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Identification of myeloid cells in the human enthesis as the main source of local IL-23 production
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Identification of myeloid cells in the human enthesis as the main source of local IL-23 production
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Journal Article
Identification of myeloid cells in the human enthesis as the main source of local IL-23 production
2019
Overview
ObjectiveWe 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.MethodsNormal 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.ResultsA 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.ConclusionsThe 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.
Publisher
BMJ Publishing Group Ltd and European League Against Rheumatism,Elsevier Limited,BMJ Publishing Group
Subject
/ Blood
/ Chemokine CCL20 - biosynthesis
/ Connective Tissue Cells - metabolism
/ Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism
/ Dendritic Cells - metabolism
/ Disease
/ enthesis
/ Histocompatibility antigen HLA
/ Humans
/ IL-23
/ Interleukin-1beta - biosynthesis
/ Interleukin-23 - biosynthesis
/ Lipopolysaccharide Receptors - metabolism
/ Mannan
/ Monocyte chemoattractant protein 1
/ Tumor Necrosis Factor-alpha - biosynthesis
/ Tumors
