PT  - JOURNAL ARTICLE
AU  - Bridgewood, Charlie
AU  - Watad, Abdulla
AU  - Russell, Tobias
AU  - Palmer, Timothy M
AU  - Marzo-Ortega, Helena
AU  - Khan, Almas
AU  - Millner, Peter A
AU  - Dunsmuir, Robert
AU  - Rao, Abhay
AU  - Loughenbury, Peter
AU  - Wittmann, Miriam
AU  - Cuthbert, Richard J
AU  - McGonagle, Dennis G
TI  - Identification of myeloid cells in the human enthesis as the main source of local IL-23 production
AID  - 10.1136/annrheumdis-2018-214944
DP  - 2019 Jul 01
TA  - Annals of the Rheumatic Diseases
PG  - 929--933
VI  - 78
IP  - 7
4099  - http://ard.bmj.com/content/78/7/929.short
4100  - http://ard.bmj.com/content/78/7/929.full
SO  - Ann Rheum Dis2019 Jul 01; 78
AB  - Objective We investigated whether the normal human spinal enthesis contained resident myeloid cell populations, capable of producing pivotal proinflammatory cytokines including tumour necrosis factor (TNF) and interleukin (IL)-23 and determined whether these could be modified by PDE4 inhibition.Methods Normal human enthesis soft tissue (ST) and adjacent perientheseal bone (PEB) (n=15) were evaluated using immunohistochemistry (IHC), digested for myeloid cell phenotyping, sorted and stimulated with different adjuvants (lipopolysaccharide and mannan). Stimulated enthesis fractions were analysed for inducible production of spondyloarthropathy disease-relevant mediators (IL-23 full protein, TNF, IL-1β and CCL20). Myeloid populations were also compared with matched blood populations for further mRNA analysis and the effect of PDE4 inhibition was assessed.Results A myeloid cell population (CD45+ HLADR+ CD14+ CD11c+) phenotype was isolated from both the ST and adjacent PEB and termed ‘CD14+ myeloid cells’ with tissue localisation confirmed by CD14+ IHC. The CD14− fraction contained a CD123+ HLADR+ CD11c− cell population (plasmacytoid dendritic cells). The CD14+ population was the dominant entheseal producer of IL-23, IL-1β, TNF and CCL20. IL-23 and TNF from the CD14+ population could be downregulated by a PDE4I and other agents (histamine and 8-Bromo-cAMP) which elevate cAMP. Entheseal CD14+ cells had a broadly similar gene expression profile to the corresponding CD14+ population from matched blood but showed significantly lower CCR2 gene expression.Conclusions The human enthesis contains a CD14+ myeloid population that produces most of the inducible IL-23, IL-1β, TNF and CCL20. This population has similar gene expression profile to the matched blood CD14+ population.