which was rescued by pyruvate. Furthermore, Brd4-CKO mice infected with H. pylori exhibited reduced gastric inflammation, increased H. pylori colonization and reduced iNOS expression in gastric macrophages.
CONCLUSIONS: Our study identified BRD4 as a key regulator of HIF-1α-dependent glycolysis and macrophage activation. Furthermore, we demonstrate a novel regulatory role of BRD4 in innate immunity through glycolysis to stabilize Nos2 mRNA for NO production to eliminate H. pylori infection.

Keywords:  BRD4; H. pylori; HIF-1α; glycolysis; iNOS

DOI:  https://doi.org/10.1016/j.jcmgh.2023.10.001
Cancer Lett. 2023 Oct 05. pii: S0304-3835(23)00376-2. [Epub ahead of print] 216425

Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.

Yan Zhou, Yizhen Guo, Maoxin Ran, Wenying Shan, Carlotta Granchi, Elisa Giovannetti, Filippo Minutolo, Godefridus J Peters, Kin Yip Tam.

  Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and progression of LUAD. Pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are two key enzymes involved in glucose metabolism, whilst their aberrant expressions are often associated with tumorigenesis. Herein, we investigated the anticancer effects of combined inhibition of PDK1 and LDHA in LUAD in vitro and in vivo and its underlying mechanisms of action. The combination of a PDK1 inhibitor, 64, and a LDHA inhibitor, NHI-Glc-2, led to a synergistic growth inhibition in 3 different LUAD cell lines and more than additively suppressed tumor growth in the LUAD xenograft H1975 model. This combination also inhibited cellular migration and colony formation, while it induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) resulting in mitochondrial depolarization and apoptosis in LUAD cells. These effects were related to modulation of multiple cell signaling pathways, including AMPK, RAS/ERK, and AKT/mTOR. Our findings demonstrate that simultaneous inhibition of multiple glycolytic enzymes (PDK1 and LDHA) is a promising novel therapeutic approach for LUAD.

Keywords:  Anticancer; Combination treatment; Non-small cell lung cancer; Warburg effect

DOI:  https://doi.org/10.1016/j.canlet.2023.216425