Exploring mechanisms that govern immune homeostasis in skin

导致我的实验室当前组织免疫串扰主题的一个重要发现是阐明了毛囊(HFs)如何维持朗格汉斯细胞网络。我们发现HFs是一种免疫活性结构，当感知到机械应激时，它会产生趋化因子来吸引朗格汉斯前体细胞，并作为它们重新进入表皮的门户(Nagao等人，NAT免疫2012)。这一发现代表了一个新的概念，即组织特异性信号如何与免疫细胞沟通，以维持免疫平衡。 我们通过证明HFs产生的细胞因子使记忆T细胞能够在动态平衡、炎症和恶变后的表皮中持续存在，从而扩展了上述发现(Adachi等人，Nat Med 2015)。我们还在特应性皮炎(AD)的背景下研究了宿主-微生物的相互作用，方法是建立一种AD的小鼠模型，该模型自发地发展以金黄色葡萄球菌为主的微生物失调，这是人类AD的一个特征。我们确定金黄色葡萄球菌是湿疹形成的关键驱动因素，为一个长期存在的临床问题提供了答案，并进一步证明金属蛋白酶ADAM17-EGF受体信号轴通过EGF受体信号调节皮肤表面微生物群(Kobayashi等人，免疫学2015)。在这些发现的基础上，我们最近发现，表皮中的HF和固有淋巴样细胞(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群(Kobayashi等，Cell 2019)。 最近，我们确定，在卵泡开口处改变的宿主-微生物共生是由ADAM10-Notch信号轴介导的，在I型干扰素(IFN)反应的上HF细胞中，ADAM10-Notch信号轴的破坏导致以棒状杆菌为主的卵泡微生态失调，进一步导致由第2组ILC亚群介导的HFs的炎性破坏(Sakamoto等，免疫2021)。在这个小鼠模型中，HF干细胞不可逆转的丢失使人联想到人类的瘢痕性脱发，暗示ILCs参与了疾病的病理生理学。结合我们在缺乏表皮ADAM17的小鼠身上的发现(Kobayashi等人，免疫学2015)，我们确立了表皮角质形成细胞利用不同的机制来调节微生物群；毛囊间表皮利用ADAM17-EGFR信号轴来调节金黄色葡萄球菌的定植，而毛囊利用ADAM10-Notch信号来调节棒状杆菌的定植，这两种途径中的任何一种的破坏都会导致由生物失调驱动的病理性炎症。考虑到HF隔室表现出的不同的I型干扰素反应性(Sakamoto等，免疫力2021)，我们对聚(I：C)处理的小鼠的角质形成细胞亚群进行了分类，发现毛囊间表皮和HFs的角质形成细胞亚群在暴露于I型干扰素时表现出明显的转录转移(Sakamoto等，J Invest Dermatol，2022)。我们还发布了一份详细的协议，使科学界能够使用我们用来分析皮肤的技术(Sakamoto等人，STAR协议，2022)。 因此，我们最近的研究揭示了调节皮肤中免疫和微生物动态平衡的基本机制，临床相关的疾病模型有助于加深我们对宿主-微生物共生改变如何导致炎症性皮肤病的理解。

An important finding that led to my laboratorys 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 cell (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 hair follicles 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). Thus, our recent studies have uncovered fundamental mechanisms that mediate immune and microbial homeostasis in the skin and the clinically relevant disease models help deepen our insight of how altered host-microbial symbiosis may contribute to inflammatory skin diseases.