Modulation Of Innate Immune System Research Articles

Whole-genome DNA methylation profiling revealed epigenetic regulation of NF-κB signaling pathway involved in response to Vibrio alginolyticus infection in the Pacific oyster, Crassostrea gigas

DNA methylation, an essential epigenetic alteration, is tightly linked to a variety of biological processes, such as immune response. To identify the epigenetic regulatory mechanism in Pacific oyster (Crassostrea gigas), whole-genome bisulfite sequencing (WGBS) was conducted on C. gigas at 0 h, 6 h, and 48 h after infection with Vibrio alginolyticus. At 6 h and 48 h, a total of 11,502 and 14,196 differentially methylated regions (DMRs) were identified (p<0.05, FDR<0.001) compared to 0 h, respectively. Gene ontology (GO) analysis showed that differentially methylated genes (DMGs) were significantly enriched in various biological pathways including immunity, cytoskeleton, epigenetic modification, and metabolic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that transcription machinery (ko03021) is one of the most important pathways. Integrated transcriptome and methylome analyses allowed the identification of 167 and 379 DMG-related DEGs at 6 h and 48 h, respectively. These genes were significantly enriched in immune-related pathways, including nuclear factor kappa B (NF-κB) signaling pathway (ko04064) and tumor necrosis factor (TNF) signaling pathway (ko04668). Interestingly, it's observed that the NF-κB pathway could be activated jointly by TNF Receptor Associated Factor 2 (TRAF2) and Baculoviral IAP Repeat Containing 3 (BIRC3, the homolog of human BIRC2) which were regulated by DNA methylation in response to the challenge posed by V. alginolyticus infection. Through this study, we provided insightful information about the epigenetic regulation of immunity-related genes in the C. gigas, which will be valuable for the understanding of the innate immune system modulation and defense mechanism against bacterial infection in invertebrates.

Innate Immunomodulatory Nanodevices for Cancer Therapy: A Review.

The newly emerged cancer immunotherapy has shown a great potential in clinical trials. However, most immunotherapeutic strategies focus on restoring and/or enhancing the effector T cell responses, and only a small portion of malignancies respond favorably due to the lacking of T cell infiltration. Recently, the modulation of innate immune system has been applied as an alternative or combined strategy to improve host anti-tumor immunity. In this review, we summarize recent progress in nanotechnology-based innate immunomodulation for cancer therapy. Firstly, we present various types of nanodevices that serve to deliver or mimic the reactions of pathogen-associated molecular patterns (PAMPs), such as bacterial components, viral DNA or viral RNA, for the stimulation of type I interferons (IFNs) and pro-inflammatory cytokines. We also introduce nanodevice-mediated immunogenic cell death (ICD) for the generation of endogenous danger-associated molecular patterns (DAMPs) and improvement of immune responses. Moreover, targeted manipulation of specific types of innate immune cells by nanodevices are discussed. Lastly, we describe typical strategies of combining innate immunomodulatory nanodevices with immune checkpoint blockade to amplify the anti-tumor efficacy.

Probiotics, Prebiotics and Synbiotics for Nile tilapia: Growth performance and protection against Aeromonas hydrophila infection

The use of probiotics, prebiotics and synbiotics provides better growth rates, improves the innate immune system and protection against several bacterial pathogens. The species Aeromonas hydrophila causes high mortality rate and production loss, provoking an antimicrobial overuse. This study aimed to prove the capacity of commercial probiotic DBA® (Bifidobacterium sp, Lactobacillus acidophilus and Enterococcus faecium), prebiotics MOS and chitosan, combined as synbiotics or not to promote Nile tilapia growth performance, innate immune system modulation and protection against A. hydrophila. One experiment with 24 units, duration of 63 days, and another experiment infection assay with A. hydrophila (18 experimental units, individual recirculation system, duration of 15 days) were performed. The treatments were: control, probiotic DBA (PRO), the prebiotics mannan oligosaccharides (Actigen®) (MOS) and chitosan (CHI), and the synbiotics composed of probiotic and MOS (Actigen®) (PRO + MOS), probiotic and chitosan (PRO + CHI). Growth performance, hematology, intestinal histology and immunology, and relative protection level against A. hydrophila were analyzed. Significant differences were observed in the final biomass for the treatments PRO + CHI and CHI when compared with PRO + MOS, and greater individual weight gain in group PRO + CHI in relation to group PRO + MOS. High concentrations of Lactobacillus spp. in intestinal tract of probiotics, prebiotics and symbiotics groups were observed. The treatments PRO + MOS, PRO + CHI and PRO promoted apparent preservation of the intestinal epithelium and stimulated an increase in goblet cells, blood vessels and mast cells, associated to immune system. The symbiotics MOS and DBA® promoted better relative protection level with percentage of 40%. This study recommends the use of probiotics, prebiotics and synbiotics to improve the protection against A. hydrophila infection without growth reduction. Inclusion of feed additives may reduce the application of antimicrobials in fish farming.

The Role of Innate Immunity in Dystrophic Diaphragm Pathology

The pathophysiology of Duchenne muscular dystrophy (DMD) is complex and incompletely understood. However it is clear that the primary defect, lack of dystrophin, is necessary but not sufficient on its own to fully account for the onset of muscle fiber destruction, leading to eventual replacement by fibrotic tissue. Dystrophin restoration strategies are currently under clinical development, but the only treatment clearly shown to slow disease progression thus far in human DMD patients is the use of anti‐inflammatory corticosteroids. This presentation will focus on the role of the innate immune system in promoting the dysregulated inflammatory and aberrant muscle repair responses found in DMD. Using the mdx mouse diaphragm as a preclinical model due to its resemblance to the human DMD phenotype, the importance of monocyte‐derived macrophages in driving early disease progression will be outlined. This is exemplified by the therapeutic benefits (improved force generation and reduced fibrosis) noted when monocyte/macrophage recruitment to the dystrophic diaphragm is prevented through genetic or pharmacologic inhibition of the chemokine receptor CCR2. In addition, preventing activation of Toll‐like receptors (TLRs) is similarly beneficial and suggests significant involvement of damage‐associated molecular patterns (DAMPs) in DMD pathogenesis. Data will also be presented indicating that epigenetic alterations occur at the level of macrophage precursors in the bone marrow, which are likely stimulated by TLR4 recognition of DAMPs, and that subsequently play a role in dictating monocyte/macrophage phenotypic characteristics following their entry into the diseased muscles. Although the ideal treatment for DMD would be restoration of dystrophin to all muscles of the body including the diaphragm, significant hurdles remain for this ultimate therapy. In the meanwhile, there are serious drawbacks to the current practice of treating DMD children with corticosteroids, which have major side effects in DMD such as obesity, diabetes and osteoporosis. Future development of a more targeted therapeutic approach based on innate immune system modulation could represent an important advance in the field.Support or Funding InformationCanadian Institutes of Health Research

Innate immune responses to paraquat exposure in a Drosophila model of Parkinson\u2019s disease

Parkinson’s disease (PD) is a progressive, neurodegenerative movement disorder characterized by the loss of dopaminergic (DA) neurons. Limited understanding of the early molecular pathways associated with the demise of DA neurons, including those of inflammatory exacerbation of neurodegeneration, is a major impediment to therapeutic development. Recent studies have implicated gene-environment interactions in PD susceptibility. We used transcriptomic profiling in a Drosophila PD model in response to paraquat (PQ)-induced oxidative stress to identify pre-symptomatic signatures of impending neuron dysfunction. Our RNAseq data analysis revealed extensive regulation of innate immune response genes following PQ ingestion. We found that PQ exposure leads to the activation of the NF-κB transcription factor, Relish, and the stress signaling factor JNK, encoded by the gene basket in Drosophila. Relish knockdown in the dopaminergic neurons confers PQ resistance and rescues mobility defects and DA neuron loss. Furthermore, PQ-induced toxicity is mediated through the immune deficiency signaling pathway. Surprisingly, the expression of Relish-dependent anti-microbial peptide (AMPs) genes is suppressed upon PQ exposure causing increased sensitivity to Gram-negative bacterial infection. This work provides a novel link between PQ exposure and innate immune system modulation underlying environmental toxin-induced neurodegeneration, thereby underscoring the role of the innate immune system in PD pathogenesis.

Ethanol Consumption and Innate Neuroimmunity

Emerging researches from human and animal models have shown the role of ethanol in innate immune system modulation, particularly in the central nervous system. The activation of receptors of the innate immunity, Toll-like receptors and nucleotide- binding oligomerization domain-like (NOD-like) receptors, triggers the signaling pathways that bring to the production of pro-inflammatory cytokines and chemokines, which, in turn, provokes neuroinflammation and neural damage. The neuroimmune system response to ethanol intake, in specific brain regions such as amygdala, hippocampus and frontal cortex, is involved in addiction and in behavioural deficits observed in alcoholism. In murine models, the knockout for Toll-like or NODlike receptors abolishes most of the effects of ethanol on the immune system and preserves these mice from neural damage, neuroinflammation and alcohol dependence. Molecular targeting of immune system pathways is a new and promising area of research for the discovery of new biomarkers for neuroinflammation and for the development of novel pharmacotherapies in order to treat neurological and behavioural consequences of ethanol addiction. Biomed Rev 2017; 28: 49-61. Keywords: ethanol addiction, neuroinflammation, neuroimmunity, Toll-like receptors, NOD-like receptors, inflammasomes

Current Management of Alcoholic Hepatitis and Future Therapies

Alcohol is one of the most common etiologies of liver disease, and alcoholic liver disease overall is the second most common indication for liver transplantation in the United States. It encompasses a spectrum of disease, including fatty liver disease, alcoholic hepatitis (AH), and alcoholic cirrhosis. AH can range from mild to severe disease, with severe disease being defined as: Discriminant Function (DF) ≥ 32, or Model for End-stage Liver Disease (MELD) ≥ 21, or presence of hepatic encephalopathy. Management of the mild disease consists mainly of abstinence and supportive care. Severe AH is associated with significant mortality. Currently, there is no ideal medical treatment for this condition. Besides alcohol cessation, corticosteroids have been used with conflicting results and are associated with an inherent risk of infection. Overall steroids have shown short term benefit when compared to placebo, but they have no obvious long term benefits. Pentoxifylline does not improve survival in patients with severe AH and is no longer recommended based on the results of the STOPAH (Steroid Or Pentoxifylline for Alcoholic Hepatitis) trial. Anti-tumor necrosis factor (TNF) agents are associated with increased risk of life threatening infections and death. Currently, early stage trials are underway, mainly targeting novel pathways based on disease pathogenesis, including modulation of innate immune system, inhibition of gut-liver axis and cell death pathways, and activation of transcription factor farnesyl X receptor (FXR). Future treatment may lie in human induced pluripotent stem cell (iPSC) technology, which is currently under investigation for the study of pathogenesis, drug discovery, and stem cell transplantation. Liver transplantation has been reported with good results in highly selected patients but is controversial due to limited organ supply.

Innate immune system modulation and disease resistance in Eurasian perch fed contrasted LC-PUFA dietary contents

Geay F., Mellery J., Tinti E., Douxfils J., Larondelle, Y., Mandiki S.N.M. and Kestemont P. a Research Unit in Environmental and Evolutionary Biology (URBE), University of Namur (UNamur), Rue de Bruxelles, 61, 5000 Namur, Belgium b Life Science Institute, Catholic University of Louvain (UCL), Croix du Sud, 2/L7.05.08, 1348 Louvain-la-Neuve, Belgium c Unite de Chimie Physique Theorique et Structurale, University of Namur (UNamur), Rue de Bruxelles 61, 5000 Namur, Belgium * Corresponding author. Tel: +32 (0)81 724 363. Email address: patrick.kestemont@unamur.be

Synergism of PI3K/Akt inhibition and Fas activation on colon cancer cell death

Fas and PI3K/Akt signaling pathways pivotally impact on cancer cell death and survival respectively and are considered as promising targets for innovative anticancer therapies. To better characterize the combination effect of PI3K/Akt inhibitors and Fas agonists and understand the profile of the interaction between PI3K/Akt and Fas signaling, we qualitatively and quantitatively evaluated the combination effect of PI3K/Akt inhibitors LY294002, Akt inhibitor VIII and FasL. At the concentration that can block cell cycle progression and DNA synthesis but not elicit apoptosis, these inhibitors potentiate FasL to induce apoptosis. At higher concentrations, when the PI3K/Akt inhibitors induce apoptosis, they synergize FasL to induce apoptosis. In addition, PI3K/Akt inhibition significantly facilitates the Fas-mediated apoptotic signaling. Understanding the combination effects between PI3K/Akt inhibition and Fas activation not only leads to rational design of effective combination therapy of PI3K/Akt inhibitors but also improve our knowledge about the impact of PI3K-Akt pathway on Fas signaling and the potential modulation of innate immune system by PI3K-Akt-targeting drugs in anticancer treatment.

Sequence, Phylogenetic and Homology Analysis of Toll-Like Receptor Gene TLR7 in Bos indicus from High Altitude Areas of Uttarakhand State, India

Toll-like receptors (TLRs) play a significant role in the modulation of innate immune system, and till date 10 TLR genes have been identified in bovines. TLR3, TLR7, TLR8, and TLR9 recognize pathogen-associated molecular patterns specific to viruses. The foremost aim of this work was to characterize the TLR7 gene, which mainly recognizes the ssRNA viruses. The complete ORF of the TLR7 gene (3.17 kb) was amplified, cloned and sequenced for analysis from local non-descript cattle (Bos indicus) reared in high altitude areas of temperate western Himalayan region. It revealed 98.9–99.6 % amino acid sequence identity with different breeds of cattle, and 87.1–98.9 % identity with other species (bubaline, equine, swine, ovine). Phylogenetic analysis of the hill cattle TLR7 showed clustering of sequences in a group and nearest common ancestry with bubaline (Bubalus bubalis; Murrah buffalo). Homology prediction of hill cattle TLR7 revealed highly conserved horseshoe shaped solenoid structure as found in other TLR structures. The structure consisted of 25 parallel β-strands, perpendicular to the solenoid axis and connected to each other by intervening loops. The hill cattle TLR7 showed unique substitutions at three amino acid positions compared to any other cattle breeds viz. Sahiwal, Red Sindhi, Gir, Kankrej, Hariana (K687 → Q, S731 → P, and Y890 → H). The substitution, S731 → P appeared to be critical, as the amino acid proline is involved in the formation of hinge or kink in a protein molecule.

Glycoinositolphospholipids from Leishmania braziliensis and L. infantum: Modulation of Innate Immune System and Variations in Carbohydrate Structure

The essential role of the lipophosphoglycan (LPG) of Leishmania in innate immune response has been extensively reported. However, information about the role of the LPG-related glycoinositolphospholipids (GIPLs) is limited, especially with respect to the New World species of Leishmania. GIPLs are low molecular weight molecules covering the parasite surface and are similar to LPG in sharing a common lipid backbone and a glycan motif containing up to 7 sugars. Critical aspects of their structure and functions are still obscure in the interaction with the vertebrate host. In this study, we evaluated the role of those molecules in two medically important South American species Leishmania infantum and L. braziliensis, causative agents of visceral (VL) and cutaneous Leishmaniasis (CL), respectively. GIPLs derived from both species did not induce NO or TNF-α production by non-primed murine macrophages. Additionally, primed macrophages from mice (BALB/c, C57BL/6, TLR2−/− and TLR4−/−) exposed to GIPLs from both species, with exception to TNF-α, did not produce any of the cytokines analyzed (IL1-β, IL-2, IL-4, IL-5, IL-10, IL-12p40, IFN-γ) or p38 activation. GIPLs induced the production of TNF-α and NO by C57BL/6 mice, primarily via TLR4. Pre incubation of macrophages with GIPLs reduced significantly the amount of NO and IL-12 in the presence of IFN-γ or lipopolysaccharide (LPS), which was more pronounced with L. braziliensis GIPLs. This inhibition was reversed after PI-specific phospholipase C treatment. A structural analysis of the GIPLs showed that L. infantum has manose rich GIPLs, suggestive of type I and Hybrid GIPLs while L. braziliensis has galactose rich GIPLs, suggestive of Type II GIPLs. In conclusion, there are major differences in the structure and composition of GIPLs from L. braziliensis and L. infantum. Also, GIPLs are important inhibitory molecules during the interaction with macrophages.

Allergen immunotherapy

To provide a historical perspective on the development of allergen immunotherapy and to describe the progress that has been made in both the clinical application and the scientific understanding of this therapeutic technique in the 100 years since its inception. Although allergen immunotherapy has been part of allergy practice for a century, it is only in relatively recent years that the cellular and molecular mechanisms which underlie its clinical efficacy have been elucidated. Most recent studies implicate the T-regulatory cell response as central to the development of a tolerogenic state in response to allergen immunotherapy, with both IL-10 and TGF-β playing crucial roles in the development of this cell subset. The clinical application of immunotherapy continues to advance, with promising contemporary studies noting improved safety and efficacy with pretreatment using omalizumab prior to an immunotherapy program as well as the potential for innate immune system modulation with allergen conjugates which can stimulate pattern recognition receptors such as the toll-like receptors. After 100 years of clinical application, allergen immunotherapy remains the only treatment modality with the potential for long-term immunologic amelioration of atopic diseases. Future treatment advances in allergen immunotherapy will likely harness the increasing power of molecular and genomic medicine to achieve greater allergen specificity, while improving overall efficacy and minimizing the potential for systemic reactions.

Innate Immune System Modulation During Aging: Contributions of Macrophages and Dendritic Cells

Innate Immune System Modulation During Aging: Contributions of Macrophages and Dendritic Cells

Innovative Immune-Based Therapeutic Approaches for the Treatment of Type 1 Diabetes Mellitus

Type 1 diabetes mellitus is an autoimmune disease caused by a culmination of noxious processes of autoimmunity composed of various components of the innate and adaptive immune systems. Current treatment of type 1 diabetes focuses on restraining the endocrine disease without affecting the autoimmune process that underlies it. Prevention of this disease requires immune modulation and early intervention. New therapeutic approaches can be classified on the basis of the immunological arm targeted, that is, T-cell immune modulation (using cytokines, anti-CD3 monoclonal antibodies, and peptide MHC class II dimers), innate immune system modulation (using alpha-galactosylceramide or peptide 277), or specific antigen vaccination (glutamic acid decarboxylase and insulin). Here we review the most promising therapies developed based on these targets and emphasize those that have reached human phase clinical investigation.