Decoding TGF-beta signaling pathways in skin langerhans cells

摘要 郎格汉斯细胞(LCS)是皮肤上的树突状细胞(DC)，控制着两种获得性免疫 以及皮肤的免疫耐受性，并参与多种皮肤病的发生发展。 转化生长因子-β-1(转化生长因子-β-1)是维持和发挥LC功能的重要因子。 转化生长因子β1信号通过与TGFb受体相互作用激活Smad依赖或 调节TGFb1靶基因和细胞功能的Smad非依赖性途径。然而， 信号转导途径、TGFb1介导的LC维持和调控的分子网络 胚胎LC中TGFb1的功能调控及其相关机制 事态发展仍不明朗。我们最近的工作和初步研究表明，TGFb1是 对于胚胎LC发育是绝对必要的，其中转化生长因子β激活的激酶1(Tak1)，以及 不是Smads，而是主导的TGFb1信号通路；Tak1，而不是Smads，参与其中 LC生后分化；Smad信号通路在炎症过程中占主导地位 诱导LC再布居。这些结果强烈地表明，不同的TGFb信号通路 在胚胎个体发育与出生后动态平衡或炎症中调节LC- 诱导重新繁殖。在拟议的研究中，将使用不同的特定于空间和时间的 RNA-seq、scRNA-seq、ChIP-seq、 成像流式细胞仪，以及体内/体外慢病毒介导的基因激活和缺失策略， 目的是破译TGFb信号通路和相关的上下文相关的特异性 调节LC个体发育、出生后动态平衡和再繁殖的分子网络。结果 这不仅将加深我们对LC生物学的理解，而且还将有助于 高特异性治疗LC的潜在靶点新探 疾病。

Abstract Langerhans cells (LCs), the skin residing dendritic cells (DCs), control both adaptive immunity and immune tolerance in skin and are involved in the development of a variety of skin diseases. Transforming growth factor-β1 (TGFβ1) is a crucial factor for LC maintenance and function. TGFβ1 signals through interactions with TGFb receptors to activate either Smad-dependent or Smad-independent pathways to regulate TGFb1 target genes and cellular function. However, the signaling pathways, the detailed molecular networks of TGFb1-mediated LC maintenance and functional regulation, and the specific role of TGFb1 and related mechanisms in embryonic LC development remain unclear. Our recent work and preliminary studies showed that TGFb1 is absolutely required for embryonic LC development, in which TGFβ-activated kinase 1 (Tak1), and not Smads, leads the dominant TGFb1 signaling pathway; that Tak1, not Smads, is involved in LC postnatal differentiation; and that Smad signaling pathways are dominant during inflammation- induced LC repopulation. These results strongly suggest that diverse TGFb signaling pathways mediate LC regulations in embryonic ontogeny versus postnatal homeostasis or inflammation- induced repopulation. In the proposed studies, will use different spatial- and temporal-specific and transient inducible gene mutation mouse models combined with RNA-seq, scRNA-seq, ChIP-Seq, imaging FACS, and in vivo/in vitro lentivirus-mediated gene activation and deletion strategies, aiming to decipher the context-dependent specificities of TGFb signaling pathways and related molecular networks that regulate LC ontogeny, postnatal homeostasis, and repopulation. Results from the proposed studies will not only further our understanding of LC biology, but also will shed new light on potential therapeutic targets with high specificity for the treatment of LC-related diseases.