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Gain-of-function of TRPM4 predisposes mice to psoriasiform dermatitis
Daisuke Yamada1, Simon Vu2, Xuesong Wu1
1Department of Dermatology, University of California, Davis, Sacramento, CA, United States.
Abstract:
Transient receptor potential melastatin 4 (TRPM4) is a Ca2+-activated, monovalent cation channel that is expressed in a wide range of cells. We previously reported two gain-of-function (GoF) mutations of TRPM4 as the cause of progressive symmetric erythrokeratodermia (PSEK), which shares similar clinical and histopathological features with psoriasis. Using CRISPR/Cas9 technology, we generated TRPM4I1029M mice that have the equivalent mutation to one of the two genetic mutations found in human PSEK (equivalent to human TRPM4I1033M). Using this mutant mice, we examined the effects of TRPM4 GoF at the cellular and phenotypic levels to elucidate the pathological mechanisms underlying PSEK. In the absence of experimental stimulation, TRPM4I1029M mice did not show a phenotype. When treated with imiquimod (IMQ), however, TRPM4I1029M mice were predisposed to more severe psoriasiform dermatitis (PsD) than wild-type (WT), which was characterized by greater accumulation of CCR6-expressing γδ T cells and higher mRNA levels of Il17a. In TRPM4I1029M mice, dendritic cells showed enhanced migration and keratinocytes exhibited increased proliferation. Moreover, a TRPM4 inhibitor, glibenclamide, ameliorated PsD in WT and TRPM4I1029M mice. Our results indicate elevated TRPM4 activities boosted susceptibility to cutaneous stimuli, likely through elevation of membrane potential and alteration of downstream cellular signaling, resulting in enhanced inflammation. Our results further suggest a possible therapeutic application of TRPM4 inhibitors in psoriasis.
Insights
Gain-of-function mutations in the TRPM4 channel heighten susceptibility to skin inflammation. TRPM4 inhibition may offer a therapeutic strategy for conditions like psoriasis.
Area of Science:
- Ion Channels
- Dermatology
- Immunology
Background:
- Transient receptor potential melastatin 4 (TRPM4) is a Ca2+-activated monovalent cation channel implicated in various cell types.
- Gain-of-function (GoF) mutations in TRPM4 are linked to progressive symmetric erythrokeratodermia (PSEK), a condition with features overlapping with psoriasis.
- Understanding TRPM4's role in skin inflammation is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the cellular and phenotypic effects of TRPM4 GoF mutations using a novel mouse model.
- To elucidate the pathological mechanisms underlying PSEK and its relationship to psoriasis.
- To evaluate the therapeutic potential of TRPM4 inhibition in inflammatory skin conditions.
Main Methods:
- Generation of TRPM4 I1029M mutant mice using CRISPR/Cas9 technology, mimicking a human PSEK mutation.
- Induction of psoriasiform dermatitis (PsD) using imiquimod (IMQ) in mutant and wild-type (WT) mice.
- Analysis of immune cell infiltration (γδ T cells), cytokine expression (Il17a), dendritic cell migration, and keratinocyte proliferation.
- Assessment of the therapeutic effect of the TRPM4 inhibitor glibenclamide.
Main Results:
- TRPM4 I1029M mice exhibited exacerbated PsD upon IMQ treatment compared to WT mice.
- Increased accumulation of CCR6-expressing γδ T cells and elevated Il17a mRNA levels were observed in mutant mice.
- TRPM4 GoF enhanced dendritic cell migration and keratinocyte proliferation, contributing to inflammation.
- Glibenclamide treatment ameliorated PsD in both WT and TRPM4 mutant mice.
Conclusions:
- Elevated TRPM4 activity increases susceptibility to cutaneous stimuli, likely by altering membrane potential and downstream signaling, leading to enhanced inflammation.
- TRPM4 GoF promotes key features of psoriasiform dermatitis, including specific immune cell recruitment and cytokine production.
- TRPM4 inhibitors represent a potential therapeutic avenue for managing psoriasis and related inflammatory skin diseases.
