Nuclear receptor 4A1 is Critical for Neutrophil-Dependent Pulmonary Immunity to Klebsiella pneumoniae Infection
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ABSTRACT:
PROVIDER: PRJNA1226195 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32415936_1.fastq.gz | Fastqsanger.gz | |||
| SRR32415936_2.fastq.gz | Fastqsanger.gz | |||
| SRR32415937_1.fastq.gz | Fastqsanger.gz | |||
| SRR32415937_2.fastq.gz | Fastqsanger.gz | |||
| SRR32415938_1.fastq.gz | Fastqsanger.gz |
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Project description:Bacterial pneumonia is a burdensome, costly disease and increasingly challenging to treat due to antibiotic resistance. Complex host-pathogen interactions regulate protective immunity, and immune-directed therapies could yield novel treatments. Neutrophils play a central role in pulmonary bacterial immunity, and mechanistic understanding of neutrophil antibacterial functions in pneumonia has potential clinical and fundamental application. Nuclear receptor 4a1 (Nr4a1), a member of the nuclear orphan receptor family, has been described to regulate inflammation and immune development in a cell type-specific manner, but its role in pulmonary host defense is not well understood. This study demonstrates that Nr4a1 is essential for protection against K. pneumoniae as Nr4a1 -/-mice showed increased lung bacterial burden, dissemination, and reduced survival. Notably, neutrophil-specific Nr4a1 expression was critical for defense against K. pneumoniae infection by regulating the neutrophil transcriptome. These findings suggest targeting neutrophil-specific Nr4a1 may be beneficial for bacterial pneumonia treatment.
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Project description:Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis of S. aureus-infected skin revealed that induction of neutrophil recruitment genes was largely dependent upon IL-1beta/IL-1R activation. Unexpectedly, using IL 1beta reporter mice, neutrophils were identified as the primary source of IL-1beta at the site of infection. Furthermore, IL-1beta-producing neutrophils were necessary and sufficient for abscess formation and bacterial clearance. S. aureus-induced IL 1beta production by neutrophils required TLR2, NOD2, FPRs and the ASC/NLRP3 inflammasome. Taken together, IL-1beta and neutrophil abscess formation during an infection are functionally, spatially and temporally linked as a consequence of direct IL-1beta production by neutrophils. Lesional skin biopsies obtained from C57BL/6J WT mice or IL-1R-deficient mice at 4 hours post-infection with Staphylococcus aureus. Uninfected skin biopsies were also collected from WT and IL-1R-deficient mice.
2012-12-05 | E-GEOD-36826 | biostudies-arrayexpress
Project description:Abstract<br>BACKGROUND: Gene expression profiling (GEP) in cells obtained from peripheral blood has demonstrated to be a very useful approach for biomarker discovery and for studying molecular pathogenesis of prevalent diseases. While there is limited literature availble on gene expression markers associated to Chronic Obstructive Pulmonary Disease (COPD), the transcriptomic picture associated to critical respiratory illness in this disease is not known to the present moment. <br>RESULTS: By using Agilent microarray chips, we have profiled gene expression signatures in whole blood of 28 COPD patients hospitalized with distinct degree of respiratory compromise.12 of them needed of admission to the ICU, while 16 were admitted to the Respiratory Medicine Service. GeneSpring GX 11.0 software was used for performing statistical comparison of transcript levels between ICU and non ICU patients. Ingenuity pathway analysis 8.5 (IPA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to select, annotate and visualize genes by function and pathway (gene ontology). T-test evidenced 1501 genes differentially expressed between ICU and non ICU patients. IPA and KEGG analysis of the most representative biological functions revealed that ICU patients showed increased levels of neutrohil gene transcripts, being [cathepsin G (CTSG)], [elastase, neutrophil expressed (ELANE)], [proteinase 3 (PRTN3)], [myeloperoxidase (MPO)], [cathepsin D (CTSD)], [defensin, alpha 3, neutrophil-specific (DEFA3)], azurocidin 1 (AZU1)], [bactericidal/permeability-increasing protein (BPI)] the most representative ones. Proteins codified by these genes form part of the azurophilic granules of neutrophils and are involved in both antimicrobial defence and tissue damage. This ?neutrophil signature? was paralleled by necessity of advanced respiratory and vital support, and presence of bacterial infection.<br>CONCLUSION: study of transcriptomic signatures in blood suggests a central role of neutrophil proteases in COPD patients with critical respiratory illness. Measurement / modulation of the expression of these genes could represent an option for clinical monitoring and treatment of severe COPD exacerbations. <br><br>Keywords: COPD, critical, expression, gene, microarray, neutrophil, proteases.<br><br>
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Project description:Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis of S. aureus-infected skin revealed that induction of neutrophil recruitment genes was largely dependent upon IL-1beta/IL-1R activation. Unexpectedly, using IL 1beta reporter mice, neutrophils were identified as the primary source of IL-1beta at the site of infection. Furthermore, IL-1beta-producing neutrophils were necessary and sufficient for abscess formation and bacterial clearance. S. aureus-induced IL 1beta production by neutrophils required TLR2, NOD2, FPRs and the ASC/NLRP3 inflammasome. Taken together, IL-1beta and neutrophil abscess formation during an infection are functionally, spatially and temporally linked as a consequence of direct IL-1beta production by neutrophils.
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Project description:IntroductionBacterial pneumonia is a burdensome, costly disease and increasingly challenging to treat due to antibiotic resistance. Complex host-pathogen interactions regulate protective immunity. Neutrophils play a central role in pulmonary bacterial immunity, and mechanistic understanding of neutrophil functions in bacterial pneumonia has potential clinical and fundamental application. Nuclear receptor 4a1 (Nr4a1), a member of the nuclear orphan receptor family, has been described to regulate inflammation and immune development in a cell type-specific manner, but its role in pulmonary host defense is not well understood.MethodsWild-type (WT) and Nr4a1-/- mice, as well as bone marrow chimeric and Gr-1+ antibody depleted mice, were infected with Klebsiella pneumoniae and assessed for bacterial burden in the lung and spleen, gene transcription, protein levels, histology and cellular abundance by flow cytometry in the lung. WT and Nr4a1-/- neutrophils were exposed to live Klebsiella pneumoniae to quantify bacterial killing, as well as bulk RNA sequencing to assess transcriptomic differences.ResultsNr4a1-deficient mice are highly susceptible to Klebsiella pneumoniae pneumonia, which was mediated by Nr4a1 expression in immune cells. Gr-1+ antibody depletion ameliorated the Nr4a1-dependent phenotype. Ex vivo, Nr4a1-deficient neutrophils had impaired bactericidal capacity, and transcriptomic analysis identified an Nr4a1-dependent host defense program in neutrophils.DiscussionNeutrophil Nr4a1 expression is critical for defense against K. pneumoniae infection by regulating the neutrophil transcriptome. These findings suggest targeting Nr4a1 signaling pathways in neutrophils may be useful for bacterial pneumonia treatment.
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