Male sex affects type I/type II interferon response of neutrophils during hepatic Amebiasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1011261 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25836800_1.fastq.gz | Fastqsanger.gz | |||
| SRR25836800_2.fastq.gz | Fastqsanger.gz | |||
| SRR25836801_1.fastq.gz | Fastqsanger.gz | |||
| SRR25836801_2.fastq.gz | Fastqsanger.gz | |||
| SRR25836802_1.fastq.gz | Fastqsanger.gz |
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Project description:Hepatic amebiasis, a serious complication caused by the parasite Entamoeba histolytica, predominantly affects men. Earlier research in the murine disease model indicated that testosterone modulates an intense immune reaction, triggering destructive immunopathological changes in the liver. Inflammatory monocytes expressing proinflammatory chemokines, crucial for neutrophil recruitment, worsen this process. This study examines sex-related variances in neutrophils during hepatic amebiasis in a mouse model. Male subjects exhibited higher levels and recruitment of neutrophils compared to females. Androgens directly contributed to this bias, enhancing neutrophil recruitment and retarding maturation in response to infection. Transcriptomic analysis revealed diminished type I and II interferon-stimulated gene expression and reduced activation pathways in male neutrophils versus female neutrophils. Upon ex-vivo stimulation, female human neutrophils showed higher expression of a key type I interferon-stimulated gene (viperin/RSAD2) at the protein level, which was similar in mice after infection, and suppressed by testosterone. In male mice with hepatic amebiasis, sex-dependent factors led to recruitment of less active neutrophils, intensifying immunopathological damage to liver tissue. This sex disparity and testosterone's impact on interferon-stimulated genes hold implications beyond hepatic amebiasis, potentially influencing broader areas, including viral infectious diseases
2024-01-10 | GSE242045 | GEO
Project description:Differences in immune response between men and women may influence the outcome of infectious diseases. Intestinal infection with Entamoeba histolytica leads to hepatic amebiasis, which is more common in males. Previously, we reported that innate immune cells contribute to liver damage in males in the murine model for hepatic amebiasis. Here, we focused on the influences of sex and androgens on neutrophils in particular. Infection associated with neutrophil accumulation in the liver was higher in male than in female mice and further increased after testosterone treatment in both sexes. Compared with female neutrophils, male neutrophils exhibit a more immature and less activated status, as evidenced by a lower proinflammatory N1-like phenotype and deconvolution, decreased gene expression of type I and type II interferon stimulated genes (ISGs) as well as downregulation of signaling pathways related to neutrophil activation. Neutrophils from females showed higher protein expression of the type I ISG viperin/RSAD2 during infection, which decreased by testosterone substitution. Moreover, ex vivo stimulation of human neutrophils revealed lower production of RSAD2 in neutrophils from men compared with women. These findings indicate that sex-specific effects on neutrophil physiology associated with maturation and type I IFN responsiveness might be important in the outcome of hepatic amebiasis.
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Project description:Mature neutrophis were freshly isolated from blood of pediatric systemic lupus erythematosus (SLE) patients and healthy donors. Illumina microarray was used to assess transcriptional changes between SLE group and Control group. To uderstand further the gene expression difference between SLE and healthy neutrofils, neutrophils from healthy donors were cultured with autologous sera, SLE sera or Interferon and microarray data was used to compare with fresh SLE neutrophils. (Expt 1) Neutrophils from 21 SLE samples (19 patients) and 12 healthy donors were isolated, and extracted RNAs were used generate microarray data. (Expt 2) Neutrophils isolated from 2 healthy children (not used in the first experiment) were cultured with autologous sera (control), Interferon alpha (100U and 1000U), and 4 SLE sera and 6 SLE sera for 6 hours and RNAs were extract for microarray experiment.
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Project description:Autoantibodies against nucleic acids and excessive type I Interferon (IFN) are hallmarks of human Systemic Lupus Erythematosus (SLE). We previously reported that SLE neutrophils, exposed to TLR7-agonist autoantibodies, release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized residues. When MtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor TFAM, a dual high mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFNprimed neutrophils, to anti-RNP autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, oxidized nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of oxidized nucleoids is a feature of SLE blood neutrophils, and autoantibodies against oxidized mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE. 4 samples, no replicates, 2 controls. 2 samples are Neutrophils cultured with and without CCCP (control). 2 samples are Monocytes cultured with and without CCCP (control).
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Project description:Autoantibodies against nucleic acids and excessive type I Interferon (IFN) are hallmarks of human Systemic Lupus Erythematosus (SLE). We previously reported that SLE neutrophils, exposed to TLR7-agonist autoantibodies, release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized residues. When MtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor TFAM, a dual high mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFNprimed neutrophils, to anti-RNP autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, oxidized nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of oxidized nucleoids is a feature of SLE blood neutrophils, and autoantibodies against oxidized mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE.
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Project description:While critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during COVID-19 ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using scRNA-seq and plasma proteomics, we discovered that compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin (PG) signalling. Dexamethasone during severe COVID-19 depleted circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated gene, and activated IL1R2+ve neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils, preferential steroid-induced immature neutrophil expansion, and possibly different effects on outcome. Our single-cell atlas (www.biernaskielab.ca/COVID_neutrophil) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.
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Project description:The cytokine interferon-gamma (IFN-gamma) is used as a drug to treat Chronic Granulomatous Disease (CGD), a group of genetic disorders characterized by defects in components of the neutrophil-resident NADPH oxidase/Nox2 enzyme system. Administration of IFN-gamma to these patients results in decreased incidents of severe infection, but has no effect on the characteristic defect of CGD, the inability to convert oxygen to microbicidal reactive oxygen species. To determine the mechanism by which IFN-gamma enhances the host protective properties of neutrophils, we administered INF-gamma to 10 healthy adult volunteers and carried out transcription profiling by array for neutrophils isolated from their peripheral blood. IFN-gamma was administered to each subject at 4 doses (10, 25, 50 and 100 micrograms/meter squared) with washout periods between each dose. Gene expression levels in neutrophils were measure just before (time 0) and at various times (4, 8, 12, 24, 36, 48, 72 and 96 hours) after administration of IFN-gamma. In the list of samples, individual patients are indicated by 01-10, the dose by D10, D25, D50 and D100, referring to 10, 25, 50 and 100 micrograms / meter squared respectively and the times by visit (V) numbers where VI, V2, V3, V4, V5, V6, V7, V8 and V9 refer to the 0 4, 8, 12, 24, 36, 48, 72 and 96 hour time points respectively.
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