scholarly journals Innate immune responses after stimulation with Toll-like receptor agonists in ex vivo microglial cultures and an in vivo model using mice with reduced microglia

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
James A. Carroll ◽  
Brent Race ◽  
Katie Williams ◽  
James F. Striebel ◽  
Bruce Chesebro
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Ex Vivo ◽  
Innate Immune ◽  
Cpg Odn ◽  
Innate Immune Responses ◽  
Tlr Signaling ◽  
Tlr Agonists ◽  
Tlr7 Agonist

Abstract Background Past experiments studying innate immunity in the central nervous system (CNS) utilized microglia obtained from neonatal mouse brain, which differ developmentally from adult microglia. These differences might impact our current understanding of the role of microglia in CNS development, function, and disease. Methods Cytokine protein secretion was compared in ex vivo P3 and adult microglial cultures after exposure to agonists for three different toll-like receptors (TLR4, lipopolysaccharide [LPS]; TLR7, imiquimod [IMQ]; and TLR9, CpG Oligodeoxynucleotide [CpG-ODN] 1585). In addition, changes in inflammatory gene expression in ex vivo adult microglia in response to the TLR agonists was assessed. Furthermore, in vivo experiments evaluated changes in gene expression associated with inflammation and TLR signaling in brains of mice with or without treatment with PLX5622 to reduce microglia. Results Ex vivo adult and P3 microglia increased cytokine secretion when exposed to TLR4 agonist LPS and to TLR7 agonist IMQ. However, adult microglia decreased expression of numerous genes after exposure to TLR 9 agonist CpG-ODN 1585. In contrast, in vivo studies indicated a core group of inflammatory and TLR signaling genes increased when each of the TLR agonists was introduced into the CNS. Reducing microglia in the brain led to decreased expression of various inflammatory and TLR signaling genes. Mice with reduced microglia showed extreme impairment in upregulation of genes after exposure to TLR7 agonist IMQ. Conclusions Cultured adult microglia were more reactive than P3 microglia to LPS or IMQ exposure. In vivo results indicated microglial influences on neuroinflammation were agonist specific, with responses to TLR7 agonist IMQ more dysregulated in mice with reduced microglia. Thus, TLR7-mediated innate immune responses in the CNS appeared more dependent on the presence of microglia. Furthermore, partial responses to TLR4 and TLR9 agonists in mice with reduced microglia suggested other cell types in the CNS can compensate for their absence.

scholarly journals Integrative Transcriptomics Reveals Activation of Innate Immune Responses and Inhibition of Inflammation During Oral Immunotherapy for Egg Allergy in Children

2021 ◽  
Vol 12 ◽  
Author(s):  
Piia Karisola ◽  
Kati Palosuo ◽  
Victoria Hinkkanen ◽  
Lukas Wisgrill ◽  
Terhi Savinko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Oral Immunotherapy ◽  
Innate Immune ◽  
Egg Allergy ◽  
Innate Immune Responses ◽  
Open Label

We previously reported the results of a randomized, open-label trial of egg oral immunotherapy (OIT) in 50 children where 44% were desensitized and 46% were partially desensitized after 8 months of treatment. Here we focus on cell-mediated molecular mechanisms driving desensitization during egg OIT. We sought to determine whether changes in genome-wide gene expression in blood cells during egg OIT correlate with humoral responses and the clinical outcome. The blood cell transcriptome of 50 children receiving egg OIT was profiled using peripheral blood mononuclear cell (PBMC) samples obtained at baseline and after 3 and 8 months of OIT. We identified 467 differentially expressed genes (DEGs) after 3 or 8 months of egg OIT. At 8 months, 86% of the DEGs were downregulated and played a role in the signaling of TREM1, IL-6, and IL-17. In correlation analyses, Gal d 1–4-specific IgG4 antibodies associated positively with DEGs playing a role in pathogen recognition and antigen presentation and negatively with DEGs playing a role in the signaling of IL-10, IL-6, and IL-17. Desensitized and partially desensitized patients had differences in their antibody responses, and although most of the transcriptomic changes were shared, both groups had also specific patterns, which suggest slower changes in partially desensitized and activation of NK cells in the desensitized group. OIT for egg allergy in children inhibits inflammation and activates innate immune responses regardless of the clinical outcome at 8 months. Changes in gene expression patterns first appear as posttranslational protein modifications, followed by more sustained epigenetic gene regulatory functions related to successful desensitization.

scholarly journals Stereotyped and specific gene expression programs in human innate immune responses to bacteria

2002 ◽  
Vol 99 (2) ◽  
pp. 972-977 ◽  
Author(s):  
J. C. Boldrick ◽  
A. A. Alizadeh ◽  
M. Diehn ◽  
S. Dudoit ◽  
C. L. Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Innate Immune ◽  
Specific Gene ◽  
Innate Immune Responses ◽  
Specific Gene Expression

scholarly journals Profiles of Local and Systemic Inflammation in the Outcome of Treatment of Human Cutaneous Leishmaniasis Caused by Leishmania (Viannia)

2019 ◽  
Vol 88 (3) ◽  
Author(s):  
Adriana Navas ◽  
Olga Fernández ◽  
Carolina Gallego-Marín ◽  
María del Mar Castro ◽  
Mariana Rosales-Chilama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Treatment Failure ◽  
Cutaneous Leishmaniasis ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Neutrophil Activation ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Biopsy Specimens

ABSTRACT The immune mechanisms that contribute to the efficacy of treatment of cutaneous leishmaniasis (CL) are not fully understood. The aim of this study was to define immune correlates of the outcome of treatment of CL caused by Leishmania (Viannia) species during standard of care treatment with pentavalent antimonials. We conducted a comparative expression profiling of immune response genes in peripheral blood mononuclear cells (PBMCs) and lesion biopsy specimens obtained from CL patients before and at the end of treatment (EoT) with meglumine antimoniate. The ex vivo response of PBMCs to L. (V.) panamensis partially reflected that of lesion microenvironments. Significant downregulation of gene expression profiles consistent with local innate immune responses (monocyte and neutrophil activation and chemoattractant molecules) was observed at EoT in biopsy specimens of patients who cured (n = 8), compared to those from patients with treatment failure (n = 8). Among differentially expressed genes, pretreatment expression of CCL2 was significantly predictive of the therapeutic response (receiver operating characteristic [ROC] curve, area under the curve [AUC] = 0.82, P = 0.02). Polymorphisms in regulatory regions of the CCL2 promoter were analyzed in a pilot cohort of DNA samples from CL patients (cures, n = 20, and treatment failure, n = 20), showing putative association of polymorphisms rs13900(C/T) and rs2857656(G/C) with treatment outcome. Our data indicate that dampening gene expression profiles of monocyte and neutrophil activation characterize clinical cure after treatment of CL, supporting participation of parasite-sustained inflammation or deregulated innate immune responses in treatment failure.

scholarly journals High-Resolution Profiling of Innate Immune Responses by Porcine Dendritic Cell Subsets in vitro and in vivo

2020 ◽  
Vol 11 ◽  
Author(s):  
Gaël Auray ◽  
Stephanie C. Talker ◽  
Irene Keller ◽  
Sylvie Python ◽  
Markus Gerber ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
High Resolution ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Dendritic Cell Subsets

scholarly journals Innate Immune Responses of Skin Mucosa in Common Carp (Cyprinus Carpio) Fed a Diet Supplemented with Galactooligosaccharides

Animals ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 438 ◽  
Author(s):  
Elzbieta Pietrzak ◽  
Jan Mazurkiewicz ◽  
Anna Slawinska
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Common Carp ◽  
Geometric Mean ◽  
Juvenile Fish ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Immune Related Genes ◽  
The Impact ◽  
Skin Mucosa

Galactooligosaccharides (GOS) are well-known immunomodulatory prebiotics. We hypothesize that GOS supplemented in feed modulates innate immune responses in the skin-associated lymphoid tissue (SALT) of common carp. The aim of this study was to determine the impact of GOS on mRNA expression of the immune-related genes in skin mucosa. During the feeding trial, the juvenile fish (bodyweight 180 ± 5 g) were fed two types of diet for 50 days: control and supplemented with 2% GOS. At the end of the trial, a subset of fish was euthanized (n = 8). Skin mucosa was collected, and RNA was extracted. Gene expression analysis was performed with RT-qPCR to determine the mRNA abundance of the genes associated with innate immune responses in SALT, i.e., acute-phase protein (CRP), antimicrobial proteins (His2Av and GGGT5L), cytokines (IL1β, IL4, IL8, IL10, and IFNγ), lectin (CLEC4M), lyzosymes (LyzC and LyzG), mucin (M5ACL), peroxidase (MPO), proteases (CTSB and CTSD), and oxidoreductase (TXNL). The geometric mean of 40s s11 and ACTB was used to normalize the data. Relative quantification of the gene expression was calculated with ∆∆Ct. GOS upregulated INFγ (p ≤ 0.05) and LyzG (p ≤ 0.05), and downregulated CRP (p ≤ 0.01). We conclude that GOS modulates innate immune responses in the skin mucosa of common carp.

194 A Non-Gluten Component of Wheat is a Strong Stimulator of Innate Immune Responses In Vitro and In Vivo and Acts via Toll Like Receptor 4

2010 ◽  
Vol 138 (5) ◽  
pp. S-36
Author(s):  
Yvonne Junker ◽  
Donatella Barisani ◽  
Daniel A. Leffler ◽  
Towia Libermann ◽  
Simon T. Dillon ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy

2020 ◽  
Author(s):  
Yuxun Wang ◽  
Heping Yang ◽  
Huanping Li ◽  
Shuda Zhao ◽  
Yikun Zeng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Drug Targets ◽  
Ex Vivo ◽  
Single Agent ◽  
Cancer Drug ◽  
Phase I Clinical Trials ◽  
Tlr Agonists ◽  
Favorable Safety

ABSTRACTToll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. The selectivity profile distinguished DN052 from all other TLR agonists currently in clinical development. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase I clinical trials.

scholarly journals Pneumolysin is responsible for differential gene expression and modifications in the epigenetic landscape of primary monocyte derived macrophages

2020 ◽  
Author(s):  
J. Cole ◽  
A. Angyal ◽  
R. D. Emes ◽  
T.J. Mitchell ◽  
M.J. Dickman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Streptococcus Pneumoniae ◽  
Immune Responses ◽  
Epigenetic Modification ◽  
Transcriptional Response ◽  
Innate Immune ◽  
Global Changes ◽  
Innate Immune Responses ◽  
Transcriptional Responses ◽  
Tnf Α

AbstractEpigenetic modifications regulate gene expression in the host response to a diverse range of pathogens. The extent and consequences of epigenetic modification during macrophage responses to Streptococcus pneumoniae, and the role of pneumolysin, a key Streptococcus pneumoniae virulence factor, in influencing these responses, are currently unknown. To investigate this, we infected human monocyte derived macrophages (MDMs) with Streptococcus pneumoniae and addressed whether pneumolysin altered the epigenetic landscape and the associated acute macrophage transcriptional response using a combined transcriptomic and proteomic approach. Transcriptomic analysis identified 503 genes that were differentially expressed in a pneumolysin-dependent manner in these samples. Pathway analysis highlighted the involvement of transcriptional responses to core innate responses to pneumococci including modules associated with metabolic pathways activated in response to infection, oxidative stress responses and NFκB, NOD-like receptor and TNF signalling pathways. Quantitative proteomic analysis confirmed pneumolysin-regulated protein expression, early after bacterial challenge, in representative transcriptional modules associated with innate immune responses. In parallel, quantitative mass spectrometry identified global changes in the relative abundance of histone post translational modifications (PTMs) upon pneumococcal challenge. We identified an increase in the relative abundance of H3K4me1, H4K16ac and a decrease in H3K9me2 and H3K79me2 in a PLY-dependent fashion. We confirmed that pneumolysin blunted early transcriptional responses involving TNF-α and IL-6 expression. Vorinostat, a histone deacetylase inhibitor, similarly downregulated TNF production, reprising the pattern observed with pneumolysin. In conclusion, widespread changes in the macrophage transcriptional response are regulated by pneumolysin and are associated with global changes in histone PTMs. Modulating histone PTMs can reverse pneumolysin-associated transcriptional changes influencing innate immune responses, suggesting that epigenetic modification by pneumolysin plays a role in dampening the innate responses to pneumococci.Author summaryPneumolysin is a toxin that contributes to how Streptococcus pneumoniae, the leading cause of pneumonia, causes disease. In this study, the toxin alters gene expression in immune cells called macrophages, one of the first lines of defence against bacteria at sites of infection. Modulation involved multiple immune responses, including generation of chemical signals coordinating responses in immune cells termed cytokines. In addition, changes were observed in histone proteins that are involved in controlling gene expression in the cell. Pneumolysin reduced early production of the cytokine TNF-α and a medicine vorinostat that modifies these ‘epigenetic’ histone modifications had a similar affect, suggesting epigenetic mechanisms contribute to the ability of pneumolysin to reduce immune responses.

scholarly journals SARS-CoV-2 Impairs Dendritic Cells and Regulates DC-SIGN Gene Expression in Tissues

2021 ◽  
Vol 22 (17) ◽  
pp. 9228
Author(s):  
Guoshuai Cai ◽  
Mulong Du ◽  
Yohan Bossé ◽  
Helmut Albrecht ◽  
Fei Qin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Single Cell ◽  
Upper Airway ◽  
Innate Immune ◽  
Healthy Controls ◽  
Innate Immune Responses ◽  
Current Spreading ◽  
Plasmacytoid Dcs

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22+ or ANXA1+ DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.

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