Department of Medical Science, Kosin University College of Medicine, Seo-gu, Busan 49267, Republic of Korea.
Department of Functional Foods and Biotechnology, College of Medical Sciences, Jeonju University, 303 Cheonjam-ro, Jeonju 55069, Republic of Korea.
Int J Mol Sci. 2023 Aug 28;24(17):13320. doi: 10.3390/ijms241713320.
Urban particulate matter (UPM) is a high-hazard cause of various diseases in humans, including in the respiratory tract, skin, heart, and even brain. Unfortunately, there is no established treatment for the damage caused by UPM in the respiratory epithelium. In addition, although RIPK3 is known to induce necroptosis, its intracellular role as a negative regulator in human lungs and bronchial epithelia remains unclear. Here, the endogenous expression of RIPK3 was significantly decreased 6 h after exposure to UPM. In RIPK3-ovexpressed cells, RIPK3 was not moved to the cytoplasm from the nucleus. Interestingly, the overexpression of RIPK3 dramatically decreased TEER and F-actin formation. Its overexpression also decreased the expression of genes for pro-inflammatory cytokines (IL-6 and IL-8) and tight junctions (ZO-1, -2, -3, E-cadherin, and claudin) during UPM-induced airway inflammation. Importantly, overexpression of RIPK3 inhibited the UPM-induced ROS production by inhibiting the activation of iNOS and eNOS and by regulating mitochondrial fission processing. In addition, UPM-induced activation of the iκB and NF-κB signaling pathways was dramatically decreased by RIPK3, and the expression of pro-inflammatory cytokines was decreased by inhibiting the iκB signaling pathway. Our data indicated that RIPK3 is essential for the UPM-induced inflammatory microenvironment to maintain homeostasis. Therefore, we suggest that RIPK3 is a potential therapeutic candidate for UPM-induced pulmonary inflammation.
城市颗粒物 (UPM) 是导致人类各种疾病的高危害因素，包括呼吸道、皮肤、心脏，甚至大脑。不幸的是，目前还没有针对 UPM 对呼吸道上皮细胞造成损伤的既定治疗方法。此外，虽然 RIPK3 已知可诱导细胞坏死，但它在人体肺部和支气管上皮细胞中作为负调节剂的细胞内作用仍不清楚。在这里，暴露于 UPM 后 6 小时，内源性 RIPK3 的表达明显下降。在 RIPK3 过表达的细胞中，RIPK3 没有从核内转移到细胞质。有趣的是，RIPK3 的过表达显著降低了 TEER 和 F-肌动蛋白的形成。其过表达还降低了促炎细胞因子（IL-6 和 IL-8）和紧密连接（ZO-1、-2、-3、E-钙粘蛋白和 Claudin）在 UPM 诱导的气道炎症期间的表达。重要的是，RIPK3 通过抑制 iNOS 和 eNOS 的激活以及通过调节线粒体分裂处理来抑制 UPM 诱导的 ROS 产生，从而抑制 RIPK3 的过表达。此外，RIPK3 还显著降低了 UPM 诱导的 iκB 和 NF-κB 信号通路的激活，通过抑制 iκB 信号通路降低了促炎细胞因子的表达。我们的数据表明，RIPK3 对于 UPM 诱导的炎症微环境维持稳态至关重要。因此，我们认为 RIPK3 是治疗 UPM 诱导的肺部炎症的潜在候选药物。
