Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9

The skin typically tolerates exposure to various microbes and chemicals in the environment. Here, we investigated how the epidermis maintains this innate immune tolerance to stimuli that are recognized by Toll-like receptors (TLRs). Loss of tolerance to TLR ligands occurred after silencing of the histone deacetylases (HDACs) HDAC8 and HDAC9 in keratinocytes. Transcriptional analysis identified MAP2K3 as suppressed by HDAC8/9 activity and a potential key intermediary for establishing this tolerance. HDAC8/9 influenced acetylation at H3K9 and H3K27 marks in the MAP2K3 promoter. Proteomic analysis further identified SSRP1 and SUPT16H as associated with HDAC8/9 and responsible for transcriptional elongation of MAP2K3. Silencing of MAP2K3 blocked the capacity of HDAC8/9 to influence cytokine responses. Relevance in vivo was supported by observations of increased MAP2K3 in human inflammatory skin conditions and the capacity of keratinocyte HDAC8/9 to influence dendritic cell maturation and T cell proliferation. Keratinocyte-specific deletion of HDAC8/9 also increased inflammation in mice after exposure to ultraviolet radiation, imiquimod, or Staphylococcus aureus. These findings define a mechanism for the epidermis to regulate inflammation in the presence of ubiquitous TLR ligands.

Download Full-text

Faculty Opinions recommendation of Persistently active microbial molecules prolong innate immune tolerance in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718011820.793477079 ◽

2013 ◽

Author(s):

Matthew Mulvey ◽

Travis Wiles

Keyword(s):

Immune Tolerance ◽

Innate Immune

Download Full-text

Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine

10.1101/2021.10.08.21264577 ◽

2021 ◽

Author(s):

Leetah Senkpeil ◽

Jyoti Bhardwaj ◽

Morgan Little ◽

Prasida Holla ◽

Aditi Upadhye ◽

...

Keyword(s):

Immune Activation ◽

Malaria Infection ◽

Protective Immunity ◽

Molecular Mechanisms ◽

Protective Efficacy ◽

T Cell Response ◽

Innate Immune ◽

Transcriptional Analysis ◽

Innate Immune Activation

Baseline innate immune signatures can influence protective immunity following vaccination. Here, we used systems transcriptional analysis to assess the molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole sporozoite PfSPZ Vaccine in African infants. Innate immune activation and myeloid signatures at pre-vaccination baseline correlated with protection from Plasmodium falciparum infection in placebo controls, while the same signatures predicted susceptibility to infection among infants who received the highest and most protective dose of the PfSPZ Vaccine. Machine learning identified monocytes and an antigen presentation signature as pre-vaccination features predictive of malaria infection after highest-dose PfSPZ vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against malaria infection in mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data establish a dichotomous role of innate stimulation for malaria protection and induction of protective immunity of whole-sporozoite malaria vaccines.

Download Full-text

TFIIS Enhances Transcriptional Elongation through an Artificial Arrest Site In Vivo

Molecular and Cellular Biology ◽

10.1128/mcb.21.13.4162-4168.2001 ◽

2001 ◽

Vol 21 (13) ◽

pp. 4162-4168 ◽

Cited By ~ 43

Author(s):

Dmitry Kulish ◽

Kevin Struhl

Keyword(s):

Rna Polymerase Ii ◽

Transcriptional Activation ◽

Chromatin Immunoprecipitation ◽

Transcriptional Analysis ◽

Transcriptional Elongation ◽

Specific Assay ◽

Physical Evidence ◽

Reduced Temperature

ABSTRACT Transcriptional elongation by RNA polymerase II has been well studied in vitro, but understanding of this process in vivo has been limited by the lack of a direct and specific assay. Here, we designed a specific assay for transcriptional elongation in vivo that involves an artificial arrest (ARTAR) site designed from a thermodynamic theory of DNA-dependent transcriptional arrest in vitro. Transcriptional analysis and chromatin immunoprecipitation experiments indicate that the ARTAR site can arrest Pol II in vivo at a position far from the promoter. TFIIS can counteract this arrest, thereby demonstrating that it possesses transcriptional antiarrest activity in vivo. Unexpectedly, the ARTAR site does not function under conditions of high transcriptional activation unless cells are exposed to conditions (6-azauracil or reduced temperature) that are presumed to affect elongation in vivo. Conversely, TFIIS affects gene expression under conditions of high, but not low, transcriptional activation. Our results provide physical evidence for the discontinuity of transcription elongation in vivo, and they suggest that the functional importance of transcriptional arrest sites and TFIIS is strongly influenced by the level of transcriptional activation.

Download Full-text

Systemic administration of β-glucan induces immune training in microglia

Journal of Neuroinflammation ◽

10.1186/s12974-021-02103-4 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Yang Heng ◽

Xiaoming Zhang ◽

Malte Borggrewe ◽

Hilmar R. J. van Weering ◽

Maaike L. Brummer ◽

...

Keyword(s):

Immune Tolerance ◽

Morphological Changes ◽

Innate Immune ◽

Cytokine Gene Expression ◽

Immune Memory ◽

Lps Challenge ◽

Lps Preconditioning ◽

Gene Expression Levels

Abstract Background An innate immune memory response can manifest in two ways: immune training and immune tolerance, which refers to an enhanced or suppressed immune response to a second challenge, respectively. Exposing monocytes to moderate-to-high amounts of bacterial lipopolysaccharide (LPS) induces immune tolerance, whereas fungal β-glucan (BG) induces immune training. In microglia, it has been shown that different LPS inocula in vivo can induce either immune training or tolerance. Few studies focused on impact of BG on microglia and were only performed in vitro. The aim of the current study was to determine whether BG activates and induces immune memory in microglia upon peripheral administration in vivo. Methods Two experimental designs were used. In the acute design, mice received an intraperitoneal (i.p.) injection with PBS, 1 mg/kg LPS or 20 mg/kg BG and were terminated after 3 h, 1 or 2 days. In the preconditioning design, animals were first challenged i.p. with PBS, 1 mg/kg LPS or 20 mg/kg BG. After 2, 7 or 14 days, mice received a second injection with PBS or 1 mg/kg LPS and were sacrificed 3 h later. Microglia were isolated by fluorescence-activated cell sorting, and cytokine gene expression levels were determined. In addition, a self-developed program was used to analyze microglia morphological changes. Cytokine concentrations in serum were determined by a cytokine array. Results Microglia exhibited a classical inflammatory response to LPS, showing significant upregulation of Tnf, Il6, Il1β, Ccl2, Ccl3 and Csf1 expression, three h after injection, and obvious morphological changes 1 and 2 days after injection. With an interval of 2 days between two challenges, both BG and LPS induced immune training in microglia. The training effect of LPS changed into immune tolerance after a 7-day interval between 2 LPS challenges. Preconditioning with BG and LPS resulted in increased morphological changes in microglia in response to a systemic LPS challenge compared to naïve microglia. Conclusions Our results demonstrate that preconditioning with BG and LPS both induced immune training of microglia at two days after the first challenge. However, with an interval of 7 days between the first and second challenge, LPS-preconditioning resulted in immune tolerance in microglia.

Download Full-text

Persistently Active Microbial Molecules Prolong Innate Immune Tolerance In Vivo

PLoS Pathogens ◽

10.1371/journal.ppat.1003339 ◽

2013 ◽

Vol 9 (5) ◽

pp. e1003339 ◽

Cited By ~ 21

Author(s):

Mingfang Lu ◽

Alan W. Varley ◽

Robert S. Munford

Keyword(s):

Immune Tolerance ◽

Innate Immune

Download Full-text

Systemic administration of β-glucan induces immune training in microglia

10.21203/rs.3.rs-115993/v1 ◽

2020 ◽

Author(s):

Yang Heng ◽

Xiaoming Zhang ◽

Malte Borggrewe ◽

Hilmar R.J. van Weering ◽

Maaike L. Brummer ◽

...

Keyword(s):

Immune Tolerance ◽

Morphological Changes ◽

Innate Immune ◽

Cytokine Gene Expression ◽

Immune Memory ◽

Lps Challenge ◽

Lps Preconditioning ◽

Gene Expression Levels

Abstract BackgroundAn innate immune memory response can manifest in two ways: immune training and immune tolerance, which refers to an enhanced or suppressed immune response to a second challenge, respectively. Exposing monocytes to moderate-to-high amounts of bacterial lipopolysaccharide (LPS) induces immune tolerance, whereas fungal β-glucan (BG) induces immune training. In microglia, it has been shown that different LPS inocula in vivo can induce either immune training or tolerance. Few studies focused on impact of BG on microglia and were only performed in vitro. The aim of the current study was to determine whether BG activates and induces immune memory in microglia upon peripheral administration in vivo.MethodsTwo experimental designs were used. In the acute design, mice received an intraperitoneal (i.p.) injection with PBS, 1 mg/kg LPS or 20 mg/kg BG and were terminated after 3 h, 1 or 2 days. In the preconditioning design, animals were first challenged i.p. with PBS, 1 mg/kg LPS or 20 mg/kg BG. After 2, 7 or 14 days, mice received a second injection with PBS or 1 mg/kg LPS and were sacrificed 3 h later. Microglia were isolated by fluorescence-activated cell sorting, and cytokine gene expression levels were determined. In addition, a self-developed program was used to analyze microglia morphological changes. Cytokine concentrations in serum were determined by a cytokine array.ResultsMicroglia exhibited a classical inflammatory response to LPS, showing significant upregulation of Tnf, Il6, Il1β, Ccl2, Ccl3 and Csf1 expression, three h after injection, and obvious morphological changes 1 and 2 days after injection. With an interval of 2 days between two challenges, both BG and LPS induced immune training in microglia. The training effect of LPS changed into immune tolerance after a 7-day interval between 2 LPS challenges. Preconditioning with BG and LPS resulted in increased morphological changes in microglia in response to a systemic LPS challenge compared to naïve microglia.ConclusionsOur results demonstrate that preconditioning with BG and LPS both induced immune training of microglia at two days after the first challenge. However, with an interval of 7 days between the first and second challenge, LPS-preconditioning resulted in immune tolerance in microglia.

Download Full-text