bims-traimu 2023-03-12 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–03–12
seven papers selected by
Yantong Wan, Southern Medical University

Trained immunity in monocyte/macrophage: Novel mechanism of phytochemicals in the treatment of atherosclerotic cardiovascular disease.
The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.
Emerging role for interferons in respiratory viral infections and childhood asthma.
Pulmonary and Non-Pulmonary Sepsis Differentially Modulate Lung Immunity Towards Secondary Bacterial Pneumonia: A Critical Role for Alveolar Macrophages.
Fine particulate matter (PM2.5) induces inhibitory memory alveolar macrophages through the AhR/IL-33 pathway.
NF-κB-Inducing Kinase Governs the Mitochondrial Respiratory Capacity, Differentiation, and Inflammatory Status of Innate Immune Cells.
Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer.

Front Pharmacol. 2023 ;14 1109576

Trained immunity in monocyte/macrophage: Novel mechanism of phytochemicals in the treatment of atherosclerotic cardiovascular disease.

Jie Wang, Yong-Mei Liu, Jun Hu, Cong Chen.

  Atherosclerosis (AS) is the pathology of atherosclerotic cardiovascular diseases (ASCVD), characterized by persistent chronic inflammation in the vessel wall, in which monocytes/macrophages play a key role. It has been reported that innate immune system cells can assume a persistent proinflammatory state after short stimulation with endogenous atherogenic stimuli. The pathogenesis of AS can be influenced by this persistent hyperactivation of the innate immune system, which is termed trained immunity. Trained immunity has also been implicated as a key pathological mechanism, leading to persistent chronic inflammation in AS. Trained immunity is mediated via epigenetic and metabolic reprogramming and occurs in mature innate immune cells and their bone marrow progenitors. Natural products are promising candidates for novel pharmacological agents that can be used to prevent or treat cardiovascular diseases (CVD). A variety of natural products and agents exhibiting antiatherosclerotic abilities have been reported to potentially interfere with the pharmacological targets of trained immunity. This review describes in as much detail as possible the mechanisms involved in trained immunity and how phytochemicals of this process inhibit AS by affecting trained monocytes/macrophages.

Keywords:  atherosclerosis; epigenetic reprogramming; metabolic reprogramming; monocyte/macrophage; natural products; trained immunity

DOI:  https://doi.org/10.3389/fphar.2023.1109576
Front Immunol. 2023 ;14 980711

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.

   Background and objective: A recent study has suggested that circadian rhythm has an important impact on the immunological effects induced by Bacillus Calmette-Guérin (BCG) vaccination. The objective of this study was to evaluate whether the timing of BCG vaccination (morning or afternoon) affects its impact on severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections and clinically relevant respiratory tract infections (RTIs).
Methods: This is a post-hoc analysis of the BCG-CORONA-ELDERLY (NCT04417335) multicenter, placebo-controlled trial, in which participants aged 60 years and older were randomly assigned to vaccination with BCG or placebo, and followed for 12 months. The primary endpoint was the cumulative incidence of SARS-CoV-2 infection. To assess the impact of circadian rhythm on the BCG effects, participants were divided into four groups: vaccinated with either BCG or placebo in the morning (between 9:00h and 11:30h) or in the afternoon (between 14:30h and 18:00h).
Results: The subdistribution hazard ratio of SARS-CoV-2 infection in the first six months after vaccination was 2.394 (95% confidence interval [CI], 0.856-6.696) for the morning BCG group and 0.284 (95% CI, 0.055-1.480) for the afternoon BCG group. When comparing those two groups, the interaction hazard ratio was 8.966 (95% CI, 1.366-58.836). In the period from six months until 12 months after vaccination cumulative incidences of SARS-CoV-2 infection were comparable, as well as cumulative incidences of clinically relevant RTI in both periods.
Conclusion: Vaccination with BCG in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning in the first six months after vaccination.

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.2023.980711
Front Immunol. 2023 ;14 1109001

Emerging role for interferons in respiratory viral infections and childhood asthma.

Anthony Bosco.

  Respiratory syncytial virus (RSV) and Rhinovirus (RV) infections are major triggers of severe lower respiratory illnesses (sLRI) in infants and children and are strongly associated with the subsequent development of asthma. Decades of research has focused on the role of type I interferons in antiviral immunity and ensuing airway diseases, however, recent findings have highlighted several novel aspects of the interferon response that merit further investigation. In this perspective, we discuss emerging roles of type I interferons in the pathogenesis of sLRI in children. We propose that variations in interferon response patterns exist as discrete endotypes, which operate locally in the airways and systemically through a lung-blood-bone marrow axis. We discuss new insights into the role of interferons in immune training, bacterial lysate immunotherapy, and allergen-specific immunotherapy. Interferons play complex and diverse roles in the pathogenesis of sLRI and later asthma, providing new directions for mechanistic studies and drug development.

Keywords:  childhood asthma; innate immunity; interferons; respiratory syncytial virus; rhinovirus; systems biology; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2023.1109001
Am J Respir Cell Mol Biol. 2023 Mar 08.

Pulmonary and Non-Pulmonary Sepsis Differentially Modulate Lung Immunity Towards Secondary Bacterial Pneumonia: A Critical Role for Alveolar Macrophages.

Jean-François Llitjos, Cédric Auffray, Edwige Péju, Zakaria Ait Hamou, Christophe Rousseau, Aurélie Durand, Clémence Martin, Jean-Paul Mira, Pierre-Régis Burgel, Jean-Daniel Chiche, Maha Zohra Ladjemi, Bruno Lucas, Frédéric Pène.

  Clinical observations suggest that the source of primary infection accounts for a major determinant of further nosocomial pneumonia in critically ill sepsis patients. We herein addressed the impact of primary non-pulmonary or pulmonary septic insults on lung immunity using relevant double-hit animal models. C57BL/6J mice were first subjected to either polymicrobial peritonitis induced by caecal ligation and puncture (CLP) or bacterial pneumonia induced by intratracheal challenge with Escherichia coli. Seven days after, post-septic mice received intratracheal challenge with Pseudomonas aeruginosa. When compared to controls, post-CLP mice became highly susceptible to P. aeruginosa pneumonia as demonstrated by defective lung bacterial clearance and increased mortality rate. In contrast, all post-pneumonia mice survived the P. aeruginosa challenge and even exhibited improved bacterial clearance. Non-pulmonary and pulmonary sepsis differentially modulated the amounts and some important immune functions of alveolar macrophages. Additionally, we observed a Toll-like receptor 2 (TLR2)-dependent increase in regulatory T cells (Tregs) in lungs from post-CLP mice. Antibody-mediated Tregs depletion restored the numbers and functions of alveolar macrophages in post-CLP mice. Furthermore, post-CLP TLR2-deficient mice were found resistant to secondary P. aeruginosa pneumonia. In conclusion, polymicrobial peritonitis and bacterial pneumonia conferred susceptibility or resistance to secondary Gram-negative pulmonary infection, respectively. Immune patterns in post-CLP lungs argue for a TLR2-dependent crosstalk between T-regs and alveolar macrophages, as an important regulatory mechanism in post-septic lung defense.

Keywords:  TLR2; Trained immunity; alveolar macrophage; regulatory T cells; sepsis

DOI:  https://doi.org/10.1165/rcmb.2022-0281OC
Cell Immunol. 2023 Feb 23. pii: S0008-8749(23)00033-3. [Epub ahead of print]386 104694

Fine particulate matter (PM2.5) induces inhibitory memory alveolar macrophages through the AhR/IL-33 pathway.

Yanan Liu, Qi Yuan, Xijie Zhang, Zhongqi Chen, Xinyu Jia, Min Wang, Tingting Xu, Zhengxia Wang, Jingxian Jiang, Qiyun Ma, Mingshun Zhang, Mao Huang, Ningfei Ji.

  Fine particulate matter (PM2.5) concentrations have decreased in the past decade. The adverse effects of acute PM2.5 exposure on respiratory diseases have been well recognized. To explore the long-term effects of PM2.5 exposure on chronic obstructive pulmonary disease (COPD), mice were exposed to PM2.5 for 7 days and rest for 21 days, followed by challenges with lipopolysaccharide (LPS) and porcine pancreatic elastase (PPE). Unexpectedly, PM2.5 exposure and rest alleviated the disease severity and airway inflammatory responses in COPD-like mice. Although acute PM2.5 exposure increased airway inflammation, rest for 21 days reversed the airway inflammatory responses, which was associated with the induction of inhibitory memory alveolar macrophages (AMs). Similarly, polycyclic aromatic hydrocarbons (PAHs) in PM2.5 exposure and rest decreased pulmonary inflammation, accompanied by inhibitory memory AMs. Once AMs were depleted, pulmonary inflammation was aggravated. PAHs in PM2.5 promoted the secretion of IL-33 from airway epithelial cells via the aryl hydrocarbon receptor (AhR)/ARNT pathway. High-throughput mRNA sequencing revealed that PM2.5 exposure and rest drastically changed the mRNA profiles in AMs, which was largely rescued in IL-33-/- mice. Collectively, our results indicate that PM2.5 may mitigate pulmonary inflammation, which is mediated by inhibitory trained AMs via IL-33 production from epithelial cells through the AhR/ARNT pathway. We provide the rationale that PM2.5 plays complicated roles in respiratory disease.

Keywords:  AhR; Alveolar macrophages; COPD; IL-33; PM2.5; Trained immunity

DOI:  https://doi.org/10.1016/j.cellimm.2023.104694
J Immunol. 2023 Mar 06. pii: ji2200596. [Epub ahead of print]

NF-κB-Inducing Kinase Governs the Mitochondrial Respiratory Capacity, Differentiation, and Inflammatory Status of Innate Immune Cells.

Justin N Keeney, Ashley A Winters, Raquel Sitcheran, A Phillip West.

NF-κB-inducing kinase (NIK), which is essential for the activation of the noncanonical NF-κB pathway, regulates diverse processes in immunity, development, and disease. Although recent studies have elucidated important functions of NIK in adaptive immune cells and cancer cell metabolism, the role of NIK in metabolic-driven inflammatory responses in innate immune cells remains unclear. In this study, we demonstrate that murine NIK-deficient bone marrow-derived macrophages exhibit defects in mitochondrial-dependent metabolism and oxidative phosphorylation, which impair the acquisition of a prorepair, anti-inflammatory phenotype. Subsequently, NIK-deficient mice exhibit skewing of myeloid cells characterized by aberrant eosinophil, monocyte, and macrophage cell populations in the blood, bone marrow, and adipose tissue. Furthermore, NIK-deficient blood monocytes display hyperresponsiveness to bacterial LPS and elevated TNF-α production ex vivo. These findings suggest that NIK governs metabolic rewiring, which is critical for balancing proinflammatory and anti-inflammatory myeloid immune cell function. Overall, our work highlights a previously unrecognized role for NIK as a molecular rheostat that fine-tunes immunometabolism in innate immunity, and suggests that metabolic dysfunction may be an important driver of inflammatory diseases caused by aberrant NIK expression or activity.

DOI: https://doi.org/10.4049/jimmunol.2200596
NPJ Precis Oncol. 2023 Mar 08. 7(1): 26

Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer.

Christian Rolfo, Elisa Giovannetti, Pablo Martinez, Shannon McCue, Aung Naing.

Toll-like receptors (TLRs), which serve as a bridge between innate and adaptive immunity, may be viable treatment targets. TLRs are the first line of defense against microbes and activate signaling cascades that induce immune and inflammatory responses. Patients with "hot" versus "cold" tumors may respond more favorably to immune checkpoint inhibition, and through their downstream effects, TLR agonists have the potential to convert "cold tumors" into "hot tumors" making TLRs in combination with immune checkpoint inhibitors, potential targets for cancer therapies. Imiquimod is a topical TLR7 agonist, approved by the FDA for antiviral and skin cancer treatments. Other TLR adjuvants are used in several vaccines including Nu Thrax, Heplisav, T-VEC, and Cervarix. Many TLR agonists are currently in development as both monotherapy and in combination with immune checkpoint inhibitors. In this review, we describe the TLR agonists that are being evaluated clinically as new therapies for solid tumors.

DOI: https://doi.org/10.1038/s41698-023-00364-1