Li Zhihua, Wang Yi, Huang Weiwei, Shi Xingyu, Ma Tao, Yu Xiangyou
The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, China.
Department of Critical Medicine, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China.
Acta Biochim Biophys Sin (Shanghai). 2024 Sep 9;56(11):1618-1632. doi: 10.3724/abbs.2024124.
Sepsis is a life-threatening state of organ dysfunction caused by systemic inflammation and a dysfunctional response to host infections that can induce severe intestinal mucosal damage. Pyroptosis is mediated by the activated NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome after stimulation by various inflammatory factors during sepsis. The inflammatory response is a major driver of intestinal damage during sepsis. Intestinal mucosal barrier dysfunction in sepsis is associated with pyroptosis, a type of programmed inflammatory cell death. Several studies have confirmed the role of miR-155 in sepsis and other diseases. However, the effect of miR-155 on intestinal pyroptosis in the context of intestinal mucosal barrier dysfunction during sepsis remains unclear. Thus, a model of sepsis in Sprague-Dawley rats is established using cecal ligation and puncture (CLP), and a series of molecular biological methods are used in this study. The results show that the expression of miR-155 is increased and that of sirtuin 1 (SIRT1) is decreased in the intestinal tissues of patients with sepsis. miR-155 expression is negatively correlated with SIRT1 expression. Increased miR-155 expression significantly inhibits SIRT1 activity and upregulates the expressions of NOD-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), interleukin-1β (IL-1β) and interleukin-18 (IL-18) to promote pyroptosis. The inhibition of miR-155 expression is associated with increased SIRT1 expression, promotes the deacetylation of p65, and significantly downregulates p65 acetylation. Herein, we propose that miR-155 induces pyroptosis in the intestine partly by regulating SIRT1, thereby reducing the deacetylation of the nuclear factor (NF)-κB subunit p65 and increasing NF-κB signaling activity in sepsis, leading to intestinal barrier damage.
脓毒症是一种由全身炎症和对宿主感染的功能失调反应引起的危及生命的器官功能障碍状态，可导致严重的肠黏膜损伤。在脓毒症期间，多种炎症因子刺激后，焦亡由活化的含NOD样受体家族吡咯结构域3（NLRP3）炎性小体介导。炎症反应是脓毒症期间肠道损伤的主要驱动因素。脓毒症中的肠黏膜屏障功能障碍与焦亡有关，焦亡是一种程序性炎症细胞死亡。多项研究证实了miR-155在脓毒症和其他疾病中的作用。然而，在脓毒症期间肠黏膜屏障功能障碍的背景下，miR-155对肠道焦亡的影响仍不清楚。因此，本研究采用盲肠结扎和穿刺（CLP）建立了Sprague-Dawley大鼠脓毒症模型，并使用了一系列分子生物学方法。结果显示，脓毒症患者肠道组织中miR-155表达增加，而沉默调节蛋白1（SIRT1）表达降低。miR-155表达与SIRT1表达呈负相关。miR-155表达增加显著抑制SIRT1活性，并上调含NOD样受体家族吡咯结构域3（NLRP3）、半胱天冬酶-1、含CARD的凋亡相关斑点样蛋白（ASC）、白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）的表达以促进焦亡。抑制miR-155表达与SIRT1表达增加有关，促进p65的去乙酰化，并显著下调p65乙酰化。在此，我们提出miR-155部分通过调节SIRT1诱导肠道焦亡，从而减少核因子（NF）-κB亚基p65的去乙酰化并增加脓毒症中NF-κB信号活性，导致肠道屏障损伤。
