The Itch-Scratch Cycle: A Neuroimmune Perspective

Abstract

Relentless, repetitive itching and scratching is a debilitating feature of many chronic inflammatory skin disorders such as atopic dermatitis. While well known clinically, this itch-scratch cycle has historically lacked in-depth mechanistic understanding. However, recent advances at the interface of itch neurobiology and skin immunology have shed new light on this phenomenon. In this review, we highlight recent advances in our understanding of the neuroimmunology of chronic itch centered around three key points of entry into the itch-scratch cycle: the epithelial barrier, the immune system, and the peripheral nervous system. Furthermore, we explore novel neuro-epithelial-immune interactions that may represent promising therapeutic paradigms.

Keywords: atopic dermatitis; cytokines; itch; neuroimmunity; proteases; scratch; skin barrier.

Figure 1. Key Figure. The Itch–Scratch Cycle

(A) Chronic itch sensations and associated scratching behaviors are components of a dynamic pathological process known as the itch–scratch cycle. Scratching behaviors exacerbate itch sensation through damage to skin epithelial cells. (B) The epithelial stress response releases cytokines, proteases, and AMPs that can activate immune cells to promote inflammation. (C) Keratinocytes may also activate itch-sensory neurons directly through soluble mediators such as cytokines and proteases. (D) Release of neuropeptides from neurons can also cause neurogenic inflammation. In contrast, cytokines and proteases produced by immune cells interface with the sensory nervous system to mediate itch. Abbreviations: AMP, antimicrobial peptide; DRG, dorsal root ganglion.

Figure 2.. Known Molecular Mediators of Epithelial and Inflammatory Itch.

(A) Skin damage from dry skin, genetic lesions, or chronic scratching causes release of epithelial cell-derived cytokines such as TSLP and IL-33, which can directly activate itch-sensory neurons (pruriceptors). Keratinocyte-derived proteases such as KLKs and cathepsin S can also trigger itch through cleavage-based activation of the PAR2 and MrgprC11; however, whether KLKs activate neuronal PAR2 directly is not yet clear. (B) Immune cells may modulate itch-sensory neurons through expression of certain cytokines, such as IL-4 from Th2 cells, mast cells, and basophils, which can exacerbate the itch sensation in atopic dermatitis. IL-31 from Th2 cells can directly trigger scratching in mice. Histamine and tryptase from mast cells and basophils can activate G-protein-coupled receptors such as H1/4R as well as PAR2. While the receptor–ligand interactions shown here have been linked to itch, and immune cells are known to produce these ligand mediators, the precise cellular sources in the context of specific itch disorders is still under investigation. Abbreviations: H1/4R, histamine 1/4 receptor; IL, interleukin; ILC2, group 2 innate lymphoid cells; KLK, kallikrein; PAR2, protease activated receptor 2; Th2, T helper type 2; TSLP, thymic stromal lymphopoietin.

Figure 3.. Neurogenic Inflammation and Itch.

Activation of sensory neurons through scratching or neuronal dysfunction can trigger release of neuropeptides such as CGRP, SP, and NMU. These neuropeptides can activate immune cells such as innate and adaptive lymphocytes and granulocytes that can lead or contribute to neurogenic inflammation. New findings describing the modulation of sensory neurons by cytokines such as IL-4 and IL-31 suggests that neurogenic inflammation may itself regulate itch. Abbreviations: CGRP, calcitonin gene-related peptide; IL, interleukin; NMU, neuromedin U; SP, substance P.