Stat2 loss disrupts damage signalling and is protective in acute pancreatitis
Stat2 loss disrupts damage signalling and is protective in acute pancreatitis
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Stat2 缺失会破坏损伤信号传导，对急性胰腺炎具有保护作用
DOI：
10.1101/770750
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Heath H
中科院分区：
文献类型：
--
作者：
Heath H
在急性胰腺炎中，无菌炎症的严重程度由损伤感受器、信号级联反应和细胞因子的产生决定。STAT2是一种I型干扰素信号介质，在脂多糖诱导的小鼠NF-κB介导的脓毒症中也具有干扰素非依赖性作用。然而，它在无菌炎症中的作用尚不清楚。我们假设，Stat2决定了胰腺中非感染性炎症的严重程度。给野生型(WT)和STAT2−/−小鼠腹腔注射。用雨蛙素或L-精氨酸。在一些实验中使用了特定的细胞因子阻断抗体。分别于末次给药后1、24 h和96 h后采集胰腺和血液。用无标记质谱仪评估全组织磷蛋白质组的变化。在WT/STAT2−/−骨髓嵌合体中，利用Cre-lox重组技术删除胰腺和十二指肠同源框1(PDX1)表达细胞中的STAT2，研究了STAT2对WT/STAT2−/−小鼠的影响。保护作用不依赖于I型干扰素信号。与WT相比，Stat2−/−小鼠的细胞因子水平较低，包括肿瘤坏死因子-α和IL-10，并且胰腺组织中的NF-κB核定位减少。抑制肿瘤坏死因子-α可改善(抑制IL-10加重)雨蛙素诱导的WT小鼠胰腺炎，但不能改善Stat2−/−小鼠。磷酸化蛋白质组学显示MAPK介体下调，但Ser412磷酸化的Tak1积聚。在表达Pdx1的腺泡细胞(STAT2flx/Pdx1-cre)中缺失Stat2可降低胰腺肿瘤坏死因子-α的表达，但不影响组织学损伤或血清淀粉酶。WT/STAT2−/−骨髓嵌合体小鼠可预防胰腺炎，而不受宿主或受体基因的影响。在非腺泡和/或骨髓来源的细胞中，STAT2的缺失导致了胰腺炎中NF-κB上游的信号转导中断。《病理学杂志》由John Wiley&Sons Ltd代表大不列颠和爱尔兰病理学会出版。
The severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage‐sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon‐independent roles in murine lipopolysaccharide‐induced NF‐κB‐mediated sepsis. However, its role in sterile inflammation is unknown. We hypothesised that Stat2 determines the severity of non‐infective inflammation in the pancreas. Wild type (WT) and Stat2−/−mice were injected i.p. with caerulein orl‐arginine. Specific cytokine‐blocking antibodies were used in some experiments. Pancreata and blood were harvested 1 and 24 h after the final dose of caerulein and up to 96 h postl‐arginine. Whole‐tissue phosphoproteomic changes were assessed using label‐free mass spectrometry. Tissue‐specific Stat2 effects were studied in WT/Stat2−/−bone marrow chimera and using Cre‐lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1 (Pdx1)‐expressing cells.Stat2−/−mice were protected from caerulein‐ andl‐arginine‐induced pancreatitis. Protection was independent of type I interferon signalling.Stat2−/−mice had lower cytokine levels, including TNF‐α and IL‐10, and reduced NF‐κB nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF‐α improved (inhibition of IL‐10 worsened) caerulein‐induced pancreatitis in WT but notStat2−/−mice. Phosphoproteomics showed downregulation of MAPK mediators but accumulation of Ser412‐phosphorylated Tak1. Stat2 deletion inPdx1‐expressing acinar cells (Stat2flox/Pdx1‐cre) reduced pancreatic TNF‐α expression, but not histological injury or serum amylase. WT/Stat2−/−bone marrow chimera mice were protected from pancreatitis irrespective of host or recipient genotype. Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF‐κB in non‐acinar and/or bone marrow‐derived cells. © 2020 The Authors.The Journal of Pathologypublished by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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影响因子：
29
作者：
Magnuson MA;Osipovich AB
通讯作者：
Osipovich AB
影响因子：
11.1
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用于激酶信号分析的无标记磷酸化蛋白质组学方法。
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通讯作者：
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影响因子：
29.4
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Peery AF;Dellon ES;Lund J;Crockett SD;McGowan CE;Bulsiewicz WJ;Gangarosa LM;Thiny MT;Stizenberg K;Morgan DR;Ringel Y;Kim HP;DiBonaventura MD;Carroll CF;Allen JK;Cook SF;Sandler RS;Kappelman MD;Shaheen NJ
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Shaheen NJ
影响因子：
29.4
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