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皮肤驻留的先天性淋巴样细胞能够形成一种致病性效应子状态
2021-02-05 16:48

美国耶鲁大学医学院Richard A. Flavell等研究人员合作发现,皮肤驻留的先天性淋巴样细胞能够形成一种致病性效应子状态。相关论文于2021年2月3日在线发表在《自然》杂志上。

研究人员表示,组织驻留的先天淋巴样细胞(ILC)帮助维持屏障功能并响应局部信号。根据其特定转录因子和细胞因子的表达,传统上将ILC分为ILC1、ILC2或ILC3。在皮肤中,ILC3相关细胞因子白介素(IL)-17和IL-22对IL-23信号的疾病特异性产生会导致牛皮癣的皮肤炎症 。但是,尚不清楚此响应是由已确定的ILC引起还是由细胞状态转换引起。

研究人员发现,由IL-23或咪喹莫特在小鼠中引起的牛皮癣会重置一系列的皮肤ILC,并逐渐成为致病性ILC3样状态。在没有循环ILC的情况下,组织驻留ILC对于驱动病理是必要且充分的。在牛皮癣炎症形成中,皮肤ILC的单细胞RNA测序(scRNA-seq)图谱形成了密集的转录连续体(即使在稳态下),这反映出流动的ILC状态,包括初始或静止状态和ILC2效应子状态。疾病诱发后,这种连续状态迅速改变为一个混合的、类似ILC3的亚群,该亚群也表达了ILC2的细胞因子特征,研究人员推测这是通过多种轨迹产生的。

通过体外实验、转座酶可及染色质单细胞测序((scATAC-seq))以及体内命运图谱,研究人员确定了静态样状态和ILC2状态的转变潜力。这些研究结果突出了皮肤ILC反应的范围和灵活性,从而表明健康组织中引发的免疫活性可动态适应炎症,并且不受控制地推动病理重塑。 

附:英文原文

Title: Skin-resident innate lymphoid cells converge on a pathogenic effector state

Author: Piotr Bielecki, Samantha J. Riesenfeld, Jan-Christian Htter, Elena Torlai Triglia, Monika S. Kowalczyk, Roberto R. Ricardo-Gonzalez, Mi Lian, Maria C. Amezcua Vesely, Lina Kroehling, Hao Xu, Michal Slyper, Christoph Muus, Leif S. Ludwig, Elena Christian, Liming Tao, Amanda J. Kedaigle, Holly R. Steach, Autumn G. York, Mathias H. Skadow, Parastou Yaghoubi, Danielle Dionne, Abigail Jarret, Heather M. McGee, Caroline B. M. Porter, Paula Licona-Limn, Will Bailis, Ruaidhr Jackson, Nicola Gagliani, Georg Gasteiger, Richard M. Locksley, Aviv Regev, Richard A. Flavell

Issue&Volume: 2021-02-03

Abstract: Tissue-resident innate lymphoid cells (ILCs) help sustain barrier function and respond to local signals. ILCs are traditionally classified as ILC1, ILC2 or ILC3 on the basis of their expression of specific transcription factors and cytokines1. In the skin, disease-specific production of ILC3-associated cytokines interleukin (IL)-17 and IL-22 in response to IL-23 signalling contributes to dermal inflammation in psoriasis. However, it is not known whether this response is initiated by pre-committed ILCs or by cell-state transitions. Here we show that the induction of psoriasis in mice by IL-23 or imiquimod reconfigures a spectrum of skin ILCs, which converge on a pathogenic ILC3-like state. Tissue-resident ILCs were necessary and sufficient, in the absence of circulatory ILCs, to drive pathology. Single-cell RNA-sequencing (scRNA-seq) profiles of skin ILCs along a time course of psoriatic inflammation formed a dense transcriptional continuum—even at steady state—reflecting fluid ILC states, including a naive or quiescent-like state and an ILC2 effector state. Upon disease induction, the continuum shifted rapidly to span a mixed, ILC3-like subset also expressing cytokines characteristic of ILC2s, which we inferred as arising through multiple trajectories. We confirmed the transition potential of quiescent-like and ILC2 states using in vitro experiments, single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) and in vivo fate mapping. Our results highlight the range and flexibility of skin ILC responses, suggesting that immune activities primed in healthy tissues dynamically adapt to provocations and, left unchecked, drive pathological remodelling.

DOI: 10.1038/s41586-021-03188-w

Source: https://www.nature.com/articles/s41586-021-03188-w

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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