Inflammatory and Noninflammatory Itch: Implications in Pathophysiology-Directed Treatments

Abstract

Itch is the main chief complaint in patients visiting dermatologic clinics and has the ability to deeply impair life quality. Itch results from activation of cutaneous nerve endings by noxious stimuli such as inflammatory mediators, neurotransmitters and neuropeptides, causing itch signal transduction from peripheral skin, through the spinal cord and thalamus, to the brain cortex. Primarily noninflammatory diseases, such as uremic pruritus, cause itch through certain pruritogens in the skin. In inflammatory skin diseases, atopic dermatitis (AD) is the prototypic disease causing intensive itch by aberrant skin inflammation and epidermal barrier disruption. Recent understanding of disease susceptibility, severity markers, and mechanisms have helped to develop targeted therapy for itch in AD, including monoclonal antibodies against IL-4, IL-13, thymic stromal lymphopoietin (TSLP), IgE and IL-31. Promising effects have been observed in some of them. In this review, we summarized targeted therapies for inflammatory itch in AD and for managing abnormal itch transductions in other common itching skin diseases.

Inflammatory mediators causing cutaneous chronic itch in some diseases via transient receptor potential channel subfamily V member 1 and subfamily A member 1

“…Thus, it suggests that IL-31 secreted by Th2 cells may act on peripheral nerves, directly causing the pruritus. 29,30 Interestingly, skin biopsies from PN patients with an atopic background, in comparison with healthy skin from healthy individuals, showed a 50fold upregulation of IL-31 mRNA. s.c. injection of IL-31 can cause severe itch in rats.…”

“…26,28 The DRG neurons co-express TRPV1 and IL-31R. 29 Targeting therapy of IL-31Ra may control the Th2 caused itch, including AD and CTCL. 6,23 Interestingly, in vitro, the culture of DRG accompanied by IL-31 for 3 days resulted in growth of neurons and nerve elongation which is closely related to itch.…”

“…45 Histamine receptors belong to GPCR. 29 Scientists found that the first and second generations of antihistamines which act on H1R could reduce itch in a trail including 61 patients; however, the effect was rather moderate. These two receptors are also involved in the activation of the PKC/TRPV1 pathway.…”

“…These cells are important in the pathophysiology of AD. 29,48 A combination of H1R and H4R antagonists also attenuate itch and inflammation, similar to prednisolone.…”

“…Th1 cells and their cytokines play important roles in the chronic inflammatory diseases. 29 As we all know, the acute phase of AD is caused by Th2 and Th22 infiltration. As commonly known, IL-2 is a strong itch mediator whether in a healthy person or patient.…”