Trained immunity, tolerance, priming and differentiation: distinct immunological processes

Divangahi, Maziar; Aaby, Péter; Khader, Shabaana A.; Barreiro, Luis B.; Bekkering, Siroon; Chavakis, Triantafyllos; Crevel, Reinout van; Curtis, Nigel; DiNardo, Andrew; Domínguez‐Andrés, Jorge; Duivenwoorden, Raphael; Fanucchi, Stephanie; Fayad, Zahi A.; Fuchs, Elaine; Hamon, Mélanie; Jeffrey, Kate L.; Khan, Nargis; Joosten, Leo A. B.; Kaufmann, Eva; Latz, Eicke; Matarese, Giuseppe; Meer, J.W.M. van der; Mhlanga, Musa M.; Moorlag, Simone J.C.F.M.; Mulder, Willem J. M.; Naik, Shruti; Novakovic, Boris; O’Neill, Luke A.J.; Ochando, Jordi; Ozato, Keiko; Riksen, Niels P.; Sauerwein, Robert W.; Sherwood, Edward R.; Schlitzer, Andreas; Schultze, Joachim L.; Sieweke, Michael H.; Benn, Christine Stabell; Stunnenberg, Henk; Sun, Joseph C.; Veerdonk, Frank L. van de; Weis, Sebastian; Williams, David L.; Xavier, Ramnik J.; Netea, Mihai G.

doi:10.1038/s41590-020-00845-6

Cited by 382 publications

(394 citation statements)

References 26 publications

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“…Innate immune tolerance is a functional adaptive program within innate immune cells that limits transcriptional activation following restimulation. Epigenetic priming mechanisms play critical roles in innate immune tolerance and training of innate immune memory ( Divangahi et al., 2021 ), and our findings support the hypothesis that pregravid obesity results in LPS tolerance in circulating monocytes. Specifically, expression of HLA-DR in monocytes at T3 measured at the protein, transcript, and epigenetic levels were significantly reduced.…”

Section: Discussionsupporting

confidence: 86%

“…These differences in outcomes could be explained by different triggers of oxidative stress (LPS vs. pathogen). Innate immune tolerance to LPS can also impact the ability of monocytes to differentiate toward M1-or M2-like states under polarizing conditions ( Divangahi et al., 2021 ). In agreement with transcriptional and cytokine responses, monocyte-derived macrophages (MoDM) from mothers with obesity polarized poorly to M1 but not to M2 skewing conditions.…”

Section: Discussionmentioning

confidence: 99%

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Functional and genomic adaptations of blood monocytes to pregravid obesity during pregnancy

et al. 2021

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Summary Pregravid obesity is associated with several adverse maternal health outcomes, such as increased risk of infection, suggesting an altered immunological state. However, the mechanisms by which obesity disrupts the pregnancy “immune clock” are still unknown. Here, we profiled circulating immune mediators, immune cell subset frequencies, and peripheral immune responses during the first and third trimesters of pregnancy in lean and obese mothers. While both Th1 and Th2 cytokines were elevated with pregnancy regardless of BMI, obese subjects had dysregulated myeloid factors in circulation at term. Pregnancy in lean subjects was associated with enhanced monocyte activation, augmented chromatin accessibility at inflammatory loci, and heightened responses to LPS. Pregravid obesity disrupted this trajectory, resulting in a lack of transcriptional, epigenetic, and metabolic changes strongly suggesting a skewing toward innate immune tolerance. These findings provide novel insight into the increased susceptibility to infections in women with obesity during pregnancy and following cesarean delivery.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Functional and genomic adaptations of blood monocytes to pregravid obesity during pregnancy

et al. 2021

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“…Epigenetics seems to be important in training immunity [ 60 , 79 ] during monocyte differentiation and in the immunological memory of macrophages [ 80 , 81 ]. Today, various bioactive phytochemicals have been identified which modulate inflammation through epigenetic reprogramming [ 82 , 83 ].…”

Section: Resultsmentioning

confidence: 99%

“…6 c) . Whether these small methylation changes are sufficient to “train” the innate immune gene response needs further investigation [ 60 , 61 , 79 ].…”

Section: Resultsmentioning

confidence: 99%

Echinacea purpurea (L.) Moench treatment of monocytes promotes tonic interferon signaling, increased innate immunity gene expression and DNA repeat hypermethylated silencing of endogenous retroviral sequences

Declerck

Novo

Grielens

et al. 2021

BMC Complement Med Ther

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Background Herbal remedies of Echinacea purpurea tinctures are widely used today to reduce common cold respiratory tract infections. Methods Transcriptome, epigenome and kinome profiling allowed a systems biology level characterisation of genomewide immunomodulatory effects of a standardized Echinacea purpurea (L.) Moench extract in THP1 monocytes. Results Gene expression and DNA methylation analysis revealed that Echinaforce® treatment triggers antiviral innate immunity pathways, involving tonic IFN signaling, activation of pattern recognition receptors, chemotaxis and immunometabolism. Furthermore, phosphopeptide based kinome activity profiling and pharmacological inhibitor experiments with filgotinib confirm a key role for Janus Kinase (JAK)-1 dependent gene expression changes in innate immune signaling. Finally, Echinaforce® treatment induces DNA hypermethylation at intergenic CpG, long/short interspersed nuclear DNA repeat elements (LINE, SINE) or long termininal DNA repeats (LTR). This changes transcription of flanking endogenous retroviral sequences (HERVs), involved in an evolutionary conserved (epi) genomic protective response against viral infections. Conclusions Altogether, our results suggest that Echinaforce® phytochemicals strengthen antiviral innate immunity through tonic IFN regulation of pattern recognition and chemokine gene expression and DNA repeat hypermethylated silencing of HERVs in monocytes. These results suggest that immunomodulation by Echinaforce® treatment holds promise to reduce symptoms and duration of infection episodes of common cold corona viruses (CoV), Severe Acute Respiratory Syndrome (SARS)-CoV, and new occurring strains such as SARS-CoV-2, with strongly impaired interferon (IFN) response and weak innate antiviral defense.

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“…6 The innate immune system after exposure to invading organisms or vaccines (BCG, measles show a heightened response following a subsequent challenge by the first trigger or diverse unrelated organisms or molecules. [7][8][9] This nonspecific "trained immunity" is different from the classical epitope-dependent memory of adaptive immunity mediated by lymphocytes. In contrast to "trained immunity," the innate immune cells may also attain a state of "immune tolerance" or a "hyporesponsiveness" to heterologous secondary challenge, typically exhibiting a decreased production of proinflammatory mediators.…”

mentioning

confidence: 98%

Cross‐immunity and trained immunity in explaining variable COVID‐19 mortality—Guidance for future pandemics

Chakrabarti

Kaur

et al. 2021

Journal of Medical Virology

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Trained immunity, tolerance, priming and differentiation: distinct immunological processes

Cited by 382 publications

References 26 publications

Functional and genomic adaptations of blood monocytes to pregravid obesity during pregnancy

Functional and genomic adaptations of blood monocytes to pregravid obesity during pregnancy

Echinacea purpurea (L.) Moench treatment of monocytes promotes tonic interferon signaling, increased innate immunity gene expression and DNA repeat hypermethylated silencing of endogenous retroviral sequences

Cross‐immunity and trained immunity in explaining variable COVID‐19 mortality—Guidance for future pandemics

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