Suppression of lncRNA NLRP3 inhibits NLRP3-triggered inflammatory responses in early acute lung injury.
Suppression of lncRNA NLRP3 inhibits NLRP3-triggered inflammatory responses in early acute lung injury.
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抑制lncRNA NLRP3可抑制早期急性肺损伤中NLRP3触发的炎症反应
DOI：
10.1038/s41419-021-04180-y
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发表时间：
2021-10-01
影响因子：
9
通讯作者：
Qian K
中科院分区：
文献类型：
--
作者：
Luo D;Dai W;Feng X;Ding C;Shao Q;Xiao R;Zhao N;Peng W;Yang Y;Cui Y;Liu F;Qian K
急性肺损伤（acute lung injury，ALI）是一种常见的肺部病变，伴有肺泡巨噬细胞（alveolar macrophage，AM）活化和炎症反应。本研究旨在探讨长链非编码RNA NONRATT 004344（lncRNA NLRP 3）在Nod样受体蛋白3（NLRP 3）诱导的急性肺损伤早期炎症反应中的作用及其机制。我们建立了LPS诱导的ALI模型，以探讨它们在体内外的相互作用机制。进行荧光素酶报告基因测定以确定miR-138- 5 p可以结合lncRNA NLRP 3和NLRP 3。在LPS诱导的ALI模型中，我们观察到lncRNA NLRP 3表达增加，miR-138- 5 p表达减少，NLRP 3炎性体活化，以及caspase-1，IL-1β和IL-18表达上调。此外，lncRNA NLRP 3过表达激活NLRP 3炎性体并促进IL-1β和IL-18分泌; miR-138- 5 p模拟物在体内和体外消除了这些作用。同样，miR-138- 5 p抑制逆转了lncRNA NLRP 3沉默对NLRP 3相关分子表达和NLRP 3/caspase-1/IL-1β信号通路抑制的影响。从机制上讲，lncRNA NLRP 3海绵miR-138- 5 p通过竞争性内源RNA（ceRNA）机制促进NLRP 3活化。总之，我们的结果表明，lncRNA NLRP 3结合miR-138- 5 p通过lncRNA NLRP 3/miR-138- 5 p/NLRP 3 ceRNA网络（ceRNET）促进NLRP 3触发的炎症反应，并为早期ALI的治疗提供了见解。
Acute lung injury (ALI) is a common lung pathology that is accompanied by alveolar macrophage (AM) activation and inflammatory response. This study investigated the role of the long non-coding RNA NONRATT004344 (hereafter named lncRNA NLRP3) in regulating the Nod-like receptor protein 3 (NLRP3)-triggered inflammatory response in early ALI and the underlying mechanism as well. We established LPS-induced ALI models to explore their interactive mechanisms in vitro and in vivo. Luciferase reporter assays were performed to determine that miR-138-5p could bind to lncRNA NLRP3 and NLRP3. We observed increased lncRNA NLRP3 expression, decreased miR-138-5p expression, NLRP3 inflammasome activation, and upregulated caspase-1, IL-1β, and IL-18 expression in the LPS-induced ALI model. Furthermore, lncRNA NLRP3 overexpression activated the NLRP3 inflammasome and promoted IL-1β and IL-18 secretion; the miR-138-5p mimic abolished these effects in vivo and in vitro. Consistently, miR-138-5p inhibition reversed the effects of lncRNA NLRP3 silencing on the expression of NLRP3-related molecules and inhibition of the NLRP3/caspase-1/IL-1β signalling pathway. Mechanistically, lncRNA NLRP3 sponging miR-138-5p facilitated NLRP3 activation through a competitive endogenous RNA (ceRNA) mechanism. In summary, our results suggested that lncRNA NLRP3 binding miR-138-5p promotes NLRP3-triggered inflammatory response via lncRNA NLRP3/miR-138-5p/NLRP3 ceRNA network (ceRNET) and provides insights into the treatment of early ALI.
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