Proresolving Mediators LXB4 and RvE1 Regulate Inflammation in Stromal Cells from Patients with Shoulder Tendon Tears

Stephanie G Dakin,Romain A Colas,Kim Wheway,Bridget Watkins,Louise Appleton,Jonathan Rees,Stephen Gwilym,Christopher Little,Jesmond Dalli,Andrew J Carr

doi:10.1016/j.ajpath.2019.07.011

Abstract

Tendon stromal cells isolated from patients with chronic shoulder rotator cuff tendon tears have dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation; therefore, new therapeutic approaches that target tendon stromal cells are required. We examined whether two specialized proresolving mediators (SPMs), lipoxin B4 (LXB4) and resolvin E1 (RvE1), modulate the bioactive lipid mediator profiles of IL-1β–stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also examined whether LXB4 or RvE1 treatments moderated the proinflammatory phenotype of tendon tear stromal cells. Incubation of IL-1β–treated patient-derived tendon cells in LXB4 or RvE1 up-regulated concentrations of SPMs. RvE1 treatment of diseased tendon stromal cells increased 15-epi-LXB4 and regulated postaglandin F2α. LXB4 or RvE1 also induced expression of the SPM biosynthetic enzymes 12-lipoxygenase and 15-lipoxygenase. RvE1 treatment up-regulated the proresolving receptor human resolvin E1 compared with vehicle-treated cells. Incubation in LXB4 or RvE1 moderated the proinflammatory phenotype of patient-derived tendon tear cells, regulating markers of tendon inflammation, including podoplanin, CD90, phosphorylated signal transducer and activator of transcription 1, and IL-6. LXB4 and RvE1 counterregulate inflammatory processes in tendon stromal cells, supporting the role of these molecules as potential therapeutics to resolve tendon inflammation.

Highlights

Tendon stromal cells isolated from patients with chronic shoulder rotator cuff tendon tears have dysregulated resolution responses
We examined whether two specialized proresolving mediators (SPMs), lipoxin B4 (LXB4) and resolvin E1 (RvE1), modulate the bioactive lipid mediator profiles of IL-1bestimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers
We recently identified tendon stromal cells isolated from patients with shoulder tendon tears exhibit a proinflammatory phenotype, highly expressing markers of fibroblast activation and proinflammatory molecules, including IL-6 and signal transducer and activator of transcription (STAT)-1.12,15,16 Cells isolated from patients with shoulder tendon tears had dysregulated resolution responses compared with respective cells isolated from the tendons of healthy volunteers.[15]

Summary

Introduction

Tendon stromal cells isolated from patients with chronic shoulder rotator cuff tendon tears have dysregulated resolution responses. Diseases of the joint are a considerable global economic burden, accounting for five of the top 15 causes of years lived with disability in well-resourced health care systems.[1] Shoulder rotator cuff tendon tears are a progressive inflammatory and fibrotic condition, affecting 15% of 60-yeareolds and 50% of 80-yeareolds.[2,3] Affected patients experience pain and restricted joint motion, severely limiting activities and disrupting life quality.[4] Current treatments include physical therapy, nonsteroidal anti-inflammatory drugs, plateletrich plasma, glucocorticoid injections, and surgery to repair torn tendons. We provide evidence that these SPMs regulate the proinflammatory phenotype and promote resolution responses in patient-derived tendon stromal cells

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