bims-traimu 2023-06-11 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023‒06‒11
eight papers selected by
Yantong Wan
Southern Medical University

Immunometabolic changes of β-glucan-trained immunity induction and inhibition on neonatal calf immune innate cells.
Trained immunity in the pathogenesis of vitiligo.
Corrigendum: The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.
"Trained Immunity" from Mycobacterium spp. exposure (BCG vaccination and environmental) may have an impact on the incidence of early childhood leukemia.
STAT1 is required to establish but not maintain interferon-γ-induced transcriptional memory.
Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.
Do vaccinations influence the development of Alzheimer disease?
Intranasal administration of lipopolysaccharide reverses chronic stress-induced depression-like behavior in mice by microglial stimulation.

Mol Immunol. 2023 Jun 02. pii: S0161-5890(23)00111-6. [Epub ahead of print]159 58-68

Immunometabolic changes of β-glucan-trained immunity induction and inhibition on neonatal calf immune innate cells.

Miriam Angulo, Carlos Angulo.

  The growing antibiotic resistance and low-efficient vaccines make searching for alternatives a need to fight infectious diseases in newborn calves. Thus, trained immunity could be used as a tool to optimize immune response against a wide range of pathogens. Although β-glucans have shown to induce trained immunity, it has not been demonstrated in bovines yet. Uncontrolled trained immunity activation can generate chronic inflammation in mice and humans, and inhibiting it might reduce excessive immune activation. The aim of this study is to demonstrate that in vitro β-glucan training induces metabolic changes in calf monocytes, characterized by an increase in lactate production and glucose consumption upon restimulation with lipopolysaccharide. These metabolic shifts can be abolished by co-incubation with MCC950, a trained immunity inhibitor. Moreover, the dose-response relationship of β-glucan on the viability of calf monocytes was demonstrated. In newborn calves, in vivo β-glucan oral administration also induced a trained phenotype in innate immune cells, leading to immunometabolic changes, upon ex vivo challenge with E.coli. β-glucan-induced trained immunity improved phagocytosis, nitric oxide production, myeloperoxidase activity, and TNF-α gene expression through up-regulation genes of the TLR2/NF-κB pathway. Furthermore, β-glucan oral doses enhanced consumption and production of glycolysis metabolites (glucose and lactate, respectively), as well as up-regulated expression of mTOR and HIF1-α mRNA. Therefore, the results suggest that β-glucan immune training may confer calf protection from a secondary bacterial challenge, and trained phenotype induced by β-glucan can be inhibited.

Keywords:  Calves; Innate immune memory; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.molimm.2023.05.008
Pigment Cell Melanoma Res. 2023 Jun 09.

Trained immunity in the pathogenesis of vitiligo.

Nicoline F Post, Greta Ginski, Rens Peters, Nathalie O P Van Uden, Marcel W Bekkenk, Albert Wolkerstorfer, Mihai G Netea, Rosalie M Luiten.

  Vitiligo is caused by an autoimmune reaction against melanocytes leading to melanocyte loss. The cause of vitiligo is an interaction between genetic susceptibility and environmental factors. Both the adaptive immune system-through cytotoxic CD8+ T cells and melanocyte specific antibodies-and the innate immune system are involved in these immune processes in vitiligo. While recent data stressed the importance of innate immunity in vitiligo, the question remains why vitiligo patients' immune response becomes overly activated. Could a long-term increase in innate memory function, described as trained immunity after vaccination and in other inflammatory diseases, play a role as an enhancer and continuous trigger in the pathogenesis of vitiligo? After exposure to certain stimuli, innate immune system is able to show an enhanced immunological response to a secondary trigger, indicating a memory function of the innate immune system, a concept termed trained immunity. Trained immunity is regulated by epigenetic reprogramming, including histone chemical modifications and changes in chromatin accessibility that cause sustained changes in the transcription of specific genes. In responses to an infection, trained immunity is beneficial. However, there are indications of a pathogenic role of trained immunity in inflammatory and autoimmune diseases, with monocytes presenting features of a trained phenotype, resulting in increased cytokine production, altered cell metabolism through mTOR signaling, and epigenetic modifications. This hypothesis paper focusses on vitiligo studies that have shown these indications, suggesting the involvement of trained immunity in vitiligo. Future studies focusing on metabolic and epigenetic changes in innate immune cell populations in vitiligo could help in elucidating the potential role of trained immunity in vitiligo pathogenesis.

Keywords:  innate immunity; pathogenesis; trained immunity; vitiligo

DOI:  https://doi.org/10.1111/pcmr.13101
Front Immunol. 2023 ;14 1208659

Corrigendum: The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.

Konstantin Föhse, Esther J M Taks, Simone J C F M Moorlag, Marc J M Bonten, Reinout van Crevel, Jaap Ten Oever, Cornelis H van Werkhoven, Mihai G Netea, Josephine S van de Maat, Jacobien J Hoogerwerf.

  [This corrects the article DOI: 10.3389/fimmu.2023.980711.].

Keywords:  BCG; COVID-19; SARS-CoV-2; circadian clock; circadian rhythm; heterologous protection; respiratory tract infection; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2023.1208659
Front Immunol. 2023 ;14 1193859

"Trained Immunity" from Mycobacterium spp. exposure (BCG vaccination and environmental) may have an impact on the incidence of early childhood leukemia.

Samer Singh, Dhiraj Kishore, Rakesh K Singh.

  Preventive variables for childhood leukemia incidence (LI) remain unknown. Past assertions that childhood vaccinations, especially BCG, may be potentially protective have remained disputed for over five decades because of the lack of a unifying framework to explain variable outcomes in different studies. An examination of the early childhood LI for 2020 in European Region countries with supposedly similar underlying confounders but differential childhood vaccination coverage displays negative covariation with prevailing Mycobacterium spp. exposure in BCG-vaccinated children. The childhood LI in 0-4-year-old populations with >90% childhood BCG vaccination coverage is found to be strongly but negatively correlated with prevailing tuberculin immunoreactivity [r(24): -0.7868, p-value: < 0.0001]. No such correlation existed for the LI in 0-4-year-old populations without BCG vaccinations, though weak associations are hinted at by the available data for MCV2, PCV3, and DTP3 vaccinations. We hypothesize that early childhood BCG vaccination "priming" and subsequent "trained immunity" augmentation by "natural" boosting from Mycobacterium spp. exposure play a preventive and protective role in childhood LI. The non-consideration of prevailing "trained immunity" could have been a cause behind the conflicting outcomes in past studies. Exploratory studies, preferably performed in high-burden countries and controlling for the trained-immunity correlate and other potential confounders, would be warranted in order to establish a role for BCG vaccination and early-life immune training (or lack thereof) in childhood LI and help put the current controversy to rest.

Keywords:  BCG vaccine; DTP3; MCV2; Mycobacterium spp.; PCV3; childhood leukemia; childhood vaccinations; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2023.1193859
EMBO J. 2023 Jun 05. e112259

STAT1 is required to establish but not maintain interferon-γ-induced transcriptional memory.

Sahar Sh Tehrani, Pawel Mikulski, Izma Abdul-Zani, João F Mata, Wojciech Siwek, Lars Et Jansen.

  Exposure of human cells to interferon-γ (IFNγ) results in a mitotically heritable yet reversible state called long-term transcriptional memory. We previously identified the clustered GBP genes as strongly primed by IFNγ. Here, we discovered that in primed cells, both interferon-responsive transcription factors STAT1 and IRF1 target chromatin with accelerated kinetics upon re-exposure to IFNγ, specifically at promotors of primed genes. Priming does not alter the degree of IFNγ-induced STAT1 activation or nuclear import, indicating that memory does not alter upstream JAK-STAT signaling. We found STAT1 to be critical to establish transcriptional memory but in a manner that is independent of mere transcription activation. Interestingly, while Serine 727 phosphorylation of STAT1 was maintained during the primed state, STAT1 is not required for the heritability of GBP gene memory. Our results suggest that the memory of interferon exposure constitutes a STAT1-mediated, heritable state that is established during priming. This renders GBP genes poised for subsequent STAT1 and IRF1 binding and accelerated gene activation upon a secondary interferon exposure.

Keywords:  GBPs; IRF1; STAT1; epigenetic memory; epigenetics; trained immunity

DOI:  https://doi.org/10.15252/embj.2022112259
Nat Biomed Eng. 2023 Jun 08.

Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.

David P Schrijver, Rutger J Röring, Jeroen Deckers, Anne de Dreu, Yohana C Toner, Geoffrey Prevot, Bram Priem, Jazz Munitz, Eveline G Nugraha, Yuri van Elsas, Anthony Azzun, Tom Anbergen, Laszlo A Groh, Anouk M D Becker, Carlos Pérez-Medina, Roderick S Oosterwijk, Boris Novakovic, Simone J C F M Moorlag, Aron Jansen, Peter Pickkers, Matthijs Kox, Thijs J Beldman, Ewelina Kluza, Mandy M T van Leent, Abraham J P Teunissen, Roy van der Meel, Zahi A Fayad, Leo A B Joosten, Edward A Fisher, Maarten Merkx, Mihai G Netea, Willem J M Mulder.

Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.

DOI: https://doi.org/10.1038/s41551-023-01050-0
Hum Vaccin Immunother. 2023 Jun 08. 2216625

Do vaccinations influence the development of Alzheimer disease?

Avram S Bukhbinder, Yaobin Ling, Kristofer Harris, Xiaoqian Jiang, Paul E Schulz.

  A growing literature supports a protective association between vaccines targeting an array of pathogens (e.g., influenza, pneumococcus, herpes zoster) and the risk of Alzheimer disease (AD). This article discusses the potential underlying mechanisms for this apparent protective effect of immunizations against infectious pathogens on the risk of AD; explores the basic and pharmacoepidemiologic evidence for this association, with particular attention paid to important methodological variations among the epidemiologic studies; and reviews the remaining uncertainties regarding the effects of anti-pathogen vaccines on Alzheimer disease and all-cause dementia, with recommendations for future directions to address those uncertainties.

Keywords:  Alzheimer disease; Vaccines; dementia; diphtheria-tetanus-acellular pertussis vaccines; influenza vaccines; innate immunity; neuroimmunomodulation; pharmacoepidemiology; pneumococcal vaccines; trained immunity

DOI:  https://doi.org/10.1080/21645515.2023.2216625
Int Immunopharmacol. 2023 Jun 02. pii: S1567-5769(23)00670-7. [Epub ahead of print]120 110347

Intranasal administration of lipopolysaccharide reverses chronic stress-induced depression-like behavior in mice by microglial stimulation.

Chao Huang, Ting Ye, Bingran Chen, Zhuo Chen, Ying Ye, Huijun Liu.

  We recently reported that intraperitoneal injection of a low dose of lipopolysaccharide (LPS) reversed depression-like behavior in mice induced by chronic stress by stimulating microglia in the hippocampus. In this study, we found that a single intranasal administration of LPS at a dose of 5 or 10 μg/mouse, but not at a dose of 1 μg/mouse, rapidly reversed depression-like behavior in mice stimulated with chronic unpredictable stress (CUS). In the time-dependent experiment, a single intranasal administration of LPS (10 μg/mouse) reversed CUS-induced depression-like behavior in mice 5 and 8 h but not 3 h after drug administration. The antidepressant effect of a single intranasal LPS administration (10 μg/mouse) lasted at least 10 days and disappeared 14 days after administration. Fourteen days after the first intranasal LPS administration, a second intranasal LPS administration (10 μg/mouse) still reversed the increased immobility time in TST and FST and the decreased sucrose uptake in SPT in CUS mice, which again exhibited depression-like behaviors 5 h after LPS administration. The antidepressant effect of intranasal LPS administration was dependent on microglial activation, because inhibition of microglia by pretreatment with minocycline (40 mg/kg) or depletion of microglia by pretreatment with PLX3397 (290 mg/kg) prevented the antidepressant effect of intranasal LPS administration in CUS mice. These results suggest that stimulation of the microglia-mediated innate immune response by intranasal administration of LPS can produce rapid and sustained antidepressant effects in animals under chronic stress conditions.

Keywords:  Depression; Hippocampus; Innate immune response; Intranasal LPS administration

DOI:  https://doi.org/10.1016/j.intimp.2023.110347