Exploring mechanisms that govern immune homeostasis in skin

一个重要的发现，导致我的实验室的组织免疫串扰目前的主题是阐明如何朗格汉斯细胞网络是由毛囊（HF）维持。我们发现，HF是免疫活性结构，其在感测机械应力时产生趋化因子以吸引朗格汉斯前体并充当其再增殖到表皮中的通道（Nagao等人，Nat Immunol 2012）。这一发现代表了组织特异性信号如何与免疫细胞通信以维持免疫稳态的新概念。 我们通过证明HF产生细胞因子来扩展上述发现，所述细胞因子使得记忆T细胞在稳态、炎症期间和恶性转化后能够在表皮中持续存在（阿达奇等人，Nat Med 2015）。我们还研究了宿主-微生物相互作用的背景下，特应性皮炎（AD），通过产生一个小鼠模型的AD，自发发展的生态失调为主的S。金黄色葡萄球菌，这是一种重现人类AD的特征。我们确定了S。金黄色葡萄球菌是湿疹形成的关键驱动因素，为长期存在的临床问题提供了答案，并进一步证明了金属蛋白酶ADAM 17-EGF受体信号传导轴通过EGF受体信号传导调节皮肤表面微生物组（小林等人，Immunity 2015）。在这些发现的基础上，我们最近发现，表皮中的HF和先天淋巴细胞（ILC）参与了双边交流，通过控制皮脂腺功能来调节皮肤微生物组（小林等人，Cell 2019）。 最近，我们确定在滤泡开口处改变的宿主-微生物共生由ADAM 10-Notch信号传导轴介导，其在I型干扰素（IFN）响应性上部HF细胞中的破坏导致由棒状杆菌属占主导地位的滤泡生态失调，进一步导致由第2组ILC的子集介导的HF的炎性破坏（Sakamoto等人，Immunity 2021）。在这种小鼠模型中HF干细胞的不可逆损失使人联想到人类的瘢痕性脱发，暗示ILC参与疾病病理生理学。结合我们在表皮缺乏ADAM 17的小鼠中的发现（小林等人，Immunity 2015），我们确定表皮角质形成细胞利用不同的机制来调节微生物组;滤泡间表皮利用ADAM 17-EGFR信号传导轴来调节S.金黄色葡萄球菌定殖，而HF利用ADAM 10-Notch信号传导来调节棒状杆菌属定殖，并且任一途径的破坏导致由生态失调驱动的病理性炎症。考虑到HF隔室显示的不同I型IFN反应性（Sakamoto等人，Immunity 2021），我们对来自poly（I：C）处理的小鼠的角质形成细胞亚群进行分类，并发现当暴露于I型IFN时，来自滤泡间表皮和HF的角质形成细胞亚群表现出不同的转录组学变化（Sakamoto等人，J Invest Dermatol，2022）。我们还发布了一份详细的方案，使科学界能够采用我们用于分析皮肤的技术（Sakamoto等人，星星方案，2022）。

An important finding that led to my laboratory's current theme of tissue-immune crosstalk was elucidating how the Langerhans cell network was maintained by hair follicles (HFs). We discovered that HFs were immunologically active structures that, upon sensing mechanical stress, produced chemokines to attract Langerhans precursors and served as a gateway for their repopulation into epidermis (Nagao et al, Nat Immunol 2012). This finding represented a novel concept of how tissue-specific signals communicate with immune cells to maintain immunological homeostasis. We expanded the above findings by demonstrating that HFs produced cytokines that enabled the persistence of memory T cells in the epidermis during homeostasis, inflammation, and after malignant transformation (Adachi et al, Nat Med 2015). We also studied host-microbe interactions in the context of atopic dermatitis (AD) by generating a mouse model of AD that spontaneously developed dysbiosis predominated by S. aureus, a feature that recapitulates human AD. We determined S. aureus to be a crucial driver of eczema formation, providing an answer to a long-standing clinical question, and further demonstrated that the metalloproteinase ADAM17-EGF receptor signaling axis regulated the skin surface microbiome via EGF receptor signaling (Kobayashi et al, Immunity 2015). Expanding upon these findings, we recently discovered that HF and innate lymphoid cells (ILC) in the epidermis engaged in bilateral communication that regulated the skin microbiome by controlling sebaceous gland functions (Kobayashi et al, Cell 2019). Most recently, we determined that altered host-microbial symbiosis at the follicular opening was mediated by ADAM10-Notch signaling axis, the disruption of which in type I interferon (IFN)-responsive upper HF cells led to follicular dysbiosis predominated by Corynebacterium spp, further resulting in inflammatory destruction of the HFs mediated by a subset of group 2 ILCs (Sakamoto et al, Immunity 2021). The irreversible loss of HF stem cells in this mouse model was reminiscent of cicatricial alopecia in humans, implicating the involvement of ILCs in disease pathophysiology. Taken together with our findings in mice that lack ADAM17 from the epidermis (Kobayashi et al, Immunity 2015), we established that the epidermal keratinocytes utilize distinct mechanisms to regulate the microbiome; the interfollicular epidermis utilizes ADAM17-EGFR signaling axis to regulate S. aureus colonization, whereas the HFs utilize ADAM10-Notch signaling to regulate Corynebacterium spp colonization and the disruption of either pathway leads to pathological inflammation that is driven by dysbiosis. Considering the differential type I IFN responsiveness that HF compartments displayed (Sakamoto et al, Immunity 2021), we sorted keratinocytes subsets from poly(I:C) treated mice and found that keratinocyte subsets from the interfollicular epidermis and HFs exhibited distinct transcriptomic shifts when exposed to type I IFN (Sakamoto et al, J Invest Dermatol, 2022). We have also published a detailed protocol that enables the scientific community to employ the techniques we utilize to analyze the skin (Sakamoto et al, STAR Protocol, 2022).