Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Front Immunol. 2022 Aug 30;13:886374. doi: 10.3389/fimmu.2022.886374. eCollection 2022.
Fibrosis is defined as the abnormal and excessive deposition of extracellular matrix (ECM) components, which leads to tissue or organ dysfunction and failure. However, the pathological mechanisms underlying fibrosis remain unclear. The inflammatory response induced by tissue injury is closely associated with tissue fibrosis. Recently, an increasing number of studies have linked necroptosis to inflammation and fibrosis. Necroptosis is a type of preprogrammed death caused by death receptors, interferons, Toll-like receptors, intracellular RNA and DNA sensors, and other mediators. These activate receptor-interacting protein kinase (RIPK) 1, which recruits and phosphorylates RIPK3. RIPK3 then phosphorylates a mixed lineage kinase domain-like protein and causes its oligomerization, leading to rapid plasma membrane permeabilization, the release of cellular contents, and exposure of damage-associated molecular patterns (DAMPs). DAMPs, as inflammatory mediators, are involved in the loss of balance between extensive inflammation and tissue regeneration, leading to remodeling, the hallmark of fibrosis. In this review, we discuss the role of necroptotic DAMPs in tissue fibrosis and highlight the inflammatory responses induced by DAMPs in tissue ECM remodeling. By summarizing the existing literature on this topic, we underscore the gaps in the current research, providing a framework for future investigations into the relationship among necroptosis, DAMPs, and fibrosis, as well as a reference for later transformation into clinical treatment.
纤维化定义为细胞外基质（ECM）成分的异常和过度沉积，导致组织或器官功能障碍和衰竭。然而，纤维化的病理机制尚不清楚。组织损伤引起的炎症反应与组织纤维化密切相关。最近，越来越多的研究将细胞坏死性凋亡与炎症和纤维化联系起来。细胞坏死性凋亡是一种由死亡受体、干扰素、Toll 样受体、细胞内 RNA 和 DNA 传感器和其他介质引起的程序性死亡。这些介质激活受体相互作用蛋白激酶（RIPK）1，其募集并磷酸化 RIPK3。RIPK3 随后磷酸化混合谱系激酶结构域样蛋白并导致其寡聚化，导致质膜迅速通透性增加，细胞内容物释放，并暴露出损伤相关分子模式（DAMPs）。DAMPs 作为炎症介质，参与广泛炎症和组织再生之间平衡的丧失，导致重塑，这是纤维化的标志。在这篇综述中，我们讨论了细胞坏死性凋亡 DAMPs 在组织纤维化中的作用，并强调了 DAMPs 在组织 ECM 重塑中引起的炎症反应。通过总结关于这个主题的现有文献，我们强调了当前研究中的空白，为未来研究细胞坏死性凋亡、DAMPs 和纤维化之间的关系提供了框架，并为以后转化为临床治疗提供了参考。
