Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells.

Background: Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs.
Objective: To investigate the role of senescent CD4 ⁺ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis.
Methods: We explored the expression levels of p16 ^INK4a and p21, classical markers of cellular senescence, in CD4 ⁺ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis.
Results: Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16 ^INK4a and p21 in CD4 ⁺ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and β chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4 ^cre Tet2 ^f/f mice was milder than that in Tet2 ^f/f mice in the IMQ-induced psoriasis model.
Conclusion: We revealed the roles of senescent CD4 ⁺ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αβ repertoire, and regulation of the TET2-Th17 cell pathway.
Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose.
(Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)