Possible involvement of type 2 cytokines in alloknesis in mouse models of menopause and dry skin

Abstract

Alloknesis, an abnormal itch sensation induced by innocuous stimuli, is a key phenomenon in the vicious itch‐scratch cycle in patients with atopic dermatitis. Dry skin and pruritus, including alloknesis, are major health problems in peri‐ and post‐menopausal women. We recently reported permeability barrier dysfunction in ovariectomized (OVX) mice—a model of menopause—and found that the dysfunction was related to dry skin. However, the mechanism of the itch remains unknown. Therefore, we examined touch‐ and pruritogen‐evoked alloknesis and epidermal innervation in OVX mice and acetone, diethyl ether and water (AEW)‐treated mice, for the experimental dry skin model. Both alloknesis and epidermal innervation were comparable in OVX and AEW mice. Neutralizing antibodies against IL‐4 and IL‐13 inhibited alloknesis in both OVX and AEW mice as early as 30 min after intradermal administration. Comparable values close to the measurement limit of IL‐4 were found in the skin of HRT and Sham mice as well as AEW and the control mice, but the levels of IL‐4 were within the measurement limit in OVX mice. We could not detect mRNAs of IL‐4 or IL‐13 in any groups of mice. On the other hand, the number of eosinophils and basophils was increased in OVX and AEW mice. These results suggest that impaired barrier function in cooperation with type 2 cytokines derived from eosinophils and basophils in the skin or with endogenous type 2 cytokine may trigger the development of alloknesis, and thus, these cytokines could be a therapeutic target for sensitive skin.

Oral administration of 4′-demethyl nobiletin inhibits dry skin-induced mechanical alloknesis

“…However, nalfurafine did not inhibit dry skin-induced alloknesis in AEW-treated mice 14 . Meanwhile, intradermal administration of neutralizing antibodies of IL-4 and IL-13 inhibited alloknesis in AEW-treated mice 15 . In addition, spinal toll-like receptor-4 signaling is important for spinal astrocyte activation in dry skin-induced alloknesis 16 .…”

Cux1+ proliferative basal cells promote epidermal hyperplasia in chronic dry skin disease identified by single-cell RNA transcriptomics

“…The pathological process of the AEW model involves many cell types, like eosinophils, basophils, MC, and T cells [ 5 , 48 , 49 ]. To uncover the intercellular ligand-receptor interaction between PBC and other cells in chronic dry skin, we applied CellChat to our scRNA-seq data [ 50 ].…”

Connections between Immune-Derived Mediators and Sensory Nerves for Itch Sensation

“…Moreover, IL-4 has been suggested as a modulator of itch because it enhances itch by increasing the neural responses induced by histamine, chloroquine, TSLP, and IL-31 [13,91]. Intradermal administration of IL-4 has also been reported to induce itching and alloknesis [96,97]. Dupilumab, a monoclonal antibody that binds specifically to the shared alpha chain subunit of the IL-4 and IL-13 receptors, was associated with improvements in clinical end points, including reduced pruritus in AD [98].…”

“…IL-13Rα1 alone binds IL-13 with low affinity, but when paired with IL-4Rα it binds IL-13 with high affinity and forms a functional IL-13 receptor that signals and results in activation of STAT3/6 [93,99]. Similar to IL-4, intradermal administration of IL-13 has been reported to induce itching and alloknesis [96,97].…”