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Infections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guérin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses., (© 2023. The Author(s).)

Dysregulation and hyperactivation of innate immune responses can lead to the onset of systemic autoinflammatory diseases. Monogenic autoinflammatory diseases are caused by inborn genetic errors and based on molecular mechanisms at play, can be divided into inflammasomopathies, interferonopathies, relopathies, protein misfolding, and endogenous antagonist deficiencies. On the other hand, more common autoinflammatory diseases are multifactorial, with both genetic and non‐genetic factors playing an important role. During the last decade, long‐term memory characteristics of innate immune responses have been described (also called trained immunity) that in physiological conditions provide enhanced host protection from pathogenic re‐infection. However, if dysregulated, induction of trained immunity can become maladaptive, perpetuating chronic inflammatory activation. Here, we describe the mechanisms of genetic and epigenetic dysregulation of the innate immune system and maladaptive trained immunity that leads to the onset and perpetuation of the most common and recently described systemic autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

Introduction: Trained Immunity represents a novel revolutionary concept of the immunological response involving innate immune cells. Bisphenol A is a wellknown endocrine disrupter, widely disseminated worldwide and accumulated in the human body. Due to the increased interest regarding the effects of plasticderived 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 (IL1b, TNF-a, 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 antiinflammatory cytokine responses upon restimulation, sustained by the modulation of the immunometabolic circuits. Moreover, we proved the nontoxic effect of BPA at each experimental concentration by performing an MTT assay. Additionally, correlation analysis were performed between pro- and antiinflammatory cytokines production after LPS acute stimulation or BPA-mediated trained immunity and BPA serum concentrations showing a significant association between TNF-a 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. [ABSTRACT FROM AUTHOR]

Objective Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production. Methods Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes. Results GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production. Conclusions Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production. [ABSTRACT FROM AUTHOR]

Trained immunity is a long-term increase in responsiveness of innate immune cells, induced by certain infections and vaccines. During the last 3 years of the COVID-19 pandemic, vaccines that induce trained immunity, such as BCG, MMR, OPV, and others, have been investigated for their capacity to protect against COVID-19. Further, trained immunity-inducing vaccines have been shown to improve B and T cell responsiveness to both mRNA- and adenovirus-based anti-COVID-19 vaccines. Moreover, SARS-CoV-2 infection itself induces inappropriately strong programs of trained immunity in some individuals, which may contribute to the long-term inflammatory sequelae. In this review, we detail these and other aspects of the role of trained immunity in SARS-CoV-2 infection and COVID-19. We also examine the learnings from the trained immunity studies conducted in the context of this pandemic and discuss how they may help us in preparing for future infectious outbreaks. Trained immunity-inducing vaccines have been suggested to protect against heterologous infections, including COVID-19. This review presents the studies performed during the pandemic that have investigated the effects of vaccines such as BCG, OPV, MMR, and others against COVID-19. In addition, data are reviewed that suggest that COVID-19 itself and the novel COVID-19 vaccines can also induce trained immunity programs. [ABSTRACT FROM AUTHOR]

The innate immune system is able to build memory-like features in response to certain infections or vaccines, resulting in enhanced responsiveness upon (re)challenge with the same or an unrelated pathogen, a phenomenon termed 'trained immunity'. Compared with antigen-dependent adaptive immune responses triggered by classical vaccines against specific pathogens, trained immunity-related vaccines induce enhanced innate immune responses against unrelated pathogens and provide 'heterologous protection'. Here, we discuss the heterologous effects of vaccines against infections and detail the latest insights into the cellular and molecular mechanisms mediating trained immunity. Additionally, novel vaccine strategies are suggested for fighting new pandemics in the future by taking advantage of the heterologous memory features of trained immunity. Trained innate immune cells have improved antimicrobial function mediated by transcriptional and epigenetic rewiring. Long-lasting trained immunity is centrally regulated in hematopoietic progenitors in the bone marrow and peripherally induced in tissue-resident cells. Distinct trained immunity programs at the single cell level identify trained monocyte subpopulations. Heterologous or nonspecific protection of vaccines against unrelated pathogens can be partially explained by induction of trained immunity responses. BCG, MTBVAC, influenza, measles, and possibly the new mRNA Coronavirus 2019 (COVID-19) vaccines induce trained immunity signatures, while trained immunity inducers can act as vaccine adjuvants. Environmental factors, the microbiome, circadian rhythm, genetics, and sex influence vaccine-induced trained immunity heterogeneity. [ABSTRACT FROM AUTHOR]