Artikel
Natural killer cells possess senolytic activity against non-malignant dermal myofibroblasts – a new therapeutic window in Systemic Sclerosis?
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Autoren
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Lea Rodon
- Universitätsklinikum Heidelberg, Medizinische Klinik V – Hämatologie, Onkologie und Rheumatologie, Heidelberg
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Merle Freitag
- Universitätsklinikum Heidelberg, Medizinische Klinik V – Hämatologie, Onkologie und Rheumatologie, Heidelberg
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Meike Ewald
- Universitätsklinikum Heidelberg, Medizinische Klinik V – Hämatologie, Onkologie und Rheumatologie, Heidelberg
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Wolfgang Merkt
- Universitätsklinikum Heidelberg, Medizinische Klinik V – Hämatologie, Onkologie und Rheumatologie, Heidelberg
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Lars-Oliver Tykocinski
- Universitätsklinikum Heidelberg, Medizinische Klinik V – Hämatologie, Onkologie und Rheumatologie, Heidelberg
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Hanns-Martin Lorenz
- Universitätsklinikum Heidelberg, Medizinische Klinik V – Hämatologie, Onkologie und Rheumatologie, Heidelberg
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Franca Deicher
- Universitätsklinikum Heidelberg, Medizinische Klinik V – Hämatologie, Onkologie und Rheumatologie, Heidelberg
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Ivana Andreeva
- Universitätsklinikum Heidelberg, Medizinische Klinik V – Hämatologie, Onkologie und Rheumatologie, Heidelberg
| Veröffentlicht: | 30. August 2023 |
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Gliederung
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Introduction: There is an unmet medical need for novel therapies in Systemic Sclerosis (SSc). Fibrosis is driven by the accumulation of myofibroblasts. Recent preclinical studies demonstrated that fibrosis can be ameliorated by eliminating activated (FAP+) and/or senescent myofibroblasts. Here, we hypothesized that myofibroblast accumulation is due to an impaired immune clearance and investigated the potential of natural killer (NK) cells to eliminate fibrotic myofibroblasts.
Methods: We used a co-culture system and flow cytometry to investigate the cytotoxicity of NK cells against primary skin myofibroblasts. Senescence was induced by Xray radiation. Killing mechanisms were deciphered by blocking strategies. Peripheral blood mononuclear cells from 20 SSc patients and 15 healthy donors and surface ligands of NK cell receptors on 5 healthy and 3 fibrotic (morphea) primary skin myofibroblasts were analyzed by flow cytometry.
Results: NK cells preferentially killed senescent dermal myofibroblasts. Killing of senescent myofibroblasts could be enhanced by pre-activation of NK cells with IL-2. We identified granular exocytosis and thus natural cytotoxicity as leading mechanism mediating elimination of myofibroblasts, while death receptor-mediated cytotoxicity played a minor role. Myofibroblasts expressed a set of activating ligands known to regulate granule exocytosis that was conserved across donors. An inhibitory ligand of natural cytotoxicity, HLA-E, was also expressed and significantly enhanced on myofibroblasts by NK cell-derived IFN-gamma. The corresponding receptors to the ligands found on myofibroblasts were constitutively expressed on NK cells from healthy donors and SSc patients. Interestingly, several cytotoxicity receptors were significantly enhanced on CD8+ T cells from SSc patients compared to healthy controls.
Conclusion: The elimination of fibrotic, including senescent, myofibroblasts by NK cells is performed by the “natural killing” type of cytotoxicity. Cytotoxicity is plastic and may be targeted to therapeutically enhance the immune clearance of myofibroblasts in fibrosis. HLA-E is a promising target as it may give negative feedback to activated NK cells.
References
- 1.
- Merkt W, Zhou Y, Han H, Lagares D. Myofibroblast fate plasticity in tissue repair and fibrosis: Deactivation, apoptosis, senescence and reprogramming. Wound Repair Regen. 2021 Jul;29(4):678-91. DOI: 10.1111/wrr.12952
- 2.
- Merkt W, Bueno M, Mora AL, Lagares D. Senotherapeutics: Targeting senescence in idiopathic pulmonary fibrosis. Semin Cell Dev Biol. 2020 May;101:104-10. DOI: 10.1016/j.semcdb.2019.12.008
