scholarly journals Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes

2020 ◽  
Vol 6 (34) ◽  
pp. eaay9506
Author(s):  
Katherine Warre-Cornish ◽  
Leo Perfect ◽  
Roland Nagy ◽  
Rodrigo R. R. Duarte ◽  
Matthew J. Reid ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Viral Entry ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Interferon Γ ◽  
Nuclear Bodies ◽  
Sequencing Analysis ◽  
Pml Nuclear Bodies ◽  
Ifn Γ ◽  
Cellular Phenotypes

Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-γ (IFN-γ), in offspring’s brains play a central role. IFN-γ activates an antiviral cellular state, limiting viral entry and replication. Moreover, IFN-γ is implicated in brain development. We tested the hypothesis that IFN-γ signaling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. Transient IFN-γ treatment of neural progenitors derived from human induced pluripotent stem cells increased neurite outgrowth. RNA sequencing analysis revealed that major histocompatibility complex class I (MHCI) genes were persistently up-regulated through neuronal differentiation—an effect that was mediated by IFN-γ-induced promyelocytic leukemia protein (PML) nuclear bodies. Critically, IFN-γ-induced neurite outgrowth required both PML and MHCI. We also found evidence that IFN-γ disproportionately altered the expression of genes associated with schizophrenia and autism, suggesting convergence between genetic and environmental risk factors. Together, these data implicate IFN-γ signaling in neurodevelopmental disorder etiology.

scholarly journals Antiviral signalling in human IPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes

2019 ◽  
Author(s):  
Katherine Warre-Cornish ◽  
Leo Perfect ◽  
Roland Nagy ◽  
Matthew J. Reid ◽  
Annett Mueller ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Viral Entry ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Risk Genes ◽  
Maternal Immune Activation ◽  
Pml Bodies ◽  
Induced Pluripotent ◽  
Cellular Phenotypes ◽  
Human Ipsc

AbstractMaternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-gamma (IFNγ), in offspring’s brains play a central role. IFNγ activates an antiviral cellular state, limiting viral entry and replication. In addition, IFNγ has been implicated in brain development. Here, we hypothesise that IFNγ-induced antiviral signalling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. We find that transient IFNγ treatment of neural progenitors derived from human induced pluripotent stem cells (hIPSCs) persistently increases neurite outgrowth, phenocopying hIPSC-neurons from autistic individuals. IFNγ upregulates antiviral PML bodies and MHC class I (MHCI) genes, which persists through neuronal differentiation. Critically, IFNγ-induced neurite outgrowth requires both PML and MHCI. We also find that IFNγ disproportionately alters expression of autism and schizophrenia risk genes, suggesting convergence between these genetic and environmental risk factors. Together, these data indicate that IFNγ-induced antiviral signalling may contribute to neurodevelopmental disorder aetiology.

scholarly journals Promyelocytic leukemia protein (PML) promotes the phenotypic switch of smooth muscle cells in atherosclerotic plaques of human coronary arteries

2021 ◽  
Author(s):  
Weronika Karle ◽  
Samuel Becker ◽  
Philipp Stenzel ◽  
Christoph Knosalla ◽  
Günter Siegel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Coronary Arteries ◽  
Muscle Cells ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Specific Gene ◽  
Promyelocytic Leukemia Protein ◽  
Pml Nuclear Bodies ◽  
Ifn Γ

Promyelocytic leukemia protein (PML) is a constitutive component of PML nuclear bodies (PML-NBs), which function as stress-regulated SUMOylation factories. Since PML can also act as a regulator of the inflammatory and fibroproliferative responses characteristic of atherosclerosis, we investigated whether PML is implicated in this disease. Immunoblotting, ELISA and immunohistochemistry showed a strong up-regulation of PML in segments of human atherosclerotic coronary arteries compared to non-atherosclerotic ones. In particular, PML was concentrated in PML-NBs from alpha-smooth muscle actin-immunoreactive cells in plaque areas. To identify possible functional consequences of PML-accumulation in this cell-type, differentiated human coronary artery smooth muscle cells (dHCASMCs) were transfected with a vector containing the intact PML-gene. These PML-transfected HCASMCs showed higher levels of SUMO-1-dependent SUMOylated proteins, but lower levels of markers for smooth muscle cell differentiation and revealed more proliferation and migration activities than dHCASMCs transfected with the vector lacking a specific gene insert or with the vector containing a mutated PML-gene coding for a PML-form without SUMOylation activity. When dHCASMCs were incubated with different cytokines, higher PML-levels were observed only after IFN-γ stimulation, while the expression of differentiation markers decreased. However, these phenotypic changes were not observed in dHCASMCs treated with small interfering RNA (siRNA) suppressing PML-expression prior to IFN-γ stimulation. Taken together, our results imply that PML is a previously unknown functional factor in the molecular cascades associated with the pathogenesis of atherosclerosis and is positioned in vascular smooth muscle cells between up-stream IFN-γ activation and downstream SUMOylation.

scholarly journals Stability of Smyd1 in endothelial cells is controlled by PML-dependent SUMOylation upon cytokine Stimulation

2020 ◽  
Author(s):  
Samuel Becker ◽  
Gustav Steinemann ◽  
Weronika Karle ◽  
Kerrin Roos ◽  
Celine Huajia Liem ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mrna Level ◽  
Feedback Mechanism ◽  
Nuclear Bodies ◽  
Expression Vectors ◽  
Dependent Manner ◽  
Molecular Control ◽  
Pml Nuclear Bodies ◽  
Ea.Hy926 Cells ◽  
Ifn Γ

Smyd1 is an epigenetic modulator of gene expression that has been well-characterized in muscle cells. It was recently reported that Smyd1 levels are modulated by inflammatory processes. Since inflammation affects the vascular endothelium, this study aimed to characterize Smyd1 expression in endothelial cells. We detected Smyd1 in human endothelial cells (HUVEC and EA.hy926 cells), where the protein was largely localized in PML nuclear bodies (PML-NBs). By transfection of EA.hy926 cells with expression vectors encoding Smyd1, PML, SUMO1, active or mutant forms of the SUMO protease SuPr1 and/or the SUMO-conjugating UBC9, as well as Smyd1- or PML-specific siRNAs, in the presence or absence of the translation blocker cycloheximide or the proteasome-inhibitor MG132, and supported by computational modeling, we show that Smyd1 is SUMOylated in a PML-dependent manner and thereby addressed for degradation in proteasomes. Furthermore, transfection with Smyd1-encoding vectors led to PML up-regulation at the mRNA level, while PML transfection lowered Smyd1 protein stability. Incubation of EA.hy926 cells with the pro-inflammatory cytokine TNF-α resulted in a constant increase in Smyd1 mRNA and protein over 24 h, while incubation with IFN-γ induced a transient increase of Smyd1 expression, which peaked at 6 h and decreased to control values within 24 h. The IFN-γ-induced increase of Smyd1 was accompanied by more Smyd1 SUMOylation and more/larger PML-NBs. In conclusion, our data indicate that in endothelial cells, Smyd1 levels are regulated through a negative feedback mechanism based on SUMOylation and PML availability. This molecular control loop is stimulated by various cytokines.

Interferon γ and interleukin 6 modulate the susceptibility of macrophages to human immunodeficiency virus type 1 infection

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3109-3117 ◽  
Author(s):  
Marina Zaitseva ◽  
Shirley Lee ◽  
Cheryl Lapham ◽  
Rolf Taffs ◽  
Lisa King ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Entry ◽  
Interleukin 6 ◽  
Interferon Γ ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Hiv 1

The effect of interferon γ (IFN-γ) and interleukin 6 (IL-6) on infection of macrophages with human immunodeficiency virus type 1 (HIV-1) was investigated. By using a polymerase chain reaction–based viral entry assay and viral infectivity assay, it was demonstrated that IL-6 and IFN-γ augmented susceptibility of monocyte-derived macrophages (MDMs) to infection with T-cell tropic CXCR4-utilizing (X4) HIV-1 strains. Consistent with this finding, IFN-γ and IL-6 augmented fusion of MDMs with T-tropic envelope-expressing cells. The enhanced fusion of cytokine-treated MDMs with T-tropic envelopes was inhibited by the CXCR4 ligand, SDF-1, and by T22 peptide. IFN-γ and IL-6 did not affect expression of surface CXCR4 or SDF-1–induced Ca++ flux in MDMs. In contrast to the effect of IFN-γ on the infection of MDMs with X4 strains, IFN-γ inhibited viral entry and productive infection of MDMs with macrophage-tropic (M-tropic) HIV-1. Consistent with this finding, IFN-γ induced a decrease in fusion with M-tropic envelopes that correlated with a modest reduction in surface CCR5 and CD4 on MDMs. It was further demonstrated that macrophage inflammatory protein (MIP)-1α and MIP-β secreted by cytokine-treated MDMs augmented their fusion with T-tropic–expressing cells and inhibited their fusion with M-tropic envelope-expressing cells. These data indicate that proinflammatory cytokines, which are produced during opportunistic infections or sexually transmitted diseases, may predispose macrophages to infection with X4 strains that, in turn, could accelerate disease progression.

Interferon γ and interleukin 6 modulate the susceptibility of macrophages to human immunodeficiency virus type 1 infection

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3109-3117 ◽  
Author(s):  
Marina Zaitseva ◽  
Shirley Lee ◽  
Cheryl Lapham ◽  
Rolf Taffs ◽  
Lisa King ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Entry ◽  
Interleukin 6 ◽  
Interferon Γ ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Hiv 1

Abstract The effect of interferon γ (IFN-γ) and interleukin 6 (IL-6) on infection of macrophages with human immunodeficiency virus type 1 (HIV-1) was investigated. By using a polymerase chain reaction–based viral entry assay and viral infectivity assay, it was demonstrated that IL-6 and IFN-γ augmented susceptibility of monocyte-derived macrophages (MDMs) to infection with T-cell tropic CXCR4-utilizing (X4) HIV-1 strains. Consistent with this finding, IFN-γ and IL-6 augmented fusion of MDMs with T-tropic envelope-expressing cells. The enhanced fusion of cytokine-treated MDMs with T-tropic envelopes was inhibited by the CXCR4 ligand, SDF-1, and by T22 peptide. IFN-γ and IL-6 did not affect expression of surface CXCR4 or SDF-1–induced Ca++ flux in MDMs. In contrast to the effect of IFN-γ on the infection of MDMs with X4 strains, IFN-γ inhibited viral entry and productive infection of MDMs with macrophage-tropic (M-tropic) HIV-1. Consistent with this finding, IFN-γ induced a decrease in fusion with M-tropic envelopes that correlated with a modest reduction in surface CCR5 and CD4 on MDMs. It was further demonstrated that macrophage inflammatory protein (MIP)-1α and MIP-β secreted by cytokine-treated MDMs augmented their fusion with T-tropic–expressing cells and inhibited their fusion with M-tropic envelope-expressing cells. These data indicate that proinflammatory cytokines, which are produced during opportunistic infections or sexually transmitted diseases, may predispose macrophages to infection with X4 strains that, in turn, could accelerate disease progression.

scholarly journals PML promotes MHC class II gene expression by stabilizing the class II transactivator

2012 ◽  
Vol 199 (1) ◽  
pp. 49-63 ◽  
Author(s):  
Tobias Ulbricht ◽  
Mohammad Alzrigat ◽  
Almut Horch ◽  
Nina Reuter ◽  
Anna von Mikecz ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Cell Types ◽  
Class Ii ◽  
Nuclear Bodies ◽  
Spatial Proximity ◽  
Stable Complex ◽  
Class Ii Transactivator ◽  
Pml Nuclear Bodies ◽  
Pml Bodies ◽  
Ifn Γ

Promyelocytic leukemia (PML) nuclear bodies selectively associate with transcriptionally active genomic regions, including the gene-rich major histocompatibility (MHC) locus. In this paper, we have explored potential links between PML and interferon (IFN)-γ–induced MHC class II expression. IFN-γ induced a substantial increase in the spatial proximity between PML bodies and the MHC class II gene cluster in different human cell types. Knockdown experiments show that PML is required for efficient IFN-γ–induced MHC II gene transcription through regulation of the class II transactivator (CIITA). PML mediates this function through protection of CIITA from proteasomal degradation. We also show that PML isoform II specifically forms a stable complex with CIITA at PML bodies. These observations establish PML as a coregulator of IFN-γ–induced MHC class II expression.

scholarly journals Gamma Interferon-Dependent Transcriptional Memory via Relocalization of a Gene Locus to PML Nuclear Bodies

2010 ◽  
Vol 30 (8) ◽  
pp. 2046-2056 ◽  
Author(s):  
Manolis Gialitakis ◽  
Panagiota Arampatzi ◽  
Takis Makatounakis ◽  
Joseph Papamatheakis
Keyword(s):  
Cellular Responses ◽  
Promyelocytic Leukemia ◽  
Gamma Interferon ◽  
Nuclear Bodies ◽  
Epigenetic Memory ◽  
Pml Nuclear Bodies ◽  
Histocompatibility Complex ◽  
Primary Signal ◽  
Transcriptional Memory ◽  
Ifn Γ

ABSTRACT Memory of past cellular responses is an essential adaptation to repeating environmental stimuli. We addressed the question of whether gamma interferon (IFN-γ)-inducible transcription generates memory that sensitizes cells to a second stimulus. We have found that the major histocompatibility complex class II gene DRA is relocated to promyelocytic leukemia (PML) nuclear bodies upon induction with IFN-γ, and this topology is maintained long after transcription shut off. Concurrent interaction of PML protein with mixed-lineage leukemia generates a prolonged permissive chromatin state on the DRA gene characterized by high promoter histone H3 K4 dimethylation that facilitates rapid expression upon restimulation. We propose that the primary signal-induced transcription generates spatial and epigenetic memory that is maintained through several cell generations and endows the cell with increased responsiveness to future activation signals.

scholarly journals Natural History and Evolution of Anti-Interferon-γ Autoantibody-Associated Immunodeficiency Syndrome in Thailand and the United States

2019 ◽  
Vol 71 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Gloria H Hong ◽  
Ana M Ortega-Villa ◽  
Sally Hunsberger ◽  
Ploenchan Chetchotisakd ◽  
Siriluck Anunnatsiri ◽  
...  
Keyword(s):  
United States ◽  
Natural History ◽  
The United States ◽  
Interferon Γ ◽  
Mycobacterium Abscessus ◽  
Annual Data ◽  
Persistent Infections ◽  
Ifn Γ ◽  
Immunodeficiency Syndrome

Abstract Background The natural history of anti-interferon-γ (IFN-γ) autoantibody-associated immunodeficiency syndrome is not well understood. Methods Data of 74 patients with anti-IFN-γ autoantibodies at Srinagarind Hospital, Thailand, were collected annually (median follow-up duration, 7.5 years). Annual data for 19 patients and initial data for 4 patients with anti-IFN-γ autoantibodies at the US National Institutes of Health were collected (median follow-up duration, 4.5 years). Anti-IFN-γ autoantibody levels were measured in plasma samples. Results Ninety-one percent of US patients were of Southeast Asian descent; there was a stronger female predominance (91%) in US than Thai (64%) patients. Mycobacterium abscessus (34%) and Mycobacterium avium complex (83%) were the most common nontuberculous mycobacteria in Thailand and the United States, respectively. Skin infections were more common in Thailand (P = .001), whereas bone (P < .0001), lung (P = .002), and central nervous system (P = .03) infections were more common in the United States. Twenty-four percent of Thai patients died, most from infections. None of the 19 US patients with follow-up data died. Anti-IFN-γ autoantibody levels decreased over time in Thailand (P < .001) and the United States (P = .017), with either cyclophosphamide (P = .01) or rituximab therapy (P = .001). Conclusions Patients with anti-IFN-γ autoantibodies in Thailand and the United States had distinct demographic and clinical features. While titers generally decreased with time, anti-IFN-γ autoantibody disease had a chronic clinical course with persistent infections and death. Close long-term surveillance for new infections is recommended.

scholarly journals The Role of Interleukine-10 and Interferon-γ as Potential Markers of the Evolution of African Swine Fever Virus Infection in Wild Boar

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 757
Author(s):  
Sandra Barroso-Arévalo ◽  
Jose A. Barasona ◽  
Estefanía Cadenas-Fernández ◽  
José M. Sánchez-Vizcaíno
Keyword(s):  
Wild Boar ◽  
Vaccine Candidate ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Interferon Γ ◽  
Fever Virus ◽  
Control Group ◽  
Challenge Virus ◽  
Ifn Γ

African swine fever virus (ASFv) is one of the most challenging pathogens to affect both domestic and wild pigs. The disease has now spread to Europe and Asia, causing great damage to the pig industry. Although no commercial vaccine with which to control the disease is, as yet, available, some potential vaccine candidates have shown good results in terms of protection. However, little is known about the host immune mechanisms underlying that protection, especially in wild boar, which is the main reservoir of the disease in Europe. Here, we study the role played by two cytokines (IL-10 and IFN-γ) in wild boar orally inoculated with the attenuated vaccine candidate Lv17/WB/Rie1 and challenged with a virulent ASFv genotype II isolate. A group of naïve wild boar challenged with the latter isolate was also established as a control group. Our results showed that both cytokines play a key role in protecting the host against the challenge virus. While high levels of IL-10 in serum may trigger an immune system malfunctioning in challenged animals, the provision of stable levels of this cytokine over time may help to control the disease. This, together with high and timely induction of IFN-γ by the vaccine candidate, could help protect animals from fatal outcomes. Further studies should be conducted in order to support these preliminary results and confirm the role of these two cytokines as potential markers of the evolution of ASFV infection.

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