Laboratory of Aging Research and Nanotoxicology, State Key Laboratory of Biotherapy, West China Hospital, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
J Immunol. 2023 Jan 15;210(2):180-190. doi: 10.4049/jimmunol.2200484.
Acute pancreatitis (AP) can be complicated by inflammatory disorders of remote organs, such as lung injury, in which Jumonji domain-containing protein 3 (JMJD3) plays a vital role in proinflammatory responses. Currently, we found that JMJD3 expression was upregulated in the pancreas and lung in an AP male mouse model, which was also confirmed in AP patients. Further experiments revealed that the upregulation of JMJD3 and proinflammatory effects were possibly exerted by mitochondrial DNA (mtDNA) or oxidized-mtDNA from tissue injury caused by AP. The release of mtDNA and oxidized-mtDNA contributed to the infiltration of inflammatory monocytes in lung injury through the stimulator of IFN genes (STING)/TLR9-NF-κB-JMJD3-TNF-α pathway. The inhibition of JMJD3 or utilization of Jmjd3-cKO mice significantly alleviated pulmonary inflammation induced by AP. Blocking mtDNA oxidation or knocking down the TLR9/STING pathway effectively alleviated inflammation. Therefore, inhibition of JMJD3 or STING/TLR9 pathway blockage might be a potential therapeutic strategy to treat AP and the associated lung injury.
急性胰腺炎（AP）可并发肺等远隔器官的炎症性疾病，其中组蛋白去甲基化酶 3（JMJD3）在促炎反应中起重要作用。目前，我们发现 JMJD3 在 AP 雄性小鼠模型的胰腺和肺部表达上调，在 AP 患者中也得到了证实。进一步的实验表明，AP 引起的组织损伤导致的线粒体 DNA（mtDNA）或氧化 mtDNA 可能上调 JMJD3 并发挥促炎作用。mtDNA 和氧化 mtDNA 的释放通过干扰素基因刺激物（STING）/TLR9-NF-κB-JMJD3-TNF-α 途径促进炎症性单核细胞浸润到肺损伤中。抑制 JMJD3 或利用 Jmjd3-cKO 小鼠可显著减轻 AP 引起的肺部炎症。阻断 mtDNA 氧化或敲低 TLR9/STING 途径可有效缓解炎症。因此，抑制 JMJD3 或 STING/TLR9 通路阻断可能是治疗 AP 及相关肺损伤的一种潜在治疗策略。
