HIV-1-exposed seronegative individuals show alteration in TLR expression and pro-inflammatory cytokine production ex vivo: An innate immune quiescence status?

AbstractIntroductionThough antiretroviral therapy has led to viral suppression and increased quality of life for patients living with HIV-1, strategies to eliminate the HIV-1 latent reservoir are still necessary to eliminate HIV. Latency reversal with superior latency reversal agents (LRAs) such as protein kinase C (PKC) agonists is a promising strategy for unveiling and eliminating the latent HIV-1 reservoir. However, PKC agonists induce T cell activation and deleterious pro- inflammatory cytokine production. Secondary pharmacological agents combined with LRAs have been previously shown to reduce deleterious pro-inflammatory cytokine secretion without inhibiting HIV-1 viral reactivation. Histone deacetylase inhibitors (HDACi) are also known for inhibiting deleterious pro-inflammatory cytokines in the context of graft-versus-host disease and rheumatoid arthritis in addition to being known to synergize with PKC agonists. In this study we investigated whether HDACi and other epigenetic modifiers could decrease PKC- induced pro-inflammatory cytokines secretion while simultaneously synergizing with the PKC agonists Ingenol-3,20-dibenzoate, to enhance latency reversal.MethodsWe screened an epigenetic modifier library in health donor human peripheral blood mononuclear cells (PBMCs) to identify compounds (‘hits’) that reduced intracellular IL-6 pro-inflammatory cytokine production induced by PKC agonist Ingenol-3,20-dibenzoate. We then further tested reducers of intracellular IL-6 (‘hits’) for their ability to synergize with Ingenol-3,20-dibenzoate in the J-LAT 10.6 model of HIV-1 latency. The most promising epigenetic modifier from both screens, the HDACi Panobinostat, was then further tested for its ability to reduce pro-inflammatory cytokines and synergize with Ingenol-3,20-dibenzoate.ResultsWe show that co-treatment with Ingenol-3,20-dibenzoate and Panobinostat reduces pro-inflammatory cytokines and enhances latency reversal in vitro. Panobinostat suppressed pro-inflammatory cytokine production when combined with Ingenol-3,20- dibenzoate ex vivo when using aviremic patient cells, but antagonized Ingenol-3,20-dibenzoate dependent latency reversal ex vivo.ConclusionThe combination of Panobinostat and Ingenol-3,20-dibenzoate reduces deleterious cytokine production but is not a suitable latency reversal combination therapy.

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Glutathione Metabolism Contributes to the Induction of Trained Immunity

Cells ◽

10.3390/cells10050971 ◽

2021 ◽

Vol 10 (5) ◽

pp. 971

Author(s):

Anaisa V. Ferreira ◽

Valerie A.C.M. Koeken ◽

Vasiliki Matzaraki ◽

Sarantos Kostidis ◽

Juan Carlos Alarcon-Barrera ◽

...

Keyword(s):

Inflammatory Cytokine ◽

Cytokine Production ◽

Ex Vivo ◽

Production Capacity ◽

Innate Immune ◽

Glutathione Metabolism ◽

Nucleotide Polymorphisms ◽

Inflammatory Cytokine Production ◽

Trained Immunity

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.

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Advancing nutritional therapy: A novel polymeric formulation attenuates intestinal inflammation in a murine colitis model and suppresses pro-inflammatory cytokine production in ex-vivo cultured inflamed colonic biopsies

Clinical Nutrition ◽

10.1016/j.clnu.2016.01.010 ◽

2017 ◽

Vol 36 (2) ◽

pp. 497-505 ◽

Cited By ~ 10

Author(s):

Moftah H. Alhagamhmad ◽

Daniel A. Lemberg ◽

Andrew S. Day ◽

Li-Zsa Tan ◽

Chee Y. Ooi ◽

...

Keyword(s):

Inflammatory Cytokine ◽

Cytokine Production ◽

Intestinal Inflammation ◽

Ex Vivo ◽

Nutritional Therapy ◽

Inflammatory Cytokine Production ◽

Murine Colitis ◽

Colonic Biopsies ◽

Colitis Model ◽

Polymeric Formulation

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PWE-074 Tissue Inhibitor Of Metalloproteinase (timp)-3 Reduces Pro-inflammatory Cytokine Production By Ulcerative Colitis Mucosa Cultured Ex Vivo

Gut ◽

10.1136/gutjnl-2014-307263.334 ◽

2014 ◽

Vol 63 (Suppl 1) ◽

pp. A156.1-A156

Author(s):

IM Bell ◽

F Ammoscato ◽

P Biancheri ◽

R Curciarello ◽

T Macdonald

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Ex Vivo ◽

Tissue Inhibitor Of Metalloproteinase ◽

Tissue Inhibitor ◽

Inflammatory Cytokine Production

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Abstract 17107: Distribution of Anti-inflammatory Activity During Remodeling of High Density Lipoprotein: Studies With CSL112

Circulation ◽

10.1161/circ.132.suppl_3.17107 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Svetlana A Diditchenko ◽

Alexei V Navdaev ◽

Martin O Spycher ◽

Samuel D Wright

Keyword(s):

Cholesterol Efflux ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Ex Vivo ◽

Negative Regulator ◽

Inflammatory Activity ◽

Inhibitory Effects ◽

Inflammatory Cytokine Production ◽

Coronary Syndrome ◽

Anti Inflammatory

Elevated levels of circulating inflammatory markers predict an unfavorable cardiovascular outcome in acute coronary syndrome patients. CSL112 is human apolipoprotein A-I (apoA-I), reconstituted with phosphatidylcholine to form HDL particles suitable for infusion. Addition of CSL112 to stimulated human whole blood ex vivo strongly reduces pro-inflammatory cytokine production. Infusion of CSL112 into human subjects or addition to human plasma ex vivo causes remodeling of endogenous HDL. Similar remodeling occurs upon incubation of CSL112 with purified HDL3 and results in accumulation of three HDL species: enlarged HDL (HDL2), a smaller, dense species (HDL3c), and lipid-poor apoA-I (pre-β1 HDL). Study aim was to determine the anti-inflammatory activity of remodeled HDL species. CSL112 was incubated with HDL3 and the products of particle remodeling were purified by ultracentrifugation. The inhibitory effects on pro-inflammatory cytokine production were examined using human peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin-M (PHA-M) in vitro. Lipid-poor apoA-I, HDL3c as well as parent CSL112 exerted powerful inhibitory effects on secretion of pro-inflammatory mediators (> 89.2% + 4.0% inhibition of TNF-α, IL-1β, IL-6 and Mip-1β); HDL3 and HDL2 were much less effective (< 54.1% + 3.9% inhibition). The extent of inhibition correlated positively with induction of the transcription repressor ATF3, a negative regulator of pro-inflammatory cytokine production, with lipid-poor apoA-I and HDL3c inducing higher protein levels of ATF3 in PHA-stimulated PBMC compared to control medium, HDL3 or HDL2. Anti-inflammatory activity of the remodeled species also correlated with their ability to support cellular cholesterol efflux via the ABCA1 transporter: lipid-poor apoA-I and HDL3c were potent acceptors of cholesterol; HDL2 was inactive. The ability to generate HDL species with high cholesterol efflux and anti-inflammatory activity makes CSL112 a promising candidate for removing cholesterol and reducing inflammation in atherosclerotic plaque, thus reducing the high risk of early recurrent atherothrombotic events following acute MI (AMI). A Phase IIb trial (AEGIS-I; NCT02108262) of CSL112 in AMI patients is ongoing.

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