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Effect of JAK inhibitors Upadacitinib or Baricitinib on gene expression during human monocyte-derived macrophage differentiation

ABSTRACT: Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. GM-CSF drives the generation of human monocyte-derived macrophages with a potent pro-inflammatory activity upon stimulation. Janus Kinase (JAK) inhibitors are small molecules that reversibly inhibit JAK activity and their subsequent intracellular signaling and have become the treatment of choice for diseases with an inflammatory or immune basis. We explored the molecular impact of blocking GM-CSFR-JAK2-STAT5 axis with the Janus Kinase (JAK) inhibitors Upadacitinib or Baricitinib on the gene expression profile in GM-CSF-primed human monocyte derived macrophages.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232044 | GEO | 2024/04/04

REPOSITORIES: GEO

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RNA-seq of murine mesenchymal stem cells during differentiation to osteoblasts, treated with tofacitinib or baricitinib against vehicle control

Project description:Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, characterized by synovial hyperplasia and progressive joint destruction. For treating inflammatory diseases, such as RA, the Janus kinase (JAK)-mediated signaling pathway has emerged as a therapeutic target. Therefore, JAK inhibitors, such as tofacitinib and baricitinib, are approved for the treatment of RA. While the immunomodulatory characteristics of JAK inhibition (JAKi) are well defined, the current knowledge of how JAKi affects bone homeostasis is limited. Addressing this question becomes increasingly relevant, as current therapeutic options can slow down RA progression, but joint damage and especially perarticular bone erosion remain. Therefore, the impact of JAKi on bone homeostasis requires further elucidation. For in vitro analysis, the impact of JAK inhibitors tofacitinib and baricitinib on bone-forming osteoblasts was analyzed with respect to their mineralization capability. JAKi, by both tofacitinib and baricitinib, increased mineralization function in mesenchymal stem cells (MSCs)-derived osteoblasts. Having observed increased mineralization capability in mesenchymal stem cells (MSCs)-derived osteoblasts, RNA-seq was performed to shed light on potential signaling pathways and mediators causing this effect. For that, MSCs were plated at 6,000 cells per well in a 24-well-plate in alpha-MEM, supplemented with 10% heat-inactivated FCS and 1% P/S. After one day medium was changed to alpha-MEM, 10% heat-inactivated FCS, 1% P/S and 568 mikromolar L-Ascorbic acid 2-phosphate 351 sesquimagnesium salt hydrate, containing either tofacitinib (500 nM), baricitinib (300 nM) or DMSO as vehicle control. After osteogenic induction, RNA was isolated via phenol-chloroform extraction. At least 3 mikrogram high quality RNA were used for RNA-seq analysis with the Illumina TrueSeq Stranded mRNA Kit and sequenced on an Illumina HiSeq 2500 platform.

2020-02-12 | E-MTAB-8536 | biostudies-arrayexpress

Metabolic profiling of rheumatoid arthritis neutrophils reveals altered energy metabolism that is not affected by JAK inhibition

Project description:Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function is directly affected by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically effective treatments for RA. However clinical trials have reported increased infection rates and transient neutropenia during therapy. The subtle differences in the mode of action, efficacy and safety of JAK inhibitors has been the primary research topic of many clinical trials and systematic reviews, to provide a more precise and targeted treatment to patients. The aim of this study was to determine both the differences in the metabolome of neutrophils from healthy controls and people with RA, and the effect of different JAK inhibitors on the metabolome of healthy and RA neutrophils. Isolated neutrophils from healthy controls (HC) (n=6) and people with RA (n=7) were incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200ng/mL) for 2h. Metabolites were extracted and 1H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models show a divergent metabolic pattern in RA neutrophils compared to HC at baseline (F1 score = 86.7%) driven by energy metabolites (ATP, ADP, GTP and glucose). No difference was observed in the neutrophil metabolome when treated with JAK inhibitors. However, JAK inhibitors significantly inhibited ROS production and baricitinib decreased NET production (p-value<0.05). Bacterial killing was not inhibited by JAK inhibitors, indicating their effect on neutrophils is beneficial to inhibit joint damage in RA without impairing host defence. This study highlights altered energy metabolism in RA neutrophils which may explain the cause of their dysregulation in inflammatory disease.

2023-07-11 | MTBLS4766 | MetaboLights

Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia

Project description:We evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against Janus kinases. Solving the structure of FDA-approved type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 JH1 tyrosine kinase domain enabled the rational design and optimization of Cereblon (CRBN)-directed JAK PROTACs utilizing multiple derivatives of JAK inhibitors, linkers and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation by proteomic approaches, and activity tested in CRLF2-rearranged cell line and xenograft models of ALL.

| EGAS00001005180 | EGA

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells

Project description:SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE2 and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib, used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

2021-04-23 | GSE161665 | GEO

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells (RNA-seq)

Project description:SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

2021-04-23 | GSE161664 | GEO

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells (ChIP-seq)

Project description:SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

2021-04-23 | GSE161663 | GEO

MicroRNAs regulate DC maturation via M-CSFR

Project description:We identify a panel of microRNAs that are differentially expressed during both spontaneous and LPS-induced DC maturation and show the M-CSF receptor (M-CSFR) as a key target for microRNA-mediated regulation. MicroRNA-22, -34a and -155 are up-regulated in mature GM-CSF-generated DC and mediate M-CSFR mRNA and protein down-regulation.

2013-11-04 | E-MEXP-3311 | biostudies-arrayexpress

NK cell-derived GM-CSF is critical for enhancing pathological arthritis

Project description:GM-CSF is involved in immune complex (IC)-mediated arthritis. However, little is known about what is the cellular source of GM-CSF and how it is regulated during IC-mediated inflammation. Using novel GM-CSF reporter mice, we show that NK cells produce GM-CSF during an IC-mediated model of inflammatory arthritis. NK cells promoted STIA in a GM-CSF-dependent manner, as deletion of NK cells and selective removal of GM-CSF production by NK cells abrogated disease. Furthermore, we show that myeloid cell activation by GM-CSF is restrained by induction of JAK/STAT checkpoint inhibitor cytokine-inducible SH2-containing protein, CIS. Myeloid cells from CIS-deficient mice had exaggerated responses to GM-CSF, and these mice develop exacerbated STIA. Our data suggest that tissue NK cells may amplify joint inflammation in arthritis via GM-CSF production and thus represent a novel target in IC-mediated pathology. Endogenous CIS provides a key brake on signaling through the GM-CSF receptor and strategies that boost its function may provide an alternative anti-inflammatory approach.

2020-02-19 | PXD012794 | Pride

Human CD14+ monocytes from rheumatoid arthritis patients before and after a 3-month period of Upadacitinib treatment

Project description:Janus Kinase (JAK) inhibitors are small molecules that reversibly inhibit JAK activity and their subsequent intracellular signaling and have become the treatment of choice for diseases with an inflammatory or immune basis. We explored the molecular impact of the JAK inhibitor Upadacitinib on the gene expression of human peripheral blood monocytes from three seropositive rheumatoid arthritis patients. The three patients showed disease improvementatthree months follow-up.

2024-04-04 | GSE253495 | GEO

Stretch-Enhancers Delineate Disease-Associated Regulatory Nodes in T Cells

Project description:T Cell stretch-enhancers are vulnerable to Jak inhibitor tofacitinib Treatment of T cells with the Janus kinase (JAK) inhibitor, tofacitinib, disproportionately altered the expression of RA risk genes with stretech-enhancer (SE) structures.

2015-02-18 | E-GEOD-60482 | biostudies-arrayexpress

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