scholarly journals C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

2021 ◽  
Vol 22 (18) ◽  
pp. 9912
Author(s):  
Jacquelyn C. Serfecz ◽  
Afsoon Saadin ◽  
Clayton P. Santiago ◽  
Yuji Zhang ◽  
Søren M. Bentzen ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Responses ◽  
Gene Array ◽  
Induced Pluripotent Stem Cell ◽  
Autosomal Recessive Disorder ◽  
Novel Therapy ◽  
Complement Inhibitors ◽  
Expression Of Genes ◽  
Tnf Α ◽  
Induced Pluripotent

Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8–10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD.

scholarly journals ACVR1R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages

Bone ◽  
2021 ◽  
pp. 116129
Author(s):  
Koji Matsuo ◽  
Abigail Lepinski ◽  
Robert D. Chavez ◽  
Emilie Barruet ◽  
Ashley Pereira ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Inflammatory Responses ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation

2020 ◽  
Vol 6 (46) ◽  
pp. eabc1428
Author(s):  
A. Nakano-Kobayashi ◽  
A. Fukumoto ◽  
A. Morizane ◽  
D. T. Nguyen ◽  
T. M. Le ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Neuronal Survival ◽  
Disease Model ◽  
Neuronal Loss ◽  
Induced Pluripotent Stem Cell ◽  
Related Factor ◽  
Induced Pluripotent ◽  
Novel Therapeutic

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

scholarly journals Oral Mucosal Endotoxin Tolerance Induction in Chronic Periodontitis

2005 ◽  
Vol 73 (2) ◽  
pp. 687-694 ◽  
Author(s):  
Manoj Muthukuru ◽  
Ravi Jotwani ◽  
Christopher W. Cutler
Keyword(s):  
Immune Response ◽  
Oral Mucosa ◽  
Chronic Periodontitis ◽  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Endotoxin Tolerance ◽  
Necrosis Factor Alpha ◽  
Initial Stimulus ◽  
Tlr4 Mrna ◽  
Tnf Α

ABSTRACT The oral mucosa is exposed to a high density and diversity of gram-positive and gram-negative bacteria, but very little is known about how immune homeostasis is maintained in this environment, particularly in the inflammatory disease chronic periodontitis (CP). The cells of the innate immune response recognize bacterial structures via the Toll-like receptors (TLR). This activates intracellular signaling and transcription of proteins essential for the induction of an adaptive immune response; however, if unregulated, it can lead to destructive inflammatory responses. Using single-immunoenzyme labeling, we show that the human oral mucosa (gingiva) is infiltrated by large numbers of TLR2+ and TLR4+ cells and that their numbers increase significantly in CP, relative to health (P < 0.05, Student's t test). We also show that the numbers of TLR2+ but not TLR4+ cells increase linearly with inflammation (r 2 = 0.33, P < 0.05). Double-immunofluorescence analysis confirms that TLR2 is coexpressed by monocytes (MC)/macrophages (mφ) in situ. Further analysis of gingival tissues by quantitative real-time PCR, however, indicates that despite a threefold increase in the expression of interleukin-1β (IL-1β) mRNA during CP, there is significant (30-fold) downregulation of TLR2 mRNA (P < 0.05, Student's t test). Also showing similar trends are the levels of TLR4 (ninefold reduction), TLR5 (twofold reduction), and MD-2 (sevenfold reduction) mRNA in CP patients compared to healthy persons, while the level of CD14 was unchanged. In vitro studies with human MC indicate that MC respond to an initial stimulus of lipopolysaccharide (LPS) from Porphyromonas gingivalis (PgLPS) or Escherichia coli (EcLPS) by upregulation of TLR2 and TLR4 mRNA and protein; moreover, IL-1β mRNA is induced and tumor necrosis factor alpha (TNF-α), IL-10, IL-6, and IL-8 proteins are secreted. However, restimulation of MC with either PgLPS or EcLPS downregulates TLR2 and TLR4 mRNA and protein and IL-1β mRNA and induces a ca. 10-fold reduction in TNF-α secretion, suggesting the induction of endotoxin tolerance by either LPS. Less susceptible to tolerance than TNF-α were IL-6, IL-10, and IL-8. These studies suggest that certain components of the innate oral mucosal immune response, most notably TLRs and inflammatory cytokines, may become tolerized during sustained exposure to bacterial structures such as LPS and that this may be one mechanism used in the oral mucosa to attempt to regulate local immune responses.

Differential modulation of innate immune response by epinephrine and estradiol

2017 ◽  
Vol 30 (3) ◽  
Author(s):  
Sona Margaryan ◽  
Armenuhi Hyusyan ◽  
Anush Martirosyan ◽  
Shushan Sargsian ◽  
Gayane Manukyan
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Dependent Manner ◽  
Induced Expression ◽  
Short Term Exposure ◽  
Tnf Α ◽  
Vitro Effect ◽  
Dose Dependent

AbstractBackgroundAlthough it is widely accepted that catecholamines and estrogens influence immunity and have consequences for health, their effect on innate immunity (e.g. monocytes and neutrophils) is still not fully investigated.Materials and methodsOur study aimed to analyze the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1 and IL-8 by whole blood cells following short-term exposure to epinephrine (Epi) and 17β-estradiol (E2) in the presence or absence of lipopolysaccharide (LPS). We also evaluated the in vitro effect of these hormones on expression of β2 integrin (CD11b/CD18) and L-selectin (CD62L) by circulating neutrophils and monocytes in the blood of healthy subjects.ResultsEpi has shown a potential to modulate the production of pro-inflammatory mediators. Its exposure resulted in significantly increased production of IL-8 in a dose-dependent manner. On the contrary, a dose-dependent suppression of LPS-induced production of IL-1β, IL-8, and MCP-1 by Epi was observed. In neutrophils, a modest rise in CD11b expression was observed after Epi exposure. Simultaneously, Epi suppressed LPS-induced expression of CD11b and CD18. In monocytes, Epi suppressed LPS-induced expression of C11b. E2 inhibited LPS-induced TNF-α production and caused a significant decrease in CD62L expression in both cell populations. No significant changes were observed after double exposure of cells with Epi and E2.ConclusionsThus, our results show that Epi and E2 differentially modulate the innate immune response and have a dual effect on cytokine modulation. The findings suggest that the observed immunoregulatory role of Epi and E2 may influence the outcome in endotoxin responses and can be critical in the regulation of inflammatory responses.

P5746Human induced pluripotent stem cell-derived mesenchymal stem cell therapy effectively reduced brain infarct volume and preserved neurological function in rat after acute intracranial hemorrhage

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y C Li ◽  
F Y Lee ◽  
S Chua ◽  
H K Yip
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Neurological Function ◽  
Opposite Pattern ◽  
Group 4 ◽  
Tnf Α ◽  
Group 3 ◽  
Group 2 ◽  
Induced Pluripotent

Abstract Intracerebral hemorrhage (ICH) causes 10%-20% of all strokes and results in higher morbidity compared to other subtypes of cerebral stroke. Although early surgical intervention can clear the expanding hematoma, clinical outcomes following ICH have not significantly improved over the decades. Since ICH elicits neuroinflammation to exacerbate brain edema, damage the blood-brain barrier (BBB), lead to secondary neuronal injury, anti-inflammation may be a critical therapeutic strategy. Mesenchymal stem cell (MSC) therapy processes anti-inflammatory, immunomodulatory and tissue regenerative properties, suggesting that MSC therapy could be an effective therapy for ICH. Therefore, this study tested the hypothesis that human induced pluripotent stem cell-derived mesenchymal stem cell (iPSC-MSC) therapy could effectively reduce brain-infract volume (BIV) and improve neurological function in rat after acute ICH induced by a weight-drop device. Adult-male SD rats (n=40) were equally divided into group 1 (sham-operated control), group 2 (ICH), group 3 (ICH + hyaluronic acid (HA)/intracranial injection/3h after ICH), group 4 [ICH + HA + iPSC-MSC (1.2x106 cells/intracranial injection/3h after ICH)] and euthanized by day 28 after ICH procedure. In vitro study showed that hemorrhagic-brain tissue augmented protein expressions of inflammation (HMGB1/MyD88/TLR-4/TLR-2/NF-κB/TNF-α/iNOS/IL-1β) in cultured neurons that were significantly inhibited by iPSC-MSC treatment (all p<0.001). By days 7/14 after ICH procedure, circulating inflammatory levels of TNF-α/IL-6/MPO expressed were lowest in group 1, highest in group 2 and significantly lower in group 4 than in group 3 (all p<0.0001). By day 14 after ICH procedure, neurological function and BIV expressed an opposite pattern, whereas protein expressions of inflammation (HMGB1/MyD88/TLR-4/TLR-2/NF-κB/I-kB/TNF-α/iNOS/IL-1β/MMP-9), oxidative stress (NOX-1/NOX-2/oxidized protein) and apoptosis (mitochondrial-Bax/cleaved-caspase-2/PARP) in brain exhibited an identical pattern to circulating inflammation among the four groups (all p<0.001). Microscopy demonstrated that the number of vascular remodeling/GFAP+/53BP1+/γ-H2AX+ cells displayed an identical pattern of inflammation, whereas the NeuN+ cells displayed an opposite pattern of inflammation among the four groups (all p<0.001). In conclusion, iPSC-MSC therapy markedly reduced BIV and preserved neurological function mainly by inhibiting inflammatory/oxidative-stress generation. Acknowledgement/Funding Kaohsiung Chang Gung Memorial Hospital, Taiwan Society of Stem Cell Research

Lactobacillus plantarum IS-10506 supplementation increases faecal sIgA and immune response in children younger than two years

2019 ◽  
Vol 10 (3) ◽  
pp. 245-252 ◽  
Author(s):  
P.D. Kusumo ◽  
B. Bela ◽  
H. Wibowo ◽  
Z. Munasir ◽  
I.S. Surono
Keyword(s):  
Immune Response ◽  
Young Children ◽  
Lactobacillus Plantarum ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Enzyme Linked Immunosorbent Assay ◽  
Treatment Groups ◽  
Tnf Α ◽  
Intestinal Immune System ◽  
Tgf Β1

The immature intestinal immune system in young children develops as it comes into contact with dietary and microbial antigens in the gut. Intestinal microbiota plays a significant role in host defence mechanisms as shown by inflammatory responses towards potential pathogens. We investigated the probiotic function of Lactobacillus plantarum IS-10506 of ‘dadih’ origin in modulating immune response in young children. We aimed to assess its effect on their immune response by assessing transforming growth factor-β1 (TGF-β1) and tumour necrosis factor-α (TNF-α) responses and faecal secretory immunoglobulin A (sIgA) titre in a randomised, double-blinded placebo-controlled trial in 12-24-month-old children (n=38). We used four treatment groups for a 90-day supplementation period: placebo (n=11), probiotic (n=9), zinc (n=8) and probiotic and zinc (n=10). Faecal sIgA, plasma TGF-β1 and TNF-α titre were evaluated using the enzyme-linked immunosorbent assay standard technique. Statistical analysis divided the results (pre/post treatment) into high (>1) and low (<1) ratios. The results showed that faecal sIgA titre increased in all treatment groups compared with the control (placebo) and significantly increased in the probiotic group (P=0.05). In addition, the TGF-β1 ratio in the zinc group was significantly higher (P=0.05) than that in the placebo group. We observed a significant positive correlation between TGF-β1/TNF-α and faecal sIgA (r=0.27, P=0.04). Post hoc test results revealed that zinc supplementation has a significant effect on body-weight gain. Taken together, probiotic L. plantarum IS-10506 supplementation stimulates TGF-β1, which in turn increases the production of sIgA, in line with the significant correlation between TGF-β1/TNF-α and faecal sIgA.

scholarly journals Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes

2019 ◽  
Vol 28 (16) ◽  
pp. 2799-2810 ◽  
Author(s):  
Ching-On Wong ◽  
Kartik Venkatachalam
Keyword(s):  
Cell Adhesion ◽  
Motor Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Data Sets ◽  
Spinal Motor Neurons ◽  
Expression Of Genes ◽  
Sporadic Als ◽  
Elevated Expression ◽  
Induced Pluripotent ◽  
Als Patients

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that culminates in paralysis and death. Here, we present our analyses of publicly available multiOMIC data sets generated using motor neurons from ALS patients and control cohorts. Functional annotation of differentially expressed genes in induced pluripotent stem cell (iPSC)-derived motor neurons generated from patients with mutations in C9ORF72 (C9-ALS) suggests elevated expression of genes that pertain to extracellular matrix (ECM) and cell adhesion, inflammation and TGFβ targets. On the other end of the continuum, we detected diminished expression of genes repressed by quiescence-promoting E2F4/DREAM complex. Proteins whose abundance was significantly altered in C9-ALS neurons faithfully recapitulated the transcriptional aberrations. Importantly, patterns of gene expression in spinal motor neurons dissected from C9-ALS or sporadic ALS patients were highly concordant with each other and with the C9-ALS iPSC neurons. In contrast, motor neurons from patients with mutations in SOD1 exhibited dramatically different signatures. Elevated expression of gene sets such as ECM and cell adhesion genes occurs in C9 and sporadic ALS but not SOD1-ALS. These analyses indicate that despite the similarities in outward manifestations, transcriptional and proteomic signatures in ALS motor neurons can vary significantly depending on the identity of the causal mutations.

scholarly journals Acinetobacter baumannii LOS Regulate the Expression of Inflammatory Cytokine Genes and Proteins in Human Mast Cells

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 290
Author(s):  
Takane Kikuchi-Ueda ◽  
Tsuneyuki Ubagai ◽  
Go Kamoshida ◽  
Ryuichi Nakano ◽  
Akiyo Nakano ◽  
...  
Keyword(s):  
Mast Cells ◽  
Acinetobacter Baumannii ◽  
Bacterial Infections ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Bacterial Invasion ◽  
Inflammatory Genes ◽  
Human Mast Cells ◽  
Expression Of Genes ◽  
Tnf Α

Herein, we investigated the effect of bacterial lipooligosaccharides (LOS), from Acinetobacter baumannii, on the expression of pro-inflammatory genes that play an essential role in bacterial clearance. LAD2 human mast cells were stimulated with LOS derived from two strains of A. baumannii—ATCC 19606 and MDRA T14. LOS exposure induced the expression of genes for pro-inflammatory mediators, including TNF-α, IL-8, LTC4S, CCL4, and TLR4. The mRNA expression levels of a majority of the pro-inflammatory genes, except TLR4, in A. baumannii-LOS stimulated mast cells were increased. Moreover, co-culture of neutrophils with the supernatant obtained from LOS (ATCC 19606 and MDRA T14)-induced LAD2 cells increased the transmigration of neutrophils, which plays a critical role in the early protection against bacterial infections. The results of the present study suggest that LOS could be involved in the pathogenicity of A. baumannii by inducing inflammatory responses via mast cells and that IL-8 is involved in recruiting neutrophils in response to bacterial invasion.

scholarly journals Multicellular Human Cardiac Organoids Transcriptomically Model Distinct Tissue-Level Features of Adult Myocardium

2021 ◽  
Vol 22 (16) ◽  
pp. 8482
Author(s):  
Charles M. Kerr ◽  
Dylan Richards ◽  
Donald R. Menick ◽  
Kristine Y. Deleon-Pennell ◽  
Ying Mei
Keyword(s):  
Immune Cells ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Tissue Level ◽  
In Vitro Models ◽  
Human Myocardium ◽  
Expression Of Genes ◽  
Induced Pluripotent

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for disease modeling and drug cardiotoxicity screening. To this end, we recently developed human cardiac organoids (hCOs) for modeling human myocardium. Here, we perform a transcriptomic analysis of various in vitro hiPSC-CM platforms (2D iPSC-CM, 3D iPSC-CM and hCOs) to deduce the strengths and limitations of these in vitro models. We further compared iPSC-CM models to human myocardium samples. Our data show that the 3D in vitro environment of 3D hiPSC-CMs and hCOs stimulates the expression of genes associated with tissue formation. The hCOs demonstrated diverse physiologically relevant cellular functions compared to the hiPSC-CM only models. Including other cardiac cell types within hCOs led to more transcriptomic similarities to adult myocardium. hCOs lack matured cardiomyocytes and immune cells, which limits a complete replication of human adult myocardium. In conclusion, 3D hCOs are transcriptomically similar to myocardium, and future developments of engineered 3D cardiac models would benefit from diversifying cell populations, especially immune cells.

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