IL-38 prevents induction of trained immunity by inhibition of mTOR signaling.
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ABSTRACT:
SUBMITTER: de Graaf DM
PROVIDER: S-EPMC8380748 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Vaccines represent an important strategy to protect humans against a wide variety of pathogens and have even led to eradicating some diseases. Although every vaccine is developed to induce specific protection for a particular pathogen, some vaccine formulations can also promote trained immunity, which is a non-specific memory-like feature developed by the innate immune system. It is thought that trained immunity can protect against a wide variety of pathogens other than those contained in the vaccine formulation. The non-specific memory of the trained immunity-based vaccines (TIbV) seems beneficial for the immunized individual, as it may represent a powerful strategy that contributes to the control of pathogen outbreaks, reducing morbidity and mortality. A wide variety of respiratory viruses, including respiratory syncytial virus (hRSV) and metapneumovirus (hMPV), cause serious illness in children under 5 years old and the elderly. To address this public health problem, we have developed recombinant BCG vaccines that have shown to be safe and immunogenic against hRSV or hMPV. Besides the induction of specific adaptive immunity against the viral antigens, these vaccines could generate trained immunity against other respiratory pathogens. Here, we discuss some of the features of trained immunity induced by BCG and put forward the notion that recombinant BCGs expressing hRSV or hMPV antigens have the capacity to simultaneously induce specific adaptive immunity and non-specific trained immunity. These recombinant BCG vaccines could be considered as TIbV capable of inducing simultaneously the development of specific protection against hRSV or hMPV, as well as non-specific trained-immunity-based protection against other pathogenic viruses.
| S-EPMC7873984 | biostudies-literature
Project description:BackgroundTrained immunity is the ability of the innate immune system to form immune memory responses to provide support the formation of appropriate adaptive responses. Allergic airways disease (AAD) is a maladapted immune response to allergens, initiated and maintained by the type 2 (T2) inflammatory pathway. It is predicated by the elaboration of cytokines IL-4 and IL-13 and follows activation of the STAT6 transcription factor.ObjectiveTo investigate the role of trained immunity in mucosal immune responses following neonatal vaccination with the STAT6 inhibitory peptide (STAT6-IP), in preventing the development of ragweed-induced AAD.MethodsWe demonstrate that transfer of CD4+ T cells or dendritic cells (DC) from STAT6-IP vaccinated wild-type BALB/c mice to naïve mice, that were subsequently chronically exposed to sensitizing doses of ragweed allergen, is sufficient to prevent development of T2 responses in recipients.ResultsOur results demonstrate significant reductions in; airways hyperresponsiveness (AHR); ragweed-specific IgE; pulmonary inflammation; T2 cytokines; and inflammatory gene expressions in recipient mice. Expression of IDO, TGFβ and T regulatory cells were all significantly increased. Anti-TGFβ treatment during the ragweed sensitization phase re-constituted the pro-inflammatory T2 immune response. We show that tolerance can be attained via DC trained in the STAT6-IP-mediated tolerant milieu. This effect is not restricted to a particular allergen and does not require antigen-mediated T cell activation prior to transfer.ConclusionAdoptive transfer experiments suggest that STAT6-IP treatment trains dendritic and cells to mediate tolerant immunity to chronic ragweed exposure in the airways. This indicates that early transient STAT6-inhibition constitutes an effective immunomodulatory airways allergy preventative strategy.
| S-EPMC8059037 | biostudies-literature
Project description:The innate immune system displays heterologous memory characteristics, which are characterized by stronger responses to a secondary challenge. This phenomenon termed trained immunity relies on epigenetic and metabolic rewiring of innate immune cells. As reactive oxygen species (ROS) production has been associated with the trained immunity phenotype, we hypothesized that the increased ROS levels and the main intracellular redox molecule glutathione play a role in the induction of trained immunity. Here we show that pharmacological inhibition of ROS in an in vitro model of trained immunity did not influence cell responsiveness; the modulation of glutathione levels reduced pro-inflammatory cytokine production in human monocytes. Single nucleotide polymorphisms (SNPs) in genes involved in glutathione metabolism were found to be associated with changes in pro-inflammatory cytokine production capacity upon trained immunity. Also, plasma glutathione concentrations were positively associated with ex vivo IL-1β production, a biomarker of trained immunity, produced by monocytes of BCG-vaccinated individuals. In conclusion, glutathione metabolism is involved in the induction of trained immunity, and future studies are warranted to explore its functional consequences in human diseases.
| S-EPMC8143087 | biostudies-literature
Project description:The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. Here, we used a mycobacterial growth inhibition assay (MGIA) based on peripheral blood mononuclear cells to investigate the capacity to control outgrowth of bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3 receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb-exposed individuals. Cytokines previously associated with trained immunity were detected in MGIA supernatants, and CXCL9, CXCL10, and CXCL11 represent new markers of trained immunity. These data indicate that CXCR3 ligands are associated with trained immunity and are critical factors in controlling mycobacterial outgrowth. In conclusion, control of mycobacterial outgrowth early after exposure to Mtb is the result of trained immunity mediated by a CXCL10-producing nonclassical CD14dim monocyte subset.
| S-EPMC5919803 | biostudies-other
Project description:BACKGROUNDThe antituberculosis vaccine bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity.METHODSEighteen volunteers were vaccinated with BCG at 6 pm and compared with 36 age- and sex-matched volunteers vaccinated between 8 am and 9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as 2 weeks and 3 months after, BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8 am and 12 pm with BCG.RESULTSCompared with evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning- compared with evening-isolated monocytes.CONCLUSIONSBCG vaccination in the morning induces stronger trained immunity and adaptive responses compared with evening vaccination. Future studies should take vaccine administration time into account when studying specific and nonspecific effects of vaccines; early morning should be the preferred moment of BCG administration.FUNDINGThe Netherlands Organization for Scientific Research, the European Research Council, and the Danish National Research Foundation.
| S-EPMC7641012 | biostudies-literature
Project description:Non-specific protective effects of certain vaccines have been reported, and long-term boosting of innate immunity, termed trained immunity, has been proposed as one of the mechanisms mediating these effects. Several epidemiological studies suggested cross-protection between influenza vaccination and COVID-19. In a large academic Dutch hospital, we found that SARS-CoV-2 infection was less common among employees who had received a previous influenza vaccination: relative risk reductions of 37% and 49% were observed following influenza vaccination during the first and second COVID-19 waves, respectively. The quadrivalent inactivated influenza vaccine induced a trained immunity program that boosted innate immune responses against various viral stimuli and fine-tuned the anti-SARS-CoV-2 response, which may result in better protection against COVID-19. Influenza vaccination led to transcriptional reprogramming of monocytes and reduced systemic inflammation. These epidemiological and immunological data argue for potential benefits of influenza vaccination against COVID-19, and future randomized trials are warranted to test this possibility. Author summary COVID-19, caused by the virus SARS-CoV-2, has claimed millions of lives and affected many more since its emergence. A number of studies have previously suggested that influenza vaccination can provide protection against COVID-19. Although multiple COVID-19 vaccines are currently available, emergence of new variants and inequity in vaccine distribution around the world make it crucial to identify alternative ways that can help in the fight against this pandemic. With this in mind, we investigated if seasonal influenza vaccination had any effect on COVID-19 incidence. Dutch healthcare workers who received the influenza vaccine in the previous flu season had 37% and 49% lower risk of SARS-CoV-2 infection in the first two waves of the pandemic, respectively. We also explored the mechanisms underlying this observation, using various techniques such as single-cell RNA sequencing, proteomics, and stimulation assays. The influenza vaccine reduced systemic inflammation and reprogrammed the immune cells to fine-tune the response against SARS-CoV-2. This study reveals influenza vaccination as a safe and helpful tool to decrease COVID-19 burden.
| S-EPMC8568262 | biostudies-literature
Project description:It has been shown recently that neutrophils are able to produce IL-22 and IL-17, which differentially regulate the pathogenesis of inflammatory bowel disease. However, it is still largely unknown how the neutrophil production of IL-22 and IL-17 is regulated, and their role in the pathogenesis of inflammatory bowel disease. In this study, we found that IL-23 promoted neutrophil production of IL-17 and IL-22. IL-23 stimulated the neutrophil expression of IL-23R as well as rorc and ahr. Retinoid acid receptor-related orphan receptor ? t and aryl-hydrocarbon receptor differentially regulated IL-23 induction of neutrophil IL-17 and IL-22. In addition, IL-23 induced the activation of mTOR in neutrophils. Blockade of the mTOR pathway inhibited IL-23-induced expression of rorc and ahr, as well as IL-17 and IL-22 production. By using a microbiota Ag-specific T cell-mediated colitis model, we demonstrated that depletion of neutrophils, as well as blockade of IL-22, resulted in a significant increase in the severity of colitis, thereby indicating a protective role of neutrophils and IL-22 in chronic colitis. Collectively, our data revealed that neutrophils negatively regulate microbiota Ag-specific T cell induction of colitis, and IL-23 induces neutrophil production of IL-22 and IL-17 through induction of rorc and ahr, which is mediated by the mTOR pathway.
| S-EPMC4868807 | biostudies-literature
Project description:Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent ?-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD(+)) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1? (hypoxia-inducible factor-1?) pathway. Inhibition of Akt, mTOR, or HIF-1? blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1? were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1? pathway represents the metabolic basis of trained immunity.
| S-EPMC4226238 | biostudies-literature
Project description:Introduction: Cells of the innate immune system particularly monocytes and macrophages have been recognized as pivotal players both during the initial insult as well as the chronic phase of atherosclerosis. It has recently been shown that oxidized low-density lipoprotein (oxLDL) induces a long-term pro-inflammatory response in monocytes due to epigenetic and metabolic reprogramming, an emerging new concept called trained innate immunity. Changes in the cellular redox state are crucial events in the regulation of many physiologic functions in macrophages including transcription, differentiation and inflammatory response. Here we have analyzed the role of reactive oxygen species (ROS) in regulating this proinflammatory monocyte priming in response to oxLDL-treatment. Methods and Results: Human monocytes were isolated and incubated with oxLDL for 24 h. After 5 days of resting, oxLDL treated cells produced significantly more inflammatory cytokines upon restimulation with the TLR2-agonist Pam3cys. Furthermore, oxLDL incubation induced persistent mTOR activation, ROS formation, HIF1? accumulation and HIF1? target gene expression, while pharmacologic mTOR inhibition or siRNA mediated inhibition of the mTORC1 subunit Raptor prevented ROS formation and proinflammatory priming. mTOR dependent ROS formation was associated with increased expression of NAPDH oxidases and necessary for the emergence of the primed phenotype as antioxidant treatment blocked oxLDL priming. Inhibition of cytosolic ROS formation could also block mTOR activation and HIF1? accumulation suggesting a positive feedback loop between mTOR and cytosolic ROS. Although mitochondrial ROS scavenging did not block HIF1?-accumulation at an early time point (24 h), it was persistently reduced on day 6. Therefore, mitochondrial ROS formation appears to occur initially downstream of the mTOR-cytoROS-HIF1? feedback loop but seems to be a crucial factor that controls the long-term activation of the mTOR-HIF1?-axis. Conclusion: In summary, our data demonstrate that mTOR dependent ROS production controls the oxLDL-induced trained innate immunity phenotype in human monocyte derived macrophages. Pharmacologic modulation of these pathways might provide a potential approach to modulate inflammation, associated with aberrant monocyte activation, during atherosclerosis development.
| S-EPMC6350618 | biostudies-literature
Project description:A growing number of studies show that innate immune cells can undergo functional reprogramming, facilitating a faster and enhanced response to heterologous secondary stimuli. This concept has been termed "trained immunity." We outline here a protocol to recapitulate this in vitro using adherent monocytes from consecutive isolation of peripheral blood mononuclear cells. The induction of trained immunity and the associated functional reprogramming of monocytes is described in detail using β-glucan (from Candida albicans) and Bacillus Calmette-Guérin as examples. For complete details on the use and execution of this protocol, please refer to Repnik et al. (2003) and Bekkering et al. (2016).
| S-EPMC7921712 | biostudies-literature