LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity.
LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity.
复制标题
LRR-蛋白RNH1抑制了炎性体的激活，并与COVID-19的严重程度有关。
DOI：
10.26508/lsa.202101226
复制
发表时间：
2022-06
影响因子：
4.4
通讯作者：
Allam R
中科院分区：
文献类型：
--
作者：
Bombaci G;Sarangdhar MA;Andina N;Tardivel A;Yu EC;Mackie GM;Pugh M;Ozan VB;Banz Y;Spinetti T;Hirzel C;Youd E;Schefold JC;Taylor G;Gazdhar A;Bonadies N;Angelillo-Scherrer A;Schneider P;Maslowski KM;Allam R
RNH1通过控制caspase-1蛋白水平抑制炎性体的激活来预防炎症。在COVID-19患者中，RNH1表达水平与疾病严重程度和炎症呈负相关，提示RNH1在sars - cov -2介导的炎症和病理中发挥作用。炎性小体是病原体感染和细胞损伤的细胞质先天免疫传感器，激活后可诱导caspase-1介导的炎症。尽管炎症具有保护作用，但不受控制的过度炎症会导致炎症性疾病，并且可能是有害的，例如冠状病毒病（COVID-19）。然而，控制炎性体激活的潜在机制尚不完全清楚。在这里，我们报道了富含亮氨酸重复序列（LRR）蛋白核糖核酸酶抑制剂（RNH1），它与NLRP（核苷酸结合寡聚化结构域、富含亮氨酸重复序列和含有pyrin结构域）蛋白的LRR具有同源性，可以减弱炎性体的激活。巨噬细胞中RNH1的缺失增加了炎症小体刺激下白细胞介素(IL)-1β的产生和caspase-1的激活。机制上，RNH1降低il -1β表达，诱导蛋白酶体介导的caspase-1降解。与野生型小鼠相比，尿酸钠（MSU）诱导的腹膜炎和脂多糖（LPS）诱导的内毒素血症小鼠模型（分别依赖于caspase-1）显示，Rnh1−/−小鼠的中性粒细胞浸润和死亡率增加。此外，RNH1蛋白水平与住院COVID-19患者疾病严重程度和炎症呈负相关。我们认为RNH1是一种与COVID-19严重程度相关的新的炎症小体调节因子。
RNH1 prevents inflammation by inhibiting inflammasome activation through controlling caspase-1 protein levels. In COVID-19 patients, RNH1 expression levels were negatively associated with disease severity and inflammation, suggesting a role for RNH1 in SARS-CoV-2–mediated inflammation and pathology. Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1–mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in coronavirus disease (COVID-19). However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine-rich repeat (LRR) protein ribonuclease inhibitor (RNH1), which shares homology with LRRs of NLRP (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing) proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases interleukin (IL)-1β production and caspase-1 activation in response to inflammasome stimulation. Mechanistically, RNH1 decreases pro-IL-1β expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and lipopolysaccharide (LPS)-induced endotoxemia, which are dependent on caspase-1, respectively, show increased neutrophil infiltration and lethality in Rnh1−/− mice compared with wild-type mice. Furthermore, RNH1 protein levels were negatively related with disease severity and inflammation in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.
登录
查看更多内容
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
DOI：
10.1038/jid.2015.119
发表时间：
2015-08
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Lee DJ;Du F;Chen SW;Nakasaki M;Rana I;Shih VFS;Hoffmann A;Jamora C
通讯作者：
Jamora C
影响因子：
10.7
作者：
Katoh K;Standley DM
通讯作者：
Standley DM
影响因子：
64.8
作者：
KOBE, B;DEISENHOFER, J
通讯作者：
DEISENHOFER, J
DOI：
10.1073/pnas.1602419113
发表时间：
2016-08-09
影响因子：
11.1
作者：
Di Micco, Antonia;Frera, Gianluca;Martinon, Fabio
通讯作者：
Martinon, Fabio