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NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

ABSTRACT: Defects in neutrophil number and survival are common to both hematologic disorders and chronic inflammatory diseases. At sites of inflammation, neutrophils respond to multiple signals that activate protein kinase A (PKA) signalling, which positively regulates neutrophil survival. We aimed to study the transcriptional responses to several stimuli in human neutrophils. We used microarrays to detail the global programme of gene expression and identified distinct classes of up-regulated genes, which pointing to a key role of NR4A receptors in regulation of neutrophil lifespan and homeostasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94923 | GEO | 2017/04/03

SECONDARY ACCESSION(S): PRJNA374852

REPOSITORIES: GEO

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NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival.

Project description:The lifespan of neutrophils is plastic and highly responsive to factors that regulate cellular survival. Defects in neutrophil number and survival are common to both hematologic disorders and chronic inflammatory diseases. At sites of inflammation, neutrophils respond to multiple signals that activate protein kinase A (PKA) signaling, which positively regulates neutrophil survival. The aim of this study was to define transcriptional responses to PKA activation and to delineate the roles of these factors in neutrophil function and survival. In human neutrophil gene array studies, we show that PKA activation upregulates a significant number of apoptosis-related genes, the most highly regulated of these being NR4A2 and NR4A3 Direct PKA activation by the site-selective PKA agonist pair N6/8-AHA (8-AHA-cAMP and N6-MB-cAMP) and treatment with endogenous activators of PKA, including adenosine and prostaglandin E2, results in a profound delay of neutrophil apoptosis and concomitant upregulation of NR4A2/3 in a PKA-dependent manner. NR4A3 expression is also increased at sites of neutrophilic inflammation in a human model of intradermal inflammation. PKA activation also promotes survival of murine neutrophil progenitor cells, and small interfering RNA to NR4A2 decreases neutrophil production in this model. Antisense knockdown of NR4A2 and NR4A3 homologs in zebrafish larvae significantly reduces the absolute neutrophil number without affecting cellular migration. In summary, we show that NR4A2 and NR4A3 are components of a downstream transcriptional response to PKA activation in the neutrophil, and that they positively regulate neutrophil survival and homeostasis.

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Orphan Nuclear Receptor Family 4A (NR4A) Members NR4A2 and NR4A3 Selectively Modulate Elements of the Monocyte Response to Buffered Hypercapnia.

Project description:Hypercapnia occurs when the partial pressure of carbon dioxide (CO2) in the blood exceeds 45 mmHg. Hypercapnia is associated with several lung pathologies and is transcriptionally linked to suppression of immune and inflammatory signalling through poorly understood mechanisms. Here we propose Orphan Nuclear Receptor Family 4A (NR4A) family members NR4A2 and NR4A3 as potential transcriptional regulators of the cellular response to hypercapnia in monocytes. Using a THP-1 monocyte model, we investigated the sensitivity of NR4A family members to CO2 and the impact of depleting NR4A2 and NR4A3 on the monocyte response to buffered hypercapnia (10% CO2) using RNA-sequencing. We observed that NR4A2 and NR4A3 are CO2-sensitive transcription factors and that depletion of NR4A2 and NR4A3 led to reduced CO2-sensitivity of mitochondrial and heat shock protein (Hsp)-related genes, respectively. Several CO2-sensitive genes were, however, refractory to depletion of NR4A2 and NR4A3, indicating that NR4As regulate certain elements of the cellular response to buffered hypercapnia but that other transcription factors also contribute. Bioinformatic analysis of conserved CO2-sensitive genes implicated several novel putative CO2-sensitive transcription factors, of which the ETS Proto-Oncogene 1 Transcription Factor (ETS-1) was validated to show increased nuclear expression in buffered hypercapnia. These data give significant insights into the understanding of immune responses in patients experiencing hypercapnia.

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Elucidation of roles of Nr4a nuclear orphan receptors and Foxp3 in thymic Treg cell development

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2020-07-08 | GSE153927 | GEO

NR4A1 and NR4A2 orphan nuclear receptors regulate endothelial to hematopoietic transition in mouse hematopoietic stem cell specification

Project description:Hematopoietic stem cells (HSCs) sustain life-long hematopoiesis and emerge during mid-gestation from hemogenic endothelial (HE) progenitors via an endothelial to hematopoietic transition (EHT). The full scope of molecular mechanisms governing this process remains unclear. The NR4A subfamily of orphan nuclear receptors act as tumour suppressors in myeloid leukemogenesis and have never been implicated in HSC specification. Here, we report that Nr4a1 and Nr4a2 expression is upregulated in hemogenic endothelium during EHT. Progressive genetic ablation of Nr4a gene dosage results in a gradual decrease in numbers of nascent c-Kit+ hematopoietic progenitors in developing embryos, c-Kit+ cell cluster size in the dorsal aorta, and a block in HSC maturation, revealed by an accumulation of pro-HSCs and pre-HSC-type I cells and decreased numbers of pre-HSC-type II cells. Consistent with these observations, cells isolated from E11.5 Nr4a1-/-; Nr4a2-/- aorta-gonads-mesonephros (AGM) are devoid of in vivo long-term hematopoietic repopulating potential. Molecularly, employing spatial transcriptomic analysis we determined that the genetic ablation of Nr4a1 and Nr4a2 prevents NOTCH signaling from being downregulated in intra-aortic clusters and thus for pro-HSCs to mature into HSCs. Interestingly, this defect is partially rescued via ex vivo culture of dissected AGMs with SCF, IL3 and FLT3L, which may bypass NOTCH-dependent regulation. Overall, our data reveal a novel role for the NR4A family of orphan nuclear receptors in EHT.

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