Molecular and Cellular Mechanisms of Itch in Psoriasis

Abstract

Itch (or pruritus) was not previously recognized as a serious symptom of psoriasis. However, approximately 60-90% of psoriatic patients with pruritus have stated that it deteriorates their quality of life. Since conventional antipruritic therapies, such as antihistamines, only exert limited effects, the establishment of a treatment option for itch in psoriasis is urgently needed. Although a definitive drug is not currently available, various itch mediators are known to be involved in pruritus in psoriasis. In this review, we describe the clinical features of pruritus in psoriasis, classify a wide range of itch mediators into categories, such as the nervous, immune, endocrine, and vascular systems, and discuss the mechanisms by which these mediators induce or aggravate itch in the pathophysiology of psoriasis.

Keywords: HPA axis; cytokines; itch; neurogenic inflammation; neuropeptides; pruritus; psoriasis; vascular system.

Figure 1

Mechanisms from the triggering to sensing of itch in psoriasis. Itch in psoriasis is triggered or exacerbated by external stimuli, lesional inflammation, and psychological stress. External stimuli, such as scratching behavior, promote the secretion of neuropeptides from nerve endings (axon reflex). Neuropeptides act on C-fiber neurons both (a) directly (by acting retrogradely on neurons) and (b) indirectly (via neurogenic inflammation) to convey itch signals to the central nervous system (spinal cord and brain). In lesional skin, (c) various immune cells, such as mast cells or T cells, secrete a number of cytokines, which mainly aggravate itch by enhancing inflammatory responses, such as mast cell degranulation. Some of these responses also elicit itch by directly acting on nerve endings. In addition, the HPA axis, which is stimulated by psychological stress promotes hormone secretion (such as CRH) to lesional skin. These hormones (d) are also involved in the aggravation of itch, mainly by mast cell degranulation. The vascular system also aggravates itch, mainly by (e) recruiting immune cells to lesional sites via angiogenesis or increasing vascular permeability. (Abbreviations: CRH; Corticotropin-Releasing hormone, DRG, Dorsal root ganglion, HPA; Hypothalamic–pituitary–adrenal, IL-31; Interleukin-31, SP; Substance P).

Figure 2

Changes in the expression of opioid receptors and their ligands in psoriatic lesions. In normal skin (left), itch is constitutively suppressed when KOR and its ligand dynorphin A, which attenuate itch, are strongly expressed and MOR and its ligand β-endorphin, which are involved in the induction of itch, are also expressed. However, in the lesional skin of patients with psoriasis (right), although the expression of MOR and β-endorphin remain unchanged, that of KOR and dynorphin A decreases. This imbalance between KOR and MOR controls itch in psoriasis. (KOR; κ-opioid receptor, MOR; μ-opioid receptor).