Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis

Abstract

Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca 2+ -activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-β1 (60-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-β1 (-88%) and IL-6 (-90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles PLOS ONE PLOS ONE | https://doi.org/10.

Tetracycline transactivator overexpression in keratinocytes triggers a TRPV1 primary sensory neuron-dependent neuropathic itch

“…Our group, as well as others, have demonstrated that mice in which protease activated receptor 2 is overexpressed in keratinocytes develop hypersensitivity to pruritogens and house dust mites (Frateschi et al 2011;Braz et al 2021). Constitutive expression of Ca++ activated KCa3.1 channel in keratinocytes also leads to intense pruritus and skin lesions (Lozano-Gerona et al 2020). And under inflammatory and dry skin contexts, keratinocytes can release cytokines, including thymic stromal lymphopoietin (TSLP) and IL-33, which can directly activate sensory nerves to trigger pruritus (Wilson et al 2013;Trier et al 2022;Liu et al 2016).…”

Pathophysiological Roles of Ion Channels in Epidermal Cells, Immune Cells, and Sensory Neurons in Psoriasis

“…Treatment with the KCa3.1-selective blocker Senicapoc significantly suppressed spongiosis and hyperplasia, as well as the induction of IL-1β and IL-6. That study thus identified KCa3.1 as a regulator of epidermal homeostasis and spongiosis and a potential therapeutic target for eczematous dermatitis [ 21 ]. The signaling pathways of ion channels in immune cells are summarized in Figure 3 .…”

“…nAChR α5 ↑ in keratinocytes [11] α7 ↑ in keratinocytes [4] ↑ in immune cells [23] TRPA1 ↑ in keratinocytes [26] TRPV1 ↑ in keratinocytes [14] no change in keratinocytes [26] ↑ in immune cells [27] TRPV3 ↑ in keratinocytes [28] ↓ in immune cells [27] R416Q, R416W, L655P, W692S, L694P, G568D, G568V, L673F: ion channel activity ↑ severe Olmsted syndrome (L673F, W692S) mild Olmsted syndrome variants (R416Q) [29] G573A [30] TRPV4 ↑ in keratinocytes [31] ↓ in immune cells [27] ↑ in neurons [32] TRPM TRPM2 ↑ TRPM4, M7 ↓ in immune cells [27] TRPM8 ↓ in neurons [32] I1033M, I1040T (human): ion channel activity ↑ [33] I1029M (mouse): ion channel activity ↑ [34] TRPC TRPC1,3,4,5,6,7 ↓ in keratinocytes [35] TRPC6 ↓ in immune cells [27] CaSR ↓ in epidermis [36] STIM/ORAI ↓ in epidermis [36] ANO1 ↑ in keratinocytes [9] Nav Nav1.8 ↑ in keratinocytes [37] Polycystin PC1 ↓ in keratinocytes [38] Kv Kv1.3 ↑ in epidermis [39,40] KCa Kca3.1 ↑ in epidermis [21]…”

“…Calcium release–activated channels and arachidonic acid–regulated calcium-selective channels share similar biophysical properties, and their subunits regulate calcium in T cells [ 18 , 19 , 20 ]. On the other hand, α7nAChR mediates anti-inflammatory effects in immune cells, while voltage-gated potassium channels are involved in the proliferation, differentiation, and apoptosis of effector memory T cells [ 21 , 22 , 23 ]. Understanding the diverse roles of these ion channels in immune cells provides insight into the complex mechanisms that drive psoriatic inflammation and offers potential targets for therapeutic intervention.…”

KCa3.1 in diabetic kidney disease

“…Thereby, it has been increasingly recognized as a promising drug that can be repurposed for clinical use. In an effort to repurpose senicapoc, it has been tested in Alzheimer's disease [48], pulmonary fibrosis [25], skin disease [49], acute respiratory distress syndrome [50], and most recently in COVID-19 patients with severe respiratory insufficiency [51]. The increasing interest in senicapoc has led to the development of self-nanoemulsifying drug delivery systems to improve the aqueous solubility and cell permeation of senicapoc [52].…”