Ox40-Cre-mediated deletion of BRD4 reveals an unexpected phenotype of hair follicle stem cells in alopecia.
Ox40-Cre-mediated deletion of BRD4 reveals an unexpected phenotype of hair follicle stem cells in alopecia.
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DOI：
10.1172/jci.insight.164534
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发表时间：
2022-12-08
期刊：
影响因子：
8
通讯作者：
Li, Xian C.
中科院分区：
文献类型：
--
作者：
Wen, Mou;Ying, Yuanlin;Xiao, Xiang;Arnold, Preston R.;Wang, Guangchuan;Chu, Xiufeng;Ghobrial, Rafik M.;Li, Xian C.
BRD 4是溴结构域末端外结构域家族成员，主要作为染色质阅读器调节参与细胞命运决定的基因。在这里，我们饲养了Brd 4fl/fl Ox 40-Cre小鼠，其中表达Ox 40的细胞中的Brd 4被条件性缺失，以检查BRD 4在调节免疫反应中的作用。我们发现Brd 4fl/fl Ox 40-Cre小鼠发生严重的脱发和皮炎，而其他器官和组织不受影响。令人惊讶的是，使用Rosa 26 fl/fl-Yfp小鼠的谱系追踪实验鉴定了组成型表达OX 40的毛囊干细胞（HFSC）的子集，并且在这样的HFSC中特异性地缺失Brd 4导致细胞死亡和皮肤毛发生长的完全丧失。我们还发现HFSC的死亡触发了皮内γδ T细胞的大量活化，这通过产生炎性细胞因子IL-17诱导表皮增生和皮炎。有趣的是，在Foxp 3 + T细胞中，也组成性表达OX 40的Brd 4的缺失损害了它们的抑制功能，这反过来又导致γδ T细胞的活化增强，以及皮炎和毛囊破坏的严重性。因此，我们的数据证明了BRD 4在调节皮肤毛囊干细胞和皮肤炎症中的意想不到的作用。
BRD4 is a bromodomain extraterminal domain family member and functions primarily as a chromatin reader regulating genes involved in cell-fate decisions. Here, we bred Brd4fl/fl Ox40-Cre mice in which Brd4 was conditionally deleted in OX40-expressing cells to examine the role of BRD4 in regulating immune responses. We found that the Brd4fl/fl Ox40-Cre mice developed profound alopecia and dermatitis, while other organs and tissues were not affected. Surprisingly, lineage-tracing experiments using the Rosa26fl/fl-Yfp mice identified a subset of hair follicle stem cells (HFSCs) that constitutively express OX40, and deletion of Brd4 specifically in such HFSCs resulted in cell death and a complete loss of skin hair growth. We also found that death of HFSCs triggered massive activation of the intradermal γδ T cells, which induced epidermal hyperplasia and dermatitis by producing the inflammatory cytokine IL-17. Interestingly, deletion of Brd4 in Foxp3+ Tregs, which also constitutively express OX40, compromised their suppressive functions, and this, in turn, contributed to the enhanced activation of γδ T cells, as well as the severity of dermatitis and hair follicle destruction. Thus, our data demonstrate an unexpected role of BRD4 in regulating skin follicle stem cells and skin inflammation.
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影响因子：
30.5
作者：
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
16.6
作者：
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