CD8+ T-cells, CD86+ macrophages and TNF-α signalling pathways are correlated with fetlock osteoarthritis in
E J Secor1, E N Chow1,2, M Thomas1
1Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
Background:
There is emerging evidence for the role of the immune system in osteoarthritis (OA) pathophysiology; however, little is known about how immune cells and the synovial transcriptome are altered in naturally occurring equine OA.
Objectives:
To evaluate synovial fluid (SF) and synovial membrane (SM) immune cell populations and the SM transcriptome in racehorses with fetlock OA.
Study Design:
Cross-sectional cadaver study.
Methods:
Fetlock joints from racehorses euthanised at NY racetracks were considered for inclusion. SF and SM were analysed by flow cytometry using T-cell (CD3, CD4, CD8) and macrophage (CD14, CD86, CD206) surface markers. OA severity was characterised by gross joint evaluation and SM histology. Bulk RNA-sequencing of SM was performed to identify differentially expressed genes. Flow cytometry data were analysed with mixed linear modelling, including OA severity as a fixed effect and horse as a random effect. RNA-sequencing data were evaluated with mixed linear and quadratic modelling using DREAMSeq method to capture differential gene expression over the range of OA severity.
Results:
Twenty-four fetlocks from 12 horses met inclusion criteria. CD8+ T-cells (R2 = 0.25 for SM, 0.35 for SF) and CD86+ macrophages (R2 = 0.14 for SM) were positively correlated with OA severity, while CD4+ T-cells (R2 = 0.17 for SM, 0.31 for SF) were negatively correlated. Macrophages co-expressing CD86 and CD206 correlated with OA severity in SM (R2 = 0.31). Pathways including those associated with TNF-α signalling, connective tissue development and cell and neuron projection organisation/development were differentially regulated in SM with greater OA scores.
Main Limitations:
Limited sample size, particularly of horses with severe OA.
Conclusions:
CD8+ T-cells, CD86+ macrophages and macrophages co-expressing CD206 and CD86 are enriched in horses with more advanced OA. Gene set analysis suggests the importance of TNF-α signalling and disinhibition of neuron and cell projection development in OA pathogenesis.
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