Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production.
Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production.
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DOI：
10.1016/j.celrep.2023.112141
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发表时间：
2023-02-28
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影响因子：
8.8
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中科院分区：
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--
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组织驻留免疫细胞对于炎症的启动和增强至关重要。然而，在无菌性炎症过程中由常驻免疫启动的组织保护性细胞通信网络还没有很好地理解。使用单细胞转录组学分析，我们显示了急性肝损伤期间肝驻留细胞连接组和信号组。这些分析确定IL 12 b是肝损伤相关基因表达变化的中心调节因子。由常规1型树突状细胞（cDC 1 s）产生的白细胞介素（IL）-12通过激活肝脏驻留的1型先天淋巴细胞（ILC 1 s）产生的干扰素（IFN）-γ而在急性损伤期间提供保护。使用先天免疫传感途径的靶向体内CRISPR-Cas9筛选，我们发现cDC 1-内在cGAS-STING信号传导作用于IL-12产生的上游，以启动早期保护性免疫应答。我们的研究确定了在体内无菌炎症过程中由组织驻留的先天免疫细胞启动的核心通信枢纽，并暗示cDC 1衍生的IL-12是这一过程的重要调节因子。Hildreth等人将传统的1型树突状细胞（cDC 1）和白细胞介素（IL）-12鉴定为急性肝损伤期间无菌炎症的关键调节因子。cDC 1-内在cGAS-STING信号传导诱导IL-12激活保护性回路，包括肝脏驻留1型先天淋巴细胞（ILC 1）产生IFN-γ。
Tissue-resident immune cells are critical to the initiation and potentiation of inflammation. However, the tissue-protective cellular communication networks initiated by resident immunity during sterile inflammation are not well understood. Using single-cell transcriptomic analysis, we show the liver-resident cell connectome and signalome during acute liver injury. These analyses identify Il12b as a central regulator of liver injury-associated changes in gene expression. Interleukin (IL)-12 produced by conventional type 1 dendritic cells (cDC1s) is required for protection during acute injury through activation of interferon (IFN)-γ production by liver-resident type 1 innate lymphoid cells (ILC1s). Using a targeted in vivo CRISPR-Cas9 screen of innate immune sensing pathways, we find that cDC1-intrinsic cGAS-STING signaling acts upstream of IL-12 production to initiate early protective immune responses. Our study identifies the core communication hubs initiated by tissue-resident innate immune cells during sterile inflammation in vivo and implicates cDC1-derived IL-12 as an important regulator of this process. Hildreth et al. identify conventional type 1 dendritic cells (cDC1s) and interleukin (IL)-12 as critical regulators of sterile inflammation during acute liver injury. cDC1-intrinsic cGAS-STING signaling induces IL-12 to activate protective circuits including IFN-γ production by liver-resident type 1 innate lymphoid cells (ILC1s).
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