固有淋巴细胞记忆的分子和表观遗传学机制及其与哮喘的关系
2021/06/18
摘要
反复暴露于链格孢变应原提取物的Rag1-/-小鼠产生了一种记忆形式，在3-15周后的阈下刺激中引发哮喘样反应。这种记忆与肺ICOS+ST2+ILC2s有关。遗传、药理学和抗体介导的抑制和过继转移证实了ILC2s在记忆驱动型哮喘中的重要作用。ATAC序列研究显示了记忆ILC2s的独特表观遗传学图景，并确定了Bach2和AP1（JunD和Fosl2）基序是改变基因可及性的主要驱动因素。scRNA序列、基因敲除和信号转导研究表明，反复的过敏应激诱导了涉及Nr4a2、Zeb1、Bach2和JunD的基因抑制程序，以及涉及记忆ILC2s中Fhl2、FosB、Stat6、Srebf2和MPP7的准备程序。这两个程序之间相互调节平衡建立并维持了记忆。准备程序（如Fhl2）可通过阈下同源刺激激活，该刺激可下调阻遏物并激活效应器通路以诱导记忆驱动表型。
The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma.
Mukesh Verma, Lidia Michalec, Anand Sripada, Jerome McKay, Kapil Sirohi, Divya Verma, Dipa Sheth, Richard Martin, Nathan Dyjack, Max A Seibold, Jennifer R Knapp, Ting-Hui Tu, Brian P O'Connor, Magdalena M Gorska, Rafeul Alam
Abstract
Repetitive exposure of Rag1-/- mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3-15 wk later. This memory was associated with lung ICOS+ST2+ ILC2s. Genetic, pharmacologic, and antibody-mediated inhibition and adoptive transfer established an essential role for ILC2s in memory-driven asthma. ATAC-seq demonstrated a distinct epigenetic landscape of memory ILC2s and identified Bach2 and AP1 (JunD and Fosl2) motifs as major drivers of altered gene accessibility. scRNA-seq, gene knockout, and signaling studies suggest that repetitive allergenic stress induces a gene repression program involving Nr4a2, Zeb1, Bach2, and JunD and a preparedness program involving Fhl2, FosB, Stat6, Srebf2, and MPP7 in memory ILC2s. A mutually regulated balance between these two programs establishes and maintains memory. The preparedness program (e.g., Fhl2) can be activated with a subthreshold cognate stimulation, which down-regulates repressors and activates effector pathways to elicit the memory-driven phenotype.
反复暴露于链格孢变应原提取物的Rag1-/-小鼠产生了一种记忆形式，在3-15周后的阈下刺激中引发哮喘样反应。这种记忆与肺ICOS+ST2+ILC2s有关。遗传、药理学和抗体介导的抑制和过继转移证实了ILC2s在记忆驱动型哮喘中的重要作用。ATAC序列研究显示了记忆ILC2s的独特表观遗传学图景，并确定了Bach2和AP1（JunD和Fosl2）基序是改变基因可及性的主要驱动因素。scRNA序列、基因敲除和信号转导研究表明，反复的过敏应激诱导了涉及Nr4a2、Zeb1、Bach2和JunD的基因抑制程序，以及涉及记忆ILC2s中Fhl2、FosB、Stat6、Srebf2和MPP7的准备程序。这两个程序之间相互调节平衡建立并维持了记忆。准备程序（如Fhl2）可通过阈下同源刺激激活，该刺激可下调阻遏物并激活效应器通路以诱导记忆驱动表型。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Exp Med. 2021 Jul 5;218(7):e20201354. doi: 10.1084/jem.20201354. Epub 2021 Jun 2.)
(J Exp Med. 2021 Jul 5;218(7):e20201354. doi: 10.1084/jem.20201354. Epub 2021 Jun 2.)
The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma.
Mukesh Verma, Lidia Michalec, Anand Sripada, Jerome McKay, Kapil Sirohi, Divya Verma, Dipa Sheth, Richard Martin, Nathan Dyjack, Max A Seibold, Jennifer R Knapp, Ting-Hui Tu, Brian P O'Connor, Magdalena M Gorska, Rafeul Alam
Abstract
Repetitive exposure of Rag1-/- mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3-15 wk later. This memory was associated with lung ICOS+ST2+ ILC2s. Genetic, pharmacologic, and antibody-mediated inhibition and adoptive transfer established an essential role for ILC2s in memory-driven asthma. ATAC-seq demonstrated a distinct epigenetic landscape of memory ILC2s and identified Bach2 and AP1 (JunD and Fosl2) motifs as major drivers of altered gene accessibility. scRNA-seq, gene knockout, and signaling studies suggest that repetitive allergenic stress induces a gene repression program involving Nr4a2, Zeb1, Bach2, and JunD and a preparedness program involving Fhl2, FosB, Stat6, Srebf2, and MPP7 in memory ILC2s. A mutually regulated balance between these two programs establishes and maintains memory. The preparedness program (e.g., Fhl2) can be activated with a subthreshold cognate stimulation, which down-regulates repressors and activates effector pathways to elicit the memory-driven phenotype.
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