Abstract
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.
Highlights
Ankylosing spondylitis (AS) is a common inflammatory rheumatic disorder and a prototype of Spondyloarthritis (SpA), characterized by axial skeleton and sacroiliac joint involvement [1]
We have shown that the blood and joints of AS and other axial SpA patients are enriched for GM-CSFproducing lymphocytes, and that the transcriptional signature of GM-CSF-producing CD4 T cells (“TGM−CSF”) overlaps but is distinct from that of classical IL-17A-producing TH17 cells [7]
We show that GM-CSF directly stimulates CCL17 production by AS patient blood and show elevated plasma CCL17 levels in AS patients that are reduced by TNF inhibitors (TNFi) therapy
Summary
Ankylosing spondylitis (AS) is a common inflammatory rheumatic disorder and a prototype of Spondyloarthritis (SpA), characterized by axial skeleton and sacroiliac joint involvement [1]. GM-CSF Fires Monocyte for the significant proportion of patients who either do not tolerate or do not respond fully to these therapies. GM-CSF is a key pro-inflammatory cytokine that possesses pleiotropic effects on myeloid cells including monocytes macrophages and dendritic cells augmenting innate and adaptive immune cell activation, amplifying tissue inflammation and contributing to the development of inflammatory diseases [5]. There is growing evidence that GM-CSF is produced and active locally within inflamed tissues. We have shown that the blood and joints of AS and other axial SpA patients are enriched for GM-CSFproducing lymphocytes, and that the transcriptional signature of GM-CSF-producing CD4 T cells (“TGM−CSF”) overlaps but is distinct from that of classical IL-17A-producing TH17 cells [7]
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