De La Cruz Diaz Jacinto S, Hirai Toshiro, Anh-Thu Nguyen Breanna, Zenke Yukari, Yang Yi, Li Haiyue, Nishimura Stephen, Kaplan Daniel H
Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
JID Innov. 2021 May 24;1(3):100028. doi: 10.1016/j.xjidi.2021.100028. eCollection 2021 Sep.
In the skin, Langerhans cells (LCs) require autocrine latent TGFβ that is transactivated by the integrins ανβ6 and ανβ8 expressed by keratinocytes (KCs) for long-term epidermal retention. Selective expression of a ligand-independent, constitutively active form of TGFβR1 inhibits LC migration during homeostasis and in response to UVB exposure. In this study, we found that LC migration in response to inflammatory stimuli was also inhibited by ligand-independent TGFβR1 signaling. Contrary to UVB stimulation, which reduced KC expression of ανβ6, in vitro and in vivo exposure to TNF-α or IL-1β increased ανβ6 transcript and protein expression by KCs. This resulted in increased KC-mediated transactivation of latent TGFβ. Expression of ανβ8 was largely unchanged. These findings show that ligand-independent TGFβR1 signaling in LCs can overcome inflammatory migration stimuli, but reduced KC-mediated transactivation of latent TGFβ by KCs may only drive LC migration during homeostasis and in response to UV stimulation.
在皮肤中，朗格汉斯细胞（LCs）需要自分泌的潜伏性转化生长因子β（TGFβ），角质形成细胞（KCs）表达的整合素ανβ6和ανβ8可激活该因子，以实现长期表皮滞留。TGFβR1的一种不依赖配体的组成型活性形式的选择性表达会抑制稳态期间以及对紫外线B（UVB）照射作出反应时LC的迁移。在本研究中，我们发现不依赖配体的TGFβR1信号传导也会抑制LC对炎症刺激的迁移反应。与降低KCs的ανβ6表达的UVB刺激相反，体外和体内暴露于肿瘤坏死因子-α（TNF-α）或白细胞介素-1β（IL-1β）会增加KCs的ανβ6转录本和蛋白表达。这导致KC介导的潜伏性TGFβ的反式激活增加。ανβ8的表达基本未变。这些发现表明，LC中不依赖配体的TGFβR1信号传导可克服炎症迁移刺激，但KCs介导的潜伏性TGFβ的反式激活减少可能仅在稳态期间以及对紫外线刺激作出反应时驱动LC迁移。
