Phenotype- and species-specific skin proteomic signatures for incision-induced 
pain in humans and mice

Segelcke, Daniel; van der Burgt, Max; Kappert, Christin; Schmidt Garcia, Daniela; Sondermann, Julia R.; Bigalke, Stephan; Pradier, Bruno; Gomez-Varela, David; Zahn, Peter K.; Schmidt, Manuela; Pogatzki-Zahn, Esther M.

doi:10.1016/j.bja.2022.10.040

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Phenotype- and species-specific skin proteomic signatures for incision-induced pain in humans and mice

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Kappert, Christin
Research Group of Somatosensory signaling and Systems Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Schmidt Garcia, Daniela
Research Group of Somatosensory signaling and Systems Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Segelcke, D., van der Burgt, M., Kappert, C., Schmidt Garcia, D., Sondermann, J. R., Bigalke, S., et al. (2023). Phenotype- and species-specific skin proteomic signatures for incision-induced pain in humans and mice. British Journal of Anaesthesia, 130(3), 331-342. doi:10.1016/j.bja.2022.10.040.

Cite as: https://hdl.handle.net/21.11116/0000-000C-D045-B

Abstract

Background:
Acute pain after surgery is common and often leads to chronic post-surgical pain, but neither treatment nor prevention is currently sufficient. We hypothesised that specific protein networks (protein-protein interactions) are relevant for pain after surgery in humans and mice.

Methods:
Standardised surgical incisions were performed in male human volunteers and male mice. Quantitative and qualitative sensory phenotyping were combined with unbiased quantitative mass spectrometry-based proteomics and protein network theory. The primary outcomes were skin protein signature changes in humans and phenotype-specific protein-protein interaction analysis 24 h after incision. Secondary outcomes were interspecies comparison of protein regulation as well as protein-protein interactions after incision and validation of selected proteins in human skin by immunofluorescence.

Results:
Skin biopsies in 21 human volunteers revealed 119/1569 regulated proteins 24 h after incision. Protein-protein interaction analysis delineated remarkable differences between subjects with small (low responders, n=12) and large incision-related hyperalgesic areas (high responders, n=7), a phenotype most predictive of developing chronic post-surgical pain. Whereas low responders predominantly showed an anti-inflammatory protein signature, high responders exhibited signatures associated with a distinct proteolytic environment and persistent inflammation. Compared to humans, skin biopsies in mice habored even more regulated proteins (435/1871) 24 h after incision with limited overlap between species as assessed by proteome dynamics and PPI. Immunohistochemistry confirmed the expression of high priority candidates in human skin biopsies.

Conclusions:
Proteome profiling of human skin after incision revealed protein-protein interactions correlated with pain and hyperalgesia, which may be of potential significance for preventing chronic post-surgical pain. Importantly, protein-protein interactions were differentially modulated in mice compared to humans opening new avenues for successful translational research.