Appleton, L

Carr, AJ

Colas, RA

Dakin, SG

Dalli, J

Gwilym, S

Jones, N

Newton, J

Reid, HAB

Watkins, B

Wheway, K

Wood, S

International Journal of Experimental Pathology

Queen Mary Research Online

Proresolving mediators counter inflammation in stromal cells from patients with Achilles tendon disease

Dakin, Stephanie

Gwilym, Stephen

Wheway, Kim

Oxford University Research Archive

Proresolving mediators counter inflammation in stromal cells from patients with Achilles tendon disease SG Dakin1, RA Colas2, J Newton1, S Gwilym1, N Jones1, HAB Reid1, S Wood1, L Appleton1, K Wheway1, B Watkins1, J Dalli2, AJ Carr1  1 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Oxford, OX3 7LD, UK 2 Lipid Mediator Unit, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. Introduction Achilles tendon disorders including tendinopathy and rupture cause pain and disability in athletes and non-athletic individuals. Growing evidence supports the contribution of inflammation to the onset and progression of these injuries, however the processes underpinning resolution of Achilles tendon inflammation are poorly understood.  Materials and Methods We investigated the bioactive lipid mediator profiles of tendon-derived stromal cells isolated from patients with Achilles tendinopathy (AT) or rupture (AR) under baseline and IL-1b stimulated conditions using LC-MS-MS.  RT-qPCR and immunocytochemistry were performed to determine if incubating these cells with two of the mediators produced by tendon-derived stromal cells, 15-epi-LipoxinA4 (15-epi-LXA4) or Maresin1 (MaR1), moderated their pro-inflammatory phenotype.  Results AT cells showed concurrent increased levels of pro-inflammatory eicosanoids and proresolving mediators compared to AR cells. IL-1b treatment induced profound PGE2 release in AR compared to AT cells. Incubation of IL-1b treated AT/AR tendon-derived stromal cells in 15-epi-LXA4 or MaR1 reduced pro-inflammatory eicosanoids and potentiated the release of proresolving mediators. 15-epi-LXA4 or MaR1 also induced SPM biosynthetic enzymes ALOX12, and ALOX15 and upregulated the proresolving receptor ALX compared to vehicle treated cells. 15-epi-LXA4 or MaR1 also moderated the pro-inflammatory phenotype of AT and AR cells, regulating Podoplanin, CD90, STAT-1, IL-6, IRF5, TLR4 and suppressed JNK1/2/3, Lyn, STAT-3 and STAT-6 phosphokinase signalling. Discussion Differences in the bioactive LM profiles between tendon stromal cells isolated from AT and AR patients likely reflect the temporal effects of disease stage. Proresolving mediators including 15-epi-LXA4 and MaR1 regulate the pro-inflammatory phenotype of patient derived Achilles tendon cells, dampening expression of fibroblast activation markers and regulating PGE2, STAT-1, IL-6, IRF5, TLR4. These SPM also potentiated the further release of other proresolving mediators in IL-1b stimulated AT and AR cells. In summary, we identify proresolving mediators that are active in Achilles tendinopathy and rupture, and propose SPM including 15-epi-LXA4 or MaR1 as potential therapeutics to resolve Achilles tendon inflammation.  

English

Proresolving mediators counter inflammation in stromal cells from patients with Achilles tendon disease

Abstract

Similar works

Full text

Available Versions

Queen Mary Research Online

Oxford University Research Archive