Kashiwagi Mariko, Hosoi Junichi, Lai Jen-Feng, Brissette Janice, Ziegler Steven F, Morgan Bruce A, Georgopoulos Katia
Cuteneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
Nat Immunol. 2017 Mar;18(3):334-343. doi: 10.1038/ni.3661. Epub 2017 Jan 16.
Environmental challenges to epithelial cells trigger gene expression changes that elicit context-appropriate immune responses. We found that the chromatin remodeler Mi-2β controls epidermal homeostasis by regulating the genes involved in keratinocyte and immune-cell activation to maintain an inactive state. Mi-2β depletion resulted in rapid deployment of both a pro-inflammatory and an immunosuppressive response in the skin. A key target of Mi-2β in keratinocytes is the pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP). Loss of TSLP receptor (TSLPR) signaling specifically in regulatory T (T) cells prevented their activation and permitted rapid progression from a skin pro-inflammatory response to a lethal systemic condition. Thus, in addition to their well-characterized role in pro-inflammatory responses, keratinocytes also directly support immune-suppressive responses that are critical for re-establishing organismal homeostasis.
上皮细胞面临的环境挑战会引发基因表达变化，从而引发与环境相适应的免疫反应。我们发现，染色质重塑因子Mi-2β通过调节参与角质形成细胞和免疫细胞激活的基因以维持非激活状态，从而控制表皮稳态。Mi-2β缺失导致皮肤中同时快速启动促炎反应和免疫抑制反应。角质形成细胞中Mi-2β的一个关键靶点是促炎细胞因子胸腺基质淋巴细胞生成素（TSLP）。特异性缺失调节性T（T）细胞中的TSLP受体（TSLPR）信号可阻止其激活，并使皮肤促炎反应迅速发展为致命的全身状况。因此，除了在促炎反应中具有明确作用外，角质形成细胞还直接支持对重新建立机体稳态至关重要的免疫抑制反应。
