Granulocyte macrophage colony-stimulating factor receptor α expression and its targeting in antigen-induced arthritis and inflammation.

Andrew D Cook,Reem Saleh,John A Hamilton,Matthew A Sleeman,Matthew J Robinson,Cynthia Louis

doi:10.1186/s13075-016-1185-9

Abstract

BackgroundBlockade of granulocyte macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFRα) is being successfully tested in trials in rheumatoid arthritis (RA) with clinical results equivalent to those found with neutralization of the current therapeutic targets, TNF and IL-6. To explore further the role of GM-CSF as a pro-inflammatory cytokine, we examined the effect of anti-GM-CSFRα neutralization on myeloid cell populations in antigen-driven arthritis and inflammation models and also compared its effect with that of anti-TNF and anti-IL-6.MethodsCell population changes upon neutralization by monoclonal antibodies (mAbs) in the antigen-induced arthritis (AIA) and antigen-induced peritonitis (AIP) models were monitored by flow cytometry and microarray. Adoptive transfer of monocytes into the AIP cavity was used to assess the GM-CSF dependence of the development of macrophages and monocyte-derived dendritic cells (Mo-DCs) at a site of inflammation.ResultsTherapeutic administration of a neutralizing anti-GM-CSF mAb, but not of an anti-colony-stimulating factor (anti-CSF)-1 or an anti-CSF-1R mAb, ameliorated AIA disease. Using the anti-GM-CSFRα mAb, the relative surface expression of different inflammatory myeloid populations was found to be similar in the inflamed tissues in both the AIA and AIP models; however, the GM-CSFRα mAb, but not neutralizing anti-TNF and anti-IL-6 mAbs, preferentially depleted Mo-DCs from these sites. In addition, we were able to show that locally acting GM-CSF upregulated macrophage/Mo-DC numbers via GM-CSFR signalling in donor monocytes.ConclusionsOur findings suggest that GM-CSF blockade modulates inflammatory responses differently to TNF and IL-6 blockade and may provide additional insight into how targeting the GM-CSF/GM-CSFRα system is providing efficacy in RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1185-9) contains supplementary material, which is available to authorized users.

Highlights

Blockade of granulocyte macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFRα) is being successfully tested in trials in rheumatoid arthritis (RA) with clinical results equivalent to those found with neutralization of the current therapeutic targets, tumour necrosis factor (TNF) and IL-6
Notwithstanding the challenges faced in defining categorically mononuclear phagocyte system (MPS) populations [28, 39,40,41,42], we first identified the different synovial myeloid populations, using a similar gating strategy to the one we previously published for the antigen-induced peritonitis (AIP) model [28], with some notable modifications - the marker F4/80 was used in place of CD115 (CSF-1R) for analysis of the synovial macrophage/monocyte-derived dendritic cells (Mo-DCs) populations, as done by Weiss et al [17], because surface CD115 could not be detected following tissue digestion and because we have previously shown that the CD115+ populations in the inflamed AIP peritoneal cavity are F4/80+ [28]
In summary, we show for the first time during inflammation that GM-CSFRα neutralization leads to similar changes in myeloid populations as GM-CSF neutralization [28], with local GM-CSF signalling in MPS cells being important for the regulation of inflammatory macrophage/ Mo-DC numbers

Summary

Introduction

Blockade of granulocyte macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFRα) is being successfully tested in trials in rheumatoid arthritis (RA) with clinical results equivalent to those found with neutralization of the current therapeutic targets, TNF and IL-6. Clinical trials assessing blockade of granulocyte macrophage colony-stimulating factor (GM-CSF) or its receptor (GM-CSFRα) have commenced in rheumatoid arthritis (RA), psoriasis, multiple sclerosis and asthma, with some encouraging RA data [1, 2]. Questions, such as which is the key cell type(s) regulated by GM-CSF and whether it has pro-survival, differentiation and/or activation functions, remain to be addressed. It would seem that a GM-CSFRα monoclonal antibody (mAb) may be a useful tool to define GM-CSFRα expression on GM-CSF-responsive cells driving an inflammatory response and to be able to compare the efficacy with an anti-ligand therapeutic strategy

Methods

Results

Discussion

Conclusion