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Neurobiologie des Pruritus: neue Konzepte

Neurobiology of pruritus: new concepts

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Zusammenfassung

Hintergrund

Die dem Pruritus, insbesondere dem chronischen Pruritus (CP), zugrundeliegenden Mechanismen sind nach wie vor nicht hinreichend verstanden. Aktuelle Forschungen zeigen jedoch vielversprechende neue Konzepte auf, bei denen die Bedeutung der Interaktion von neuronalen Zellen verschiedener Klassen, Immunzellen und Keratinozyten immer klarer wird.

Fragestellung

In diesem Übersichtsartikel sollen aktuelle Konzepte in Pruritusforschung dargestellt und zusammengeführt werden.

Material und Methode

Es handelt sich um eine Übersichtsarbeit, für die aktuelle Literatur zugrunde gelegt wurde.

Ergebnisse

Verschiedene Klassen von sensorischen Afferenzen wie mechanoinsensitive C‑Fasern (histaminerger Pruritus) und nichthistaminerge prurizeptive C‑ und Aδ-Fasern sind an CP beteiligt. Die zentrale Sensibilisierung bei CP äußert sich als Hyperknesis und Alloknesis, wobei letztere durch Aβ-Fasern und Merkel-Zellen ausgelöst wird. In den vergangenen Jahren ist die Bedeutung von Entzündungszellen wie Th1- und Th2-Zellen, aber auch basophilen-, eosinophilen Granulozyten und Mastzellen deutlich geworden. Bei CP scheint eine enge Kommunikation zwischen neuronalen Zellen, Immunzellen und Keratinozyten zu bestehen. Neuere Studien konzentrierten sich auf proinflammatorische Interleukine (IL), wie IL-31, IL‑4 und IL-13, und deren Rezeptoren. In den ausgelösten Signalkaskaden, die letztlich zur Prurituswahrnehmung führen, spielt auch der JAK/STAT(Januskinase/„signal transducers and activators of transcription“)-Signalweg eine wichtige Rolle. In aktuellen Therapiestudien werden daher nicht nur die Interleukine und ihre Rezeptoren, sondern auch der JAK/STAT-Signalweg direkt angegangen.

Schlussfolgerung

Die Entdeckung neuer Mechanismen und Interaktionen bei CP machen die Komplexität dieser Erkrankung deutlich. Auch wenn diese und die hieraus abgeleiteten Therapieoptionen bereits sehr vielversprechend sind, ist ein noch besseres Verständnis der Mechanismen bei CP dringend notwendig, um weitere Optionen für eine optimierte Therapie zu ermöglichen.

Abstract

Background

The underlying mechanisms of pruritus and chronic pruritus (CP) in particular, remain poorly understood; however, current research has revealed promising new concepts in which the importance of the interaction of neuronal cells of different classes, immune cells and keratinocytes is becoming increasingly clearer.

Research question

In this review article the current concepts in pruritus research are presented and summarized.

Material and method

This is a review article based on the current literature.

Results

Different classes of sensory afferents, such as mechano-insensitive C‑fibers (histaminergic pruritus) and non-histaminergic pruriceptive C‑fibers and Aδ-fibers are involved in CP. The central sensitization in CP manifests as hyperknesis and alloknesis, the latter triggered by Aβ-fibers and Merkel cells. In recent years, the importance of inflammatory cells, such as Th1 and Th2 cells but also basophilic, eosinophilic granulocytes and mast cells has become clear. In CP there appears to be close communication between neuronal cells, immune cells and keratinocytes. Recent studies have focused on proinflammatory interleukins, such as IL-31, IL‑4 and IL-13 and their receptors. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway also plays an important role in the triggered signaling cascades that ultimately lead to pruritus perception. Therefore, in current treatment studies not only the interleukins and their receptors but also the JAK/STAT signaling pathway are directly targeted.

Conclusion

The discovery of new mechanisms and interactions in CP highlights the complexity of this disease. Even if this and the treatment options derived from this are already very promising, a much better understanding of the mechanisms of CP is urgently needed in order to enable further options for an optimized treatment.

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Literatur

  1. Andersen HH, Akiyama T, Nattkemper LA et al (2018) Alloknesis and hyperknesis-mechanisms, assessment methodology, and clinical implications of itch sensitization. Pain 159:1185–1197. https://doi.org/10.1097/J.PAIN.0000000000001220

    Article  PubMed  Google Scholar 

  2. Arcilla CK, Tadi P (2022) Neuroanatomy, unmyelinated nerve fibers. StatPearls

    Google Scholar 

  3. Bobko S, Zeidler C, Osada N et al (2016) Intraepidermal nerve fibre density is decreased in lesional and inter-lesional prurigo nodularis and reconstitutes on healing of lesions. Acta Derm Venereol 96:404–406. https://doi.org/10.2340/00015555-2232

    Article  CAS  PubMed  Google Scholar 

  4. Bray ER, Chéret J, Yosipovitch G, Paus R (2020) Schwann cells as underestimated, major players in human skin physiology and pathology. Exp Dermatol 29:93–101. https://doi.org/10.1111/EXD.14060

    Article  PubMed  Google Scholar 

  5. Cevikbas F, Lerner EA (2020) Physiology and pathophysiology of itch. Physiol Rev 100:945–982. https://doi.org/10.1152/PHYSREV.00017.2019

    Article  PubMed  Google Scholar 

  6. Düll MM, Stengel M, Ries V et al (2022) Lysophosphatidic acid activates nociceptors and causes pain or itch depending on the application mode in human skin. Pain 163:445–460. https://doi.org/10.1097/J.PAIN.0000000000002363

    Article  PubMed  Google Scholar 

  7. Feng J, Luo J, Yang P et al (2018) Piezo2 channel-Merkel cell signaling modulates the conversion of touch to itch. Science 360:530–533. https://doi.org/10.1126/SCIENCE.AAR5703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Guo CJ, Mack MR, Oetjen LK et al (2020) Kallikrein 7 promotes atopic dermatitis-associated itch independently of skin inflammation. J Invest Dermatol 140:1244. https://doi.org/10.1016/J.JID.2019.10.022

    Article  CAS  PubMed  Google Scholar 

  9. Gupta K, Harvima IT (2018) Mast cell-neural interactions contribute to pain and itch. Immunol Rev 282:168–187. https://doi.org/10.1111/IMR.12622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guseva D, Rüdrich U, Kotnik N et al (2020) Neuronal branching of sensory neurons is associated with BDNF-positive eosinophils in atopic dermatitis. Clin Exp Allergy 50:577–584. https://doi.org/10.1111/cea.13560

    Article  CAS  PubMed  Google Scholar 

  11. Karlsson P, Hincker AM, Jensen TS et al (2019) Structural, functional, and symptom relations in painful distal symmetric polyneuropathies: a systematic review. Pain 160:286–297. https://doi.org/10.1097/j.pain.0000000000001381

    Article  PubMed  Google Scholar 

  12. Koga K, Yamagata R, Kohno K et al (2020) Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor. J Allergy Clin Immunol 145:183–191.e10. https://doi.org/10.1016/J.JACI.2019.09.034

    Article  CAS  PubMed  Google Scholar 

  13. Li C, Kim HJ, Back SK, Na HS (2021) Common and discrete mechanisms underlying chronic pain and itch: peripheral and central sensitization. Pflugers Arch 473:1603–1615. https://doi.org/10.1007/S00424-021-02599-Y

    Article  CAS  PubMed  Google Scholar 

  14. Liu T, Han Q, Chen G et al (2016) Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice. Pain 157:806–817. https://doi.org/10.1097/J.PAIN.0000000000000439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mack MR, Kim BS (2018) The itch–scratch cycle: a neuroimmune perspective. Trends Immunol 39:980–991. https://doi.org/10.1016/j.it.2018.10.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Maksimovic S, Nakatani M, Baba Y et al (2014) Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature 509:617–621. https://doi.org/10.1038/NATURE13250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nelson TS, Taylor BK (2021) Targeting spinal neuropeptide Y1 receptor-expressing interneurons to alleviate chronic pain and itch. Prog Neurobiol. https://doi.org/10.1016/J.PNEUROBIO.2020.101894

    Article  PubMed  Google Scholar 

  18. Oetjen LK, Mack MR, Feng J et al (2017) Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 171:217–228.e13.. https://doi.org/10.1016/J.CELL.2017.08.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Özdağ Acarli AN, Klein T, Egenolf N et al (2022) Subepidermal Schwann cell counts correlate with skin innervation—an exploratory study. Muscle Nerve. https://doi.org/10.1002/MUS.27496

    Article  PubMed  Google Scholar 

  20. Pogatzki-Zahn EM, Pereira MP, Cremer A et al (2020) Peripheral sensitization and loss of descending inhibition is a hallmark of chronic Pruritus. J Invest Dermatol 140:203–211.e4. https://doi.org/10.1016/j.jid.2019.05.029

    Article  CAS  PubMed  Google Scholar 

  21. Raap U, Gehring M, Kleiner S et al (2017) Human basophils are a source of—and are differentially activated by—IL-31. Clin Exp Allergy 47:499–508. https://doi.org/10.1111/CEA.12875

    Article  CAS  PubMed  Google Scholar 

  22. Schmelz M (2021) How do neurons signal itch? Front Med 8:643006. https://doi.org/10.3389/fmed.2021.643006

    Article  Google Scholar 

  23. Solinski HJ, Kriegbaum MC, Tseng PY et al (2019) Nppb neurons are sensors of mast cell-induced itch. Cell Rep 26:3561–3573.e4. https://doi.org/10.1016/J.CELREP.2019.02.089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stott B, Lavender P, Lehmann S et al (2013) Human IL-31 is induced by IL‑4 and promotes TH2-driven inflammation. J Allergy Clin Immunol. https://doi.org/10.1016/J.JACI.2013.03.050

    Article  PubMed  Google Scholar 

  25. Tavares-Ferreira D, Shiers S, Ray PR et al (2022) Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors. Sci Transl Med 14:eabj8186. https://doi.org/10.1126/SCITRANSLMED.ABJ8186

    Article  CAS  PubMed  Google Scholar 

  26. Trier AM, Mack MR, Fredman A et al (2021) IL-33 signaling in sensory neurons promotes dry skin itch. J Allergy Clin Immunol. https://doi.org/10.1016/J.JACI.2021.09.014

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tseng PY, Hoon MA (2021) Oncostatin M can sensitize sensory neurons in inflammatory pruritus. Sci Transl Med. https://doi.org/10.1126/SCITRANSLMED.ABE3037

    Article  PubMed  Google Scholar 

  28. Usoskin D, Furlan A, Islam S et al (2015) Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci 18:145–153. https://doi.org/10.1038/NN.3881

    Article  CAS  PubMed  Google Scholar 

  29. Wilson SR, Thé L, Batia LM et al (2013) The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155:285–295. https://doi.org/10.1016/J.CELL.2013.08.057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wolf K, Kühn H, Boehm F et al (2021) A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice. J Allergy Clin Immunol 148:506–522.e8. https://doi.org/10.1016/J.JACI.2020.12.655

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Kompetenzzentrum chronischer Pruritus, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Deutschland

    Konstantin Agelopoulos, Henning Wiegmann &  Sonja Ständer

  2. Abteilung Experimentelle Schmerzforschung, CBTM, Med. Fakultät Mannheim, Universität Heidelberg, Mannheim, Deutschland

    Martin Schmelz

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  1. Konstantin Agelopoulos
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  2. Henning Wiegmann
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Correspondence to Sonja Ständer.

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Interessenkonflikt

K. Agelopoulos, H. Wiegmann, M. Schmelz und S. Ständer geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Agelopoulos, K., Wiegmann, H., Schmelz, M. et al. Neurobiologie des Pruritus: neue Konzepte. Dermatologie 73, 593–599 (2022). https://doi.org/10.1007/s00105-022-05017-1

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