Decoding TGF-beta signaling pathways in skin langerhans cells

摘要 朗格汉斯细胞 (LC) 是皮肤中的树突状细胞 (DC)，控制适应性免疫 和皮肤的免疫耐受性，并参与多种皮肤病的发展。 转化生长因子-β1 (TGFβ1) 是 LC 维持和功能的关键因素。 TGFβ1 通过与 TGFb 受体相互作用发出信号来激活 Smad 依赖性或 调节 TGFb1 靶基因和细胞功能的 Smad 独立途径。然而， 信号通路、TGFb1 介导的 LC 维持的详细分子网络以及 TGFb1在胚胎LC中的功能调控、具体作用及相关机制 发展仍不明朗。我们最近的工作和初步研究表明 TGFb1 胚胎 LC 发育绝对必需，其中 TGFβ 激活激酶 1 (Tak1) 和 不是 Smads，而是主导 TGFb1 信号通路； Tak1，而不是 Smads，参与了 LC 产后分化；并且 Smad 信号通路在炎症过程中占主导地位- 诱导LC再增殖。这些结果强烈表明不同的 TGFb 信号通路 介导胚胎个体发育与产后稳态或炎症中的 LC 调节 诱导繁殖。在拟议的研究中，将使用不同的空间和时间特定和 结合RNA-seq、scRNA-seq、ChIP-Seq的瞬时诱导基因突变小鼠模型， 成像FACS，以及体内/体外慢病毒介导的基因激活和删除策略， 旨在破译 TGFb 信号通路和相关信号通路的上下文依赖性特异性 调节 LC 个体发育、产后稳态和再增殖的分子网络。结果 拟议的研究不仅将加深我们对 LC 生物学的理解，而且还将揭示 对治疗 LC 相关疾病具有高特异性的潜在治疗靶点的新认识 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.