gms | German Medical Science

Objectives: Tendon pathologies can develop due to autoimmune inflammation, chronic mechanical overload or after acute rupture. In autoimmune-driven Achilles tendon enthesitis, IL-23 receptor (IL-23R) expressing γδ-T-cells that secrete cytokines of the IL-17 family were described to play a driving pathogenic role [1]. With the present study, we investigated whether the IL-23R/IL-17 signaling cascade also contributes to the development of non-autoimmune-based human tendon pathologies that might result in impaired tendon regeneration.

Methods: Achilles tendon biopsies from acute ruptures (n=39) and chronic tendon pathologies including reruptures and tendinopathies (n=17) were collected at the time of surgery. Tendon samples were embedded in paraffin for immunohistological analysis of IL-23R as well as IL-17A/F expression. To identify the cellular source of the inflammatory cytokines IL-17A, IL-17F and IL-22, Achilles tendon biopsies were digested for analysis by flow cytometry.

Moreover, hematoma aspirate was harvested from the Achilles tendon rupture side and analyzed on protein level by Multiplex assay for IL-23R/IL-17 signaling mediators such as IL-22, IL-17A, IL-17F, IL-6 and IL-23 to determine potential patient-specific differences in our cohort.

Statistics: Mann Whitney U test

Results and Conclusion: Immunohistology revealed presence of IL-23R⁺ and IL-17A/F⁺ cells in non-autoimmune tendon pathologies supporting our hypothesis that the IL-23R/IL-17 axis also contributes to non-autoimmune Achilles tendon pathologies. Interestingly, 100 % of the chronic specimens contained IL-23R⁺ cells, whereas only 42.9 % of acute rupture specimens showed positive IL-23R⁺ cells (p<0.001). Furthermore, the chronic specimens showed more IL-17A/F⁺ cells (46.7 %) compared to the acute ruptures (20 %), indicating a potential driving role of the IL-23R/IL-17A signaling cascade especially in chronic Achilles tendon degeneration.

Preliminary data from our flow cytometry analysis identified tenocytes as possible source of IL-17F and IL-22, but not of IL-17A expression, which was limited to CD4⁺ and γδ-T-cells.

The analysis of hematoma aspirate revealed elevated concentrations of IL-23, IL-17F and IL-22 in 4 out of 24 patients with acute Achilles tendon rupture indicating them as potential mediators of failed tendon regeneration.

We demonstrate the presence of IL-23R⁺ and IL-17A/F⁺ cells in acute and chronic Achilles tendon pathologies. Compared to the autoimmune-driven enthesitis model reported in the literature, which described IL-17A as trigger, we propose that also IL-17F is playing a role in non-autoimmune human Achilles tendon pathologies [1].

The results of the project are contributing to a better understanding of underlying pathomechanisms of acute and chronic tendon pathologies and determine potential targets for future medical therapies aim to improve impaired Achilles tendon healing.