Introduction Resolution of inflammation is critical for effective healing of injured tissues and their return to homeostasis. Pro-resolving proteins are well characterised in murine models of experimental inflammation1,2, however little is known about their potential roles in inflamed human tissues such as tendinopathy. The aim of this study was to investigate expression of pro-resolving proteins in pathological supraspinatus tendons compared to normal samples. We hypothesised that expression of pro-resolving proteins would increase in tendinopathic compared to normal supraspinatus.
Methods Normal and tendinopathic supraspinatus were collected via ultrasound guided biopsy performed under local anaesthetic. Torn supraspinatus was collected after routine surgical debridement of the torn tendon. Expression of macrophages (CD68+ cells) iNOS, COX-2 and pro-resolving proteins FPR2/ALX, ChemR23 and Annexin A1 was determined in formalin fixed paraffin embedded samples by immunohistochemistry. Quantitative analysis was performed using ImageJ software. To identify the cell types expressing pro-resolving proteins, quadruple immunofluorescent labelling was performed to facilitate co-localisation of these proteins with markers of tissue resident macrophages (Mϕ).
Results Expression of pro-resolving proteins ChemR23 (p < 0.01) and FPR2/ALX (p < 0.05) was increased in tendinopathic compared to normal and torn supraspinatus (Figure 1). ChemR23 and FPR2/ALX were predominantly expressed by tenocytes although low-level expression occurred on Mϕ, demonstrated by co-localisation between ChemR23 or FPR2/ALX and tissue resident macrophage marker MerTK. Annexin A1 protein was significantly increased in tendinopathic supraspinatus compared to normals (p < 0.01) with predominant expression by tenocytes. There were significantly increased numbers of CD68+ Mϕ in tendinopathic (p < 0.01) and torn (p < 0.01) supraspinatus compared to normals. iNOS and COX-2 proteins were not detected in the pathological samples studied.
Discussion Tenocytes in tendinopathic supraspinatus are the predominant cell type expressing pro-resolving proteins ChemR23, FPR2/ALX and Annexin A1. Low-level expression of these proteins on Mϕ and the absence of co-expression of iNOS and COX-2 suggest Mϕ in pathological supraspinatus are not enriched for resolving inflammation. We propose that failure to adequately resolve tendon inflammation may favour development of chronic inflammation and fibrosis.
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