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Objectives: GM-CSF is a pro-inflammatory cytokine with multiple actions predominantly on myeloid cells. Enhanced GM-CSF expression by lymphocytes from patients with Ankylosing Spondylitis (AS) has recently been described, however, its potential pathogenic role(s) in AS are unknown. Methods: The effects of GM-CSF on TNF, IL-23, and CCL17 production by blood, PBMCs and isolated CD14+ monocytes from AS patients and healthy controls (HCs) were studied using ELISA. Serum CCL17 and GM-CSF and T cell GM-CSF production were studied in AS patients including pre-and on TNFi therapy. Results: GM-CSF markedly increased TNF production by LPS-stimulated whole blood, peripheral blood mononuclear cells (PBMC) and purified monocytes from AS patients, with 2 h GM-CSF exposure sufficient for monocyte "priming." Blocking of GM-CSF significantly reduced the production of TNF by whole blood from AS patients but not HCs. GM-CSF priming increased IL-23 production from LPS-stimulated AS and HC whole blood 5-fold, with baseline and stimulated IL-23 levels being significantly higher in AS whole blood. GM-CSF also stimulated CCL17 production from AS and HC blood and CCL17 levels were elevated in AS plasma. GM-CSF could be detected in plasma from 14/46 (30%) AS patients compared to 3/18 (17%) HC. Conclusion: We provide evidence that GM-CSF primes TNF and IL-23 responses in myeloid cells from AS patients and HC. We also show CCL17 levels, downstream of GM-CSF, were elevated in plasma samples of AS patients. Taken together these observations are supportive of GM-CSF neutralization as a potential novel therapeutic approach for the treatment of AS.

Original publication

DOI

10.3389/fimmu.2020.01520

Type

Journal article

Journal

Front Immunol

Publication Date

2020

Volume

11

Keywords

CCL17, IL-23, TNF-alpha, ankylosing spondylitis, monocyte GM-CSF, Biomarkers, Case-Control Studies, Chemokine CCL17, Cytokines, Disease Susceptibility, Gene Expression Regulation, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Immunophenotyping, Inflammation Mediators, Leukocytes, Mononuclear, Lipopolysaccharides, Monocytes, Spondylitis, Ankylosing, Toll-Like Receptors, Tumor Necrosis Factor Inhibitors