%0 Journal Article
%T Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells.
%A Zhu H
%A Jiang J
%A Yang M
%A Zhao M
%A He Z
%A Tang C
%A Song C
%A Zhao M
%A Akbar AN
%A Reddy V
%A Pan W
%A Li S
%A Tan Y
%A Wu H
%A Lu Q
%J J Dermatol Sci
%V 0
%N 0
%D 2024 Jun 18
%M 38960840
%F 5.408
%R 10.1016/j.jdermsci.2024.06.002
%X <B>BACKGROUND: </B>Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs.<BR><B>OBJECTIVE: </B>To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis.<BR><B>METHODS: </B>We explored the expression levels of p16INK4a 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.<BR><B>RESULTS: </B>Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a 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 CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model.<BR><B>CONCLUSIONS: </B>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.