Improved understanding of the role of inflammation in tendon disease is required to facilitate therapeutic target discovery. We studied supraspinatus tendons from patients experiencing pain before and after surgical subacromial decompression treatment. Tendons were classified as having early, intermediate or advanced disease and inflammation was characterized through activation of pathways mediated by Interferon, NF-κB, glucocorticoid receptor and STAT-6. Inflammation signatures revealed expression of genes and proteins induced by Interferon and NF-κB in early stage disease and genes and proteins induced by STAT-6 and glucocorticoid receptor activation in advanced stage disease. The pro-resolving proteins FPR2/ALX and ChemR23 were increased in early stage disease compared to intermediate-advanced stage disease. Patients who were pain-free post-treatment had tendons with increased expression of CD206 and ALOX15 mRNA compared to tendons from patients who continued to experience pain post-treatment, suggesting that these genes and their pathways may moderate tendon pain. Stromal cells from diseased tendons cultured in vitro showed increased expression of NF-κB and Interferon target genes after treatment with lipopolysaccharide or IFNγ compared to stromal cells derived from healthy tendons. We identified 15-epi Lipoxin A 4 , a stable lipoxin metabolite derived from aspirin treatment, as potentially beneficial in the resolution of tendon inflammation.
*Corresponding author Stephanie G Dakin, stephanie.dakin@ndorms.ox.ac.uk Corresponding author telephone +44 (0)1865 227374. Author contributions: SGD performed all experiments and wrote the manuscript with input from all co-authors. SGD, AJC and FOM designed the study. FOM, UO and GW provided qPCR reagents and FOM and UO performed array analysis. FOM and GW provided human macrophages for co-culture experiments. CY facilitated confocal image acquisition. BD, KW, BW, LR and AJC facilitated procurement and collection of healthy and diseased shoulder tendons from patients.
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