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The Sensation of Itch: From Biological Discovery to Medical Treatment

  • Tornike Mamuladze
    Affiliations
    Division of Biology and Biomedical Sciences (DBBS), Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
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  • Brian S. Kim
    Correspondence
    Correspondence: Brian S. Kim, Division of Dermatology, Department of Medicine, Washington University School of Medicine in St. Louis, 660 S. Euclid Avenue, Campus Box 8123, St. Louis, Missouri 63108, USA.
    Affiliations
    Division of Biology and Biomedical Sciences (DBBS), Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA

    Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA

    Division of Dermatology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA

    Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
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Published:November 17, 2021DOI:https://doi.org/10.1016/j.jid.2021.10.023
      “This collection of reviews spotlights how seminal new advances in itch biology are rapidly informing and translating to new therapies.”
      Itch is an evolutionarily conserved sensation in vertebrates, and in its acute form, elicits a scratching reflex to expel environmental irritants such as insects, parasites, and toxins. However, in its chronic form, itch becomes highly debilitating and pathologic. Although originally considered a mild form of pain, the discovery of itch-specific molecular and cellular pathways in the last 15 years have greatly emboldened itch biology as a distinct field of inquiry (
      • Wang F.
      • Kim B.S.
      Itch: a paradigm of neuroimmune crosstalk.
      ). Furthermore, the unprecedented success of numerous therapeutics in this nascent field has drawn tremendous interest in solving the central symptom of itch across a number of medical disorders.
      As part of a collection of reviews on itch published in the Journal's January 2022 issue,
      • Mu D.
      • Sun Y.-G.
      Circuit mechanisms of itch in the brain.
      highlight how the original discovery of GRPR as an itch-specific molecule (
      • Sun Y.G.
      • Chen Z.F.
      A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
      ) has unveiled complex circuitry within the spinal cord whereby different neurons promote or modulate itch signals from the periphery. They then describe how prior studies have identified a number of different itch processing centers within the brain, such as foci within the cortex and thalamus, and how recent advances point to a role for the parabrachial nuclei as well (
      • Carstens E.
      • Akiyama T.
      Central mechanisms of itch.
      ;
      • Mochizuki H.
      • Kakigi R.
      Central mechanisms of itch.
      ;
      • Mu D.
      • Deng J.
      • Liu K.
      • Wu Z.Y.
      • Shi Y.F.
      • Guo W.M.
      • et al.
      A central neural circuit for itch sensation.
      ). Within the brain, the interconnectivity of these areas to other regions such as the amygdala and ventral tegmental area are starting to reveal how itch is associated with different emotions (e.g., anxiety) and reward behavior, respectively (
      • Yuan L.
      • Liang T.Y.
      • Deng J.
      • Sun Y.G.
      Dynamics and functional role of dopaminergic neurons in the ventral tegmental area during itch processing.
      ). However, how perception of itch is triggered in a specific manner via these circuits remains an open question. Furthermore, how these areas within the brain promote a heightened perception of itch, referred to as central sensitization, is another active area of inquiry.
      Extending into the periphery,
      • Guo C.J.
      • Grabinski N.S.
      • Liu Q.
      Peripheral mechanisms of itch.
      highlight newly identified itch-associated pathways, including the Mas-related G protein-coupled receptors and brain natriuretic peptide in sensory dorsal root ganglia neurons (
      • Liu Q.
      • Tang Z.
      • Surdenikova L.
      • Kim S.
      • Patel K.N.
      • Kim A.
      • et al.
      Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
      ;
      • Mishra S.K.
      • Hoon M.A.
      The cells and circuitry for itch responses in mice.
      ). By reviewing how sensory neurons have been shown to react to a variety of exogenous signals such as pathogen-associated molecular patterns and proteases and endogenous cytokines, they put these functional studies into the context of new single-cell RNA sequencing studies that have informed and, in part, validated the itch-specific identity of pruriceptors (
      • Usoskin D.
      • Furlan A.
      • Islam S.
      • Abdo H.
      • Lönnerberg P.
      • Lou D.
      • et al.
      Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
      ). The effect of itch-associated molecules on neurons and their homologs on epithelial cells and mast cells, respectively, and their contribution to itch are also described.
      Building on the advances in the peripheral neurocircuitry of itch,
      • Tseng P.-Y.
      • Hoon M.A.
      Interactions of the neuro‒immune–stromal triad in itch.
      take a single cell systems-based approach to advance the concept that there may be modules of pruritogenic pathways that are activated and aligned across immune cells, neurons, and a variety of stromal cells beyond keratinocytes, such as endothelial cells. They propose that understanding the networks of interactions across the neuro-immune-stromal triad is critical to fully informing how itch-associated tissue programs translate to behavior.
      • Shibuya R.
      • Takimoto-Ito R.
      • Kambe N.
      • Kabashima K.
      A new era with the development of cytokine-based therapy for pruritus.
      then highlight how a number of these stromal cell– (IL-33 and TSLP) and immune effector cell–derived (e.g., IL-4, IL-13, and IL-31) cytokines act on sensory neuronal pathways (e.g., Jak) to promote itch. They then explain how these neuro-immune-stromal networks are disrupted in the context of emerging targeted therapies with profound effects on itch outcomes in diseases such as atopic dermatitis (AD), prurigo nodularis, and beyond (
      • Trier A.M.
      • Kim B.S.
      Cytokine modulation of atopic itch.
      ;
      • Yang T.B.
      • Kim B.S.
      Pruritus in allergy and immunology.
      ).
      Herein, the very pioneers of itch biology highlight a new and dynamic paradigm at the intersection of immunology, neuroscience, and stromal biology. Furthermore, they display an interdisciplinary scientific paradigm that in turn translates into multiple specialties of medicine, including allergy and immunology, dermatology, neurology, and beyond. As the mysteries of what causes itch are rapidly unraveled in the coming years, there are a number of future questions that remain. How specific are these pathways for itch at every level from the tissue to the spinal cord and brain? Can itch as a symptom be selectively targeted independently of its association with a defined disease (e.g., AD)? Finally, does the diversity of itch pathways being unveiled explain the heterogeneity of chronic pruritic disorders while also providing targets for new therapeutics? Ultimately, these articles by
      • Mu D.
      • Sun Y.-G.
      Circuit mechanisms of itch in the brain.
      ,
      • Guo C.J.
      • Grabinski N.S.
      • Liu Q.
      Peripheral mechanisms of itch.
      ,
      • Tseng P.-Y.
      • Hoon M.A.
      Interactions of the neuro‒immune–stromal triad in itch.
      , and
      • Shibuya R.
      • Takimoto-Ito R.
      • Kambe N.
      • Kabashima K.
      A new era with the development of cytokine-based therapy for pruritus.
      spotlight how seminal new advances in itch biology are rapidly informing and translating to new therapies for this historically overlooked sensation.

      Conflict of Interest

      BSK is a Consultant for AbbVie, Cara Therapeutics, Pfizer, Regeneron Pharmaceuticals, Sanofi, and Trevi Therapeutics. TM states no conflict of interest.

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