GM-CSF Primes Proinflammatory Monocyte Responses in Ankylosing Spondylitis

Shi, Hui; Chen, Liye; Ridley, A; Zaarour, Nancy; Brough, I; Caucci, Cherilyn; Smith, Julia E.; Bowness, Paul

doi:10.3389/fimmu.2020.01520

Cited by 20 publications

(19 citation statements)

References 21 publications

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“…Since the immune cells circulate in the body through blood, research on PBMCs contributes to finding out markers for diagnosis and target therapy. For example, a recent study on PBMC of AS patients has mentioned that GM-CSF could be detected in plasma from 14/46 (30%) AS patients compared to 3/18 (17%) HC, and GM-CSF neutralization can be a potential novel therapeutic approach for the treatment of AS 14 . In our study, the landscape of active regulatory DNA in PBMCs from AS patients was surveyed at single-cell resolution using the sensitive method of scATAC-seq.…”

Section: Discussionmentioning

confidence: 99%

Gene-regulatory network analysis of ankylosing spondylitis with a single-cell chromatin accessible assay

Zheng

et al. 2020

Sci Rep

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A detailed understanding of the gene-regulatory network in ankylosing spondylitis (AS) is vital for elucidating the mechanisms of AS pathogenesis. Assaying transposase-accessible chromatin in single cell sequencing (scATAC-seq) is a suitable method for revealing such networks. Thus, scATAC-seq was applied to define the landscape of active regulatory DNA in AS. As a result, there was a significant change in the percent of CD8+ T cells in PBMCs, and 37 differentially accessible transcription factor (TF) motifs were identified. T cells, monocytes-1 and dendritic cells were found to be crucial for the IL-17 signaling pathway and TNF signaling pathway, since they had 73 potential target genes regulated by 8 TF motifs with decreased accessibility in AS. Moreover, natural killer cells were involved in AS by increasing the accessibility to TF motifs TEAD1 and JUN to induce cytokine-cytokine receptor interactions. In addition, CD4+ T cells and CD8+ T cells may be vital for altering host immune functions through increasing the accessibility of TF motifs NR1H4 and OLIG (OLIGI and OLIG2), respectively. These results explain clear gene regulatory variation in PBMCs from AS patients, providing a foundational framework for the study of personal regulomes and delivering insights into epigenetic therapy.

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Section: Discussionmentioning

confidence: 99%

Gene-regulatory network analysis of ankylosing spondylitis with a single-cell chromatin accessible assay

Zheng

et al. 2020

Sci Rep

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“…1 A). Because GM-CSF may prime PBMCs and monocytes from patients with AS for increased TNF production, we also determined the effect of CC-99677 on GM-CSF production [ 28 , 29 ]. CC-99677 inhibited GM-CSF in PBMCs from AS patients to similar levels as those seen in healthy volunteers (Fig.…”

Section: Resultsmentioning

confidence: 99%

CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production

et al. 2022

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Background Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated downstream of p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. CC-99677 is a novel, irreversible, covalent MK2 inhibitor under development for the treatment of ankylosing spondylitis (AS) and other inflammatory diseases. As part of a phase I clinical trial to assess safety and tolerability, we evaluated target engagement, pharmacokinetics, and pharmacodynamics of CC-99677. Methods The MK2 inhibitor CC-99677 was evaluated for its effect on cytokine expression in vitro in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with a definitive AS diagnosis. A novel in vitro model was developed to compare the potential for tachyphylaxis of CC-99677 and p38 inhibitors in THP-1 cells. The effect of CC-99677 on tristetraprolin (TTP) and cytokine mRNA was assessed in stimulated human monocyte-derived macrophages. In a first-in-human study, thirty-seven healthy volunteers were randomly assigned to daily oral doses of CC-99677 or placebo, and blood was collected at pre-specified time points before and after dosing. CC-99677 concentrations were assessed in the plasma, and CC-99677 binding to MK2 was evaluated in PBMCs. Ex vivo stimulation of the whole blood was conducted from participants in the first-in-human study to assess the pharmacodynamic effects. Results In vitro, CC-99677 inhibited tumor necrosis factor (TNF), interleukin (IL)-6, and IL-17 protein production in samples of monocytes and macrophages from AS patients and healthy volunteers via an mRNA-destabilization mechanism. In the in vitro model of tachyphylaxis, CC-99677 showed a differentiated pattern of sustained TNF protein inhibition compared with p38 inhibitors. CC-99677 reduced TTP phosphorylation and accelerated the decay of inflammatory cytokine mRNA in lipopolysaccharide-stimulated macrophages. Administration of CC-99677 to healthy volunteers was safe and well-tolerated, with linear pharmacokinetics and sustained reduction of ex vivo whole blood TNF, IL-6, and chemokine synthesis. Conclusions CC-99677 inhibition of MK2 is a promising approach for the treatment of inflammatory diseases and may overcome the limitations of p38 MAPK inhibition. Trial registration ClinicalTrials.gov NCT03554993.

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“…Since AS is an autoimmune disease, and the immune cells circulate in the body through blood, research on PBMCs contributes to the identification of markers for diagnosis and targeted therapy. For example, a recent study ( 47 ) on PBMC of AS patients has mentioned that granulocyte macrophage-colony stimulating factor (GM-CSF) could be detected in plasma from 14/46 (30%) AS patients compared to 3/18 (17%) healthy controls, and GM-CSF neutralization can be a potential novel therapeutic approach for the treatment of AS.…”

Section: Discussionmentioning

confidence: 99%

Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Peripheral Mononuclear Cells in Patients With Ankylosing Spondylitis

Liu

et al. 2021

Front. Immunol.

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ObjectiveGenetic studies on ankylosing spondylitis (AS) have identified more than 100 pathogenic genes. Building a bridge between these genes and biologically targeted therapies is the current research hotspot.MethodsWe integrated single-cell assaying transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) to explore the key genes and related mechanisms associated with AS pathogenesis.ResultsWe identified 18 cell types in peripheral mononuclear cells from patients with AS and normal controls and summarized the cell-type-specific abnormal genes by scRNA-seq. Interestingly, we found that the pathogenic gene NFKB involved in AS progression originated from CD8+ T cells. Moreover, we observed an abnormal tumor TNF pathway mediated by abnormal expression of TNF, NFKB, FOS, JUN, and JUNB, and scATAC-seq results confirmed the abnormal accessible binding sites of transcriptional factors FOS, JUN, and JUNB. The final magnetic bead sorting and quantitative real-time PCR(RT-qPCR) confirmed that NFKB, FOS, JUN, and JUNB in CD8+ T cells differed in the AS group.ConclusionsOur results revealed a possible mechanism by which NFKB abnormally regulates FOS, JUN, and JUNB and drives AS progression, providing a novel perspective from a single cell point of view in AS.

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GM-CSF Primes Proinflammatory Monocyte Responses in Ankylosing Spondylitis

Cited by 20 publications

References 21 publications

Gene-regulatory network analysis of ankylosing spondylitis with a single-cell chromatin accessible assay

Gene-regulatory network analysis of ankylosing spondylitis with a single-cell chromatin accessible assay

CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production

Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Peripheral Mononuclear Cells in Patients With Ankylosing Spondylitis

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