bims-traimu 2023-12-17 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–12–17
ten papers selected by
Yantong Wan, Southern Medical University

Microinjection of β-glucan Into Larval Zebrafish (Danio rerio) for the Assessment of a Trained-Like Immunity Phenotype.
Environmental bisphenol A exposure triggers trained immunity-related pathways in monocytes.
COVID-19 and trained immunity: the inflammatory burden of long covid.
BCG vaccination impacts the epigenetic landscape of progenitor cells in human bone marrow.
Research progress in the off-target effects of Bacille Calmette-Guérin vaccine.
Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.
Bacille-Calmette-Guerin modulates human macrophage and dendritic cell response to SARS-CoV-2 S-glycoprotein.
Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection.
Poly(I:C) induces anti-inflammatory response against secondary LPS challenge in zebrafish larvae.
A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation.

Bio Protoc. 2023 Dec 05. 13(23): e4888

Microinjection of β-glucan Into Larval Zebrafish (Danio rerio) for the Assessment of a Trained-Like Immunity Phenotype.

Hannah Darroch, Jonathan W Astin, Christopher J Hall.

  The innate immune system can remember previous inflammatory insults, enabling long-term heightened responsiveness to secondary immune challenges in a process termed "trained immunity." Trained innate immune cells undergo metabolic and epigenetic remodelling and, upon a secondary challenge, provide enhanced protection with therapeutic potential. Trained immunity has largely been studied in innate immune cells in vitro or following ex vivo re-stimulation where the primary insult is typically injected into a mouse, adult zebrafish, or human. While highly informative, there is an opportunity to investigate trained immunity entirely in vivo within an unperturbed, intact whole organism. The exclusively innate immune response of larval zebrafish offers an attractive system to model trained immunity. Larval zebrafish have a functional innate immune system by 2 days post fertilisation (dpf) and are amenable to high-resolution, high-throughput analysis. This, combined with their optical transparency, conserved antibacterial responses, and availability of transgenic reporter lines, makes them an attractive alternative model to study trained immunity in vivo. We have devised a protocol where β-glucan (one of the most widely used experimental triggers of trained immunity) is systemically delivered into larval zebrafish using microinjection to stimulate a trained-like phenotype. Following stimulation, larvae are assessed for changes in gene expression, which indicate the stimulatory effect of β-glucan. This protocol describes a robust delivery method of one of the gold standard stimulators of trained immunity into a model organism that is highly amenable to several non-invasive downstream analyses. Key features • This protocol outlines the delivery of one of the most common experimental stimulators of trained immunity into larval zebrafish. • The protocol enables the assessment of a trained-like phenotype in vivo. • This protocol can be applied to transgenic or mutant zebrafish lines to investigate cells or genes of interest in response to β-glucan stimulation.

Keywords:  Innate immunity response; Larval zebrafish; Microinjection; Trained immunity; β-glucan

DOI:  https://doi.org/10.21769/BioProtoc.4888
Front Immunol. 2023 ;14 1270391

Environmental bisphenol A exposure triggers trained immunity-related pathways in monocytes.

Marcello Dallio, Lorenzo Ventriglia, Mario Romeo, Flavia Scognamiglio, Nadia Diano, Martina Moggio, Marina Cipullo, Annachiara Coppola, Athanasios Ziogas, Mihai G Netea, Alessandro Federico.

   Introduction: Trained Immunity represents a novel revolutionary concept of the immunological response involving innate immune cells. Bisphenol A is a well-known endocrine disrupter, widely disseminated worldwide and accumulated in the human body. Due to the increased interest regarding the effects of plastic-derived compounds on the immune system, our purpose was to explore whether BPA was able to induce trained immunity in human primary monocytes in vitro using low environmental concentrations.
Materials and methods: We extracted BPA from the serum of 10 healthy individuals through a liquid-liquid extraction followed by a solid phase extraction and measured the concentration using an HPLC system coupled to a triple quadrupole mass spectrometer. In parallel, monocytes were isolated from whole blood and acutely stimulated or trained with BPA at three different concentrations (1 nM, 10 nM, 20 nM). Pro- and anti-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-10) production were assessed after 24 hours of acute stimulation and after Lipopolysaccharide (LPS) rechallenge. A comprehensive overview of the metabolic changes after BPA acute stimulation and trained immunity induction was assessed through extracellular lactate measurements, Seahorse XFb metabolic flux analysis and ROS production.
Results: Monocytes primed with BPA showed increased pro- and anti-inflammatory cytokine responses upon restimulation, sustained by the modulation of the immunometabolic circuits. Moreover, we proved the non-toxic effect of BPA at each experimental concentration by performing an MTT assay. Additionally, correlation analysis were performed between pro- and anti-inflammatory cytokines production after LPS acute stimulation or BPA-mediated trained immunity and BPA serum concentrations showing a significant association between TNF-α and BPA circulating levels.
Discussion: Overall, this study pointed out for the first time the immunological effects of an environmental chemical and plastic-derived compound in the induction of trained immunity in a healthy cohort.

Keywords:  bisphenol A; endocrine-disrupting compounds; inflammation; innate response; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2023.1270391
Front Immunol. 2023 ;14 1294959

COVID-19 and trained immunity: the inflammatory burden of long covid.

Jienan Gu, Qianhui Liu, Jiale Zhang, Shijie Xu.

  Severe COVID-19 elicits excessive inflammation mediated by innate immune cells like monocytes. Recent evidence reveals extensive epigenetic changes in monocytes during recovery from severe COVID-19, including increased chromatin accessibility at genes related to cytokine production and leukocyte activation. These changes likely originate from the reprogramming of upstream hematopoietic stem and progenitor cells (HSPCs) and represent "trained immunity". HSPC-to-monocyte transmission of epigenetic memory may explain the persistence of these monocyte alterations despite their short lifespan. IL-6 appears pivotal for imprinting durable epigenetic modifications in monocytes during acute infection, with IL-1β potentially playing a contributory role. The poised inflammatory phenotype of monocytes post-COVID-19 may drive chronic inflammation and tissue damage, contributing to post-acute sequelae of COVID-19 symptoms. COVID-19 could also exacerbate inflammation-related diseases, such multisystem inflammatory syndromes, by altering innate immune tendencies via hematopoietic epigenetic reprogramming. Further clinical investigations quantifying inflammatory mediators and mapping epigenetic changes in HSPCs/monocytes of recovering patients are warranted. Research should also examine whether COVID-19 elicits transgenerational inheritance of epigenetic alterations. Elucidating mechanisms underlying COVID-19-induced monocyte reprogramming and developing interventions targeting key inflammatory regulators like IL-6 may mitigate the sustained inflammatory burden imposed by the aberrant trained immunity post-COVID-19.

Keywords:  chronic inflammation; hematopoietic stem and progenitor cells; innate immune; interleukin-1β; interleukin-6; monocytes; post-acute sequelae of COVID-19 symptoms

DOI:  https://doi.org/10.3389/fimmu.2023.1294959
bioRxiv. 2023 Nov 28. pii: 2023.11.28.569076. [Epub ahead of print]

BCG vaccination impacts the epigenetic landscape of progenitor cells in human bone marrow.

Sarah J Sun, Raúl Aguirre-Gamboa, L Charlotte J de Bree, Joaquin Sanz, Anne Dumaine, Leo A B Joosten, Maziar Divangahi, Mihai G Netea, Luis B Barreiro.

While the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo administration. We show that BCG vaccination significantly alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occur primarily on the most uncommitted stem cells and are reflective of a persistent myeloid bias. In contrast, BCG-induced changes in chromatin accessibility are most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF)/SP and EGR transcription factors (TFs). These TFs are also activated in the most uncommitted stem cells, indicating that activated TFs, which drive persistent changes in HSC gene expression, likely also drive chromatin dynamics appearing within downstream progenitor cells. This perspective contests the prevailing notion that epigenetic modifications linked to innate immune memory transfer directly from stem cells to their differentiated derivatives. Finally, we show that alterations in gene expression and chromatin accessibility in HSPCs due to BCG vaccination were highly correlated (r>0.8) with the IL-1β secretion capacity of paired PBMCs upon secondary immune challenge. Overall, our findings shed light on BCG vaccination's profound and lasting effects on HSPCs and its influence on innate immune responses.

DOI: https://doi.org/10.1101/2023.11.28.569076
Chin Med J (Engl). 2023 Dec 13.

Research progress in the off-target effects of Bacille Calmette-Guérin vaccine.

Yanfei Wu, Xiaoyin Zhang, Li Zhou, Jiayu Lu, Fengcai Zhu, Jingxin Li.

ABSTRACT: Bacille Calmette-Guérin (BCG) vaccine is designed to provide protection against tuberculosis (TB). However, numerous epidemiological, clinical, and immunological studies have shown that BCG vaccination affects neonatal and infant mortality, which may be related to the reduction of TB-unrelated infections and diseases by BCG vaccine. We aimed to discuss the off-target effects of BCG vaccine on un-TB infections and diseases, as well as the potential mechanism and influencing factors. Literature was retrieved mainly from PubMed using medical subject headings "BCG, variations, and non-specific, heterologous or off-target". Studies have showed that BCG vaccination can prevent various heterologous infections, including respiratory tract infections, leprosy, and malaria, treat viral infections including human papillomavirus and herpes simplex virus infection as immunotherapy, and improve the immune responses as vaccine adjuvant. Besides, BCG vaccine can reduce the recurrence rate of non-muscle-invasive bladder cancer, and may provide protection against autoimmune diseases. These off-target effects of BCG vaccine are thought to be achieved by modulating heterologous lymphocyte responses or inducing trained immunity, which were found to be sex-differentiated and affected by the BCG vaccine strains, sequence or time of vaccination.

DOI: https://doi.org/10.1097/CM9.0000000000002890
Eur Heart J. 2023 Dec 12. pii: ehad787. [Epub ahead of print]

Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.

Zheng Dong, Lei Hou, Wei Luo, Li-Hong Pan, Xiao Li, Hai-Peng Tan, Run-Da Wu, Hao Lu, Kang Yao, Man-Di Mu, Chen-Shan Gao, Xin-Yu Weng, Jun-Bo Ge.

   BACKGROUND AND AIMS: Survivors of acute coronary syndromes face an elevated risk of recurrent atherosclerosis-related vascular events despite advanced medical treatments. The underlying causes remain unclear. This study aims to investigate whether myocardial infarction (MI)-induced trained immunity in monocytes could sustain proatherogenic traits and expedite atherosclerosis.
METHODS: Apolipoprotein-E deficient (ApoE-/-) mice and adoptive bone marrow transfer chimeric mice underwent MI or myocardial ischaemia-reperfusion (IR). A subsequent 12-week high-fat diet (HFD) regimen was implemented to elucidate the mechanism behind monocyte trained immunity. In addition, classical monocytes were analysed by flow cytometry in the blood of enrolled patients.
RESULTS: In MI and IR mice, blood monocytes and bone marrow-derived macrophages exhibited elevated spleen tyrosine kinase (SYK), lysine methyltransferase 5A (KMT5A), and CCHC-type zinc finger nucleic acid-binding protein (CNBP) expression upon exposure to a HFD or oxidized LDL (oxLDL) stimulation. MI-induced trained immunity was transmissible by transplantation of bone marrow to accelerate atherosclerosis in naive recipients. KMT5A specifically recruited monomethylation of Lys20 of histone H4 (H4K20me) to the gene body of SYK and synergistically transactivated SYK with CNBP. In vivo small interfering RNA (siRNA) inhibition of KMT5A or CNBP potentially slowed post-MI atherosclerosis. Sympathetic denervation with 6-hydroxydopamine reduced atherosclerosis and inflammation after MI. Classical monocytes from ST-elevation MI (STEMI) patients with advanced coronary lesions expressed higher SYK and KMT5A gene levels.
CONCLUSIONS: The findings underscore the crucial role of monocyte trained immunity in accelerated atherosclerosis after MI, implying that SYK in blood classical monocytes may serve as a predictive factor for the progression of atherosclerosis in STEMI patients.

Keywords:  Atherosclerosis; Epigenetics; Macrophages; Monocytes; Myocardial infarction; Trained immunity

DOI:  https://doi.org/10.1093/eurheartj/ehad787
Infect Med (Beijing). 2023 Sep;2(3): 241-245

Bacille-Calmette-Guerin modulates human macrophage and dendritic cell response to SARS-CoV-2 S-glycoprotein.

Regina C Ambe, Shubhang Bhalla, Alejandra Alvarado, Jose Barragan, Jorge Cervantes.

   Background: Given that epidemiological evidence suggests a potential protective role for Bacille-Calmette-Guerin against COVID-19, we aimed to explore whether pre-exposure of human monocyte-derived macrophages and dendritic cells to BCG could modulate their response to SARS-CoV-2 S-glycoprotein.
Methods: Dual THP-1 cells containing 2 reporter plasmids for transcription factors NF-κB, and IRF were differentiated into macrophages over 3 days using phorbol 12-myristate 13-acetate, or into dendritic cells over 6 days using commercial monocyte-dencritic cell differentiation media and matured with recombinant tumor necrosis factor-α. Cells were exposed to BCG for 24 h and then stimulated with SARS-CoV-2 S-glycoprotein for 24 hours.
Results: Pre-exposure of human macrophages and DCs to BCG increased IRF and NF-kb activation in response to the SARS-CoV-2 S-glycoprotein.
Conclusions: Our results showed that pre-exposure of both types of cells to BCG exhibited an increase in inflammatory transcription factors upon stimulation with S-glycoprotein. BCG-induced trained immunity may be an important tool for reducing susceptibility to SARS-CoV-2 infection and severity of COVID-19. Our findings help in the design of future BCG-based therapeutic approaches in the treatment of diseases caused by viral infections.

Keywords:  BCG; Dendritic cell; Macrophage; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.imj.2023.08.004
bioRxiv. 2023 Nov 27. pii: 2023.11.24.568354. [Epub ahead of print]

Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection.

Alexander Lercher, Jin-Gyu Cheong, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W Ashbrook, Yue S Yin, Corrine Quirk, Emma J DeGrace, Luis Chiriboga, Brad R Rosenberg, Steven Z Josefowicz, Charles M Rice.

Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors in airway-resident macrophages. Mechanistically, establishment of this innate immune memory required viral pattern recognition and canonical IFN-I signaling and augmented secondary antiviral responses. Past SARS-CoV-2 infection ameliorated disease caused by the heterologous respiratory pathogen influenza A virus. Insights into innate immune memory and how it affects subsequent infections with heterologous pathogens to influence disease pathology could facilitate the development of broadly effective therapeutic strategies.

DOI: https://doi.org/10.1101/2023.11.24.568354
Fish Shellfish Immunol. 2023 Dec 11. pii: S1050-4648(23)00771-4. [Epub ahead of print] 109285

Poly(I:C) induces anti-inflammatory response against secondary LPS challenge in zebrafish larvae.

Zhuang Wang, Xinwei You, Yuanxing Zhang, Qin Liu, Dahai Yang.

  Poly(I:C) is known as an agonist of the TLR3 receptor which could prime inflammation and elicit the host immune response, which is widely applied as adjuvant or antivirus treatment. However, the negative effects of poly(I:C) on regulating immune response to protect the host from inflammatory diseases remain largely unknown. Here, we established an in vivo model to pre-treat zebrafish larvae with poly(I:C) at 2 dpf, then challenge them with LPS at 6 dpf, and found that poly(I:C) training could significantly alleviate the LPS challenge-induced septic shock and inflammatory phenotype. Moreover, the poly(I:C)-trained larvae exhibit decreased number of macrophages, but not neutrophils, after secondary LPS challenge. Furthermore, training the larvae with poly(I:C) could elevate the transcripts of mTOR signaling and heighten the H3K4me3-mediated epigenetic modifications. And interestingly, we found that inhibiting the H3K4me3 modification, rather than mTOR signaling, could recover the number of macrophages in poly(I:C)-trained larvae, which is consistent with the observations of inflammatory phenotypes. Taken together, these results suggest that poly(I:C) training could induce epigenetic rewiring to mediate the anti-inflammatory response against secondary LPS challenge-induced septic shock through decreasing macrophages' number in vivo, which might expand our understanding of poly(I:C) in regulating fish immune response.

Keywords:  Anti-inflammation; Macrophages; Poly(I:C); Septic shock; Zebrafish larvae

DOI:  https://doi.org/10.1016/j.fsi.2023.109285
Nat Genet. 2023 Dec 13.

A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation.

Ezio T Fok, Simone J C F M Moorlag, Yutaka Negishi, Laszlo A Groh, Jéssica Cristina Dos Santos, Cathrin Gräwe, Valerie Villacorta Monge, Daphne D D Craenmehr, Mellanie van Roosmalen, David Pablo da Cunha Jolvino, Letícia Busato Migliorini, Ary Serpa Neto, Patricia Severino, Michiel Vermeulen, Leo A B Joosten, Mihai G Netea, Stephanie Fanucchi, Musa M Mhlanga.

Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1β (IL-1β) is a master regulator of proinflammation and is encoded within the same topologically associating domain (TAD) as IL-37, which is an anti-inflammatory cytokine that opposes the function of IL-1β. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1β expression and trained immunity through the induction of IL37 transcription. We found that the activation of IL37 occurs through the formation of a dynamic long-range chromatin contact that leads to the temporal delay of anti-inflammatory responses. The common variant rs16944 present in AMANZI augments this regulatory circuit, predisposing individuals to enhanced proinflammation or immunosuppression. Our work illuminates a chromatin-mediated biphasic circuit coordinating expression of IL-1β and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.

DOI: https://doi.org/10.1038/s41588-023-01598-2