The Genetics of Chronic Itch: Gene Expression in the Skin of Patients with Atopic Dermatitis and Psoriasis with Severe Itch

Abstract

To identify itch-related mediators and receptors that are differentially expressed in pruritic skin, we used RNA sequencing to analyze the complete transcriptome in skin from paired itchy, lesional and nonitchy, nonlesional skin biopsies from 25 patients with atopic dermatitis and 25 patients with psoriasis and site-matched biopsies from 30 healthy controls. This analysis identified 18,000 differentially expressed genes common between itchy atopic and psoriatic skin compared with healthy skin. Of those, almost 2,000 genes were differentially expressed between itchy and nonitchy skin in atopic and psoriatic subjects. Overexpression of several genes, such as phospholipase A2 IVD, substance P, voltage-gated sodium channel 1.7, and transient receptor potential (TRP) vanilloid 1, in itchy skin was positively correlated with itch intensity ratings in both atopic dermatitis and psoriasis. Cytokines such as IL-17A, IL-23A, and IL-31 had elevated gene transcript levels in both itchy atopic and psoriatic skin. However, expression of genes for TRP vanilloid 2, TRP ankyrin 1, protease-activated receptor 2, protease-activated receptor 4, and IL-10 was found to be increased only in pruritic atopic skin, whereas expression of genes for TRP melastatin 8, TRP vanilloid 3, phospholipase C, and IL-36α/γ was elevated only in pruritic psoriatic skin. This "itchscriptome" analysis will lead to an increased understanding of the molecular mechanisms of chronic pruritus and provide targets for itch treatment irrespective of disease state.

Neuroimmune interactions in chronic itch of atopic dermatitis

“…[17][18][19] The brain processes the itch signal, and motor activity (scratching) is induced. A few notable examples of pruritogen receptor-pruritogen pairs relevant to AD are as follows: (i) proteinase-associated receptor 2 (PAR2), which binds a pro-peptide released by mast cell proteases or house dust mite extract proteases 4,25 ; and (ii) several members of the Mas-related G protein-coupled receptor (Mrgprx) family, in particular Mrgprx2, which can be activated by the neuropeptide substance P. 16,[26][27][28] Many non-histaminergic pruritoceptors require the calcium ion channels TRPA1 and TRPV1 for itch signalling to the spinal cord. One system for functionally classifying groups of pruritoceptors is by sensitivity to histamine, a common pruritogen.…”

Itch: an under‐recognized problem in psoriasis

“…Interleukin 17 (IL‐17) has been thought to be able to modulate pruriception at the neuronal level of the dorsal root ganglia and the spinal cord . IL‐17A cytokine is overexpressed in itchy psoriatic skin; inhibition of IL‐17 via secukinumab or ixekizumab has improved itch in some studies, suggesting a potential role in itch induction . Similarly, some evidence suggests that IL‐31 has a potential role in inducing itch in psoriasis .…”

“…IL‐17A cytokine is overexpressed in itchy psoriatic skin; inhibition of IL‐17 via secukinumab or ixekizumab has improved itch in some studies, suggesting a potential role in itch induction . Similarly, some evidence suggests that IL‐31 has a potential role in inducing itch in psoriasis . However, other studies have found no clear correlation with itch intensity for either IL‐17 or IL‐31 .…”

“…In pruritic psoriatic skin, TrpV1 , TrpM8 and TrpV3 gene expressions are significantly elevated. Specifically, the overexpression of the TrpV1 gene is correlated with itch intensity in psoriasis; treatment with capsaicin, an agonist of the TrpV1 channel, has achieved itch relief . More intensive research is needed to improve the understanding of the pathophysiology of itch in psoriasis.…”

Interventions in the B‐type natriuretic peptide signalling pathway as a means of controlling chronic itch

“…Additionally, the signal from immuno‐reactive BNP is enhanced in skin from AD patients or from HDM‐treated mice (Meng et al, ; Figure ). Likewise, levels of BNP in the skin were increased in animal models of itch (Ewald et al, ; Liu et al, ; Meng et al, ), as well as in diseased skins with AD (Meng et al, ; Figure a) or psoriatic conditions (Meng et al, ; Nattkemper et al, ). We also observed that BNP level was increased in human prurigo nodularis skin (Figure a).…”