DNA-alkylating agents are commonly used to kill cancer cells, but the base excision repair (BER) pathway they trigger can also produce toxic intermediates that cause tissue damage, such as retinal degeneration (RD). Apoptosis, a process of programmed cell death, is assumed to be the main mechanism of this alkylation-induced photoreceptor (PR) cell death in RD. Here, we studied the involvement of necroptosis (another programmed cell death process) and inflammation in alkylation-induced RD. Male mice exposed to a methylating agent exhibited a reduced number of PR cell rows, active gliosis, and cytokine induction and macrophage infiltration in the retina. Dying PRs exhibited a necrotic morphology, increased 8-hydroxyguanosine abundance (an oxidative damage marker), and overexpression of the necroptosis-associated genes Rip1 and Rip3 The activity of PARP1, which mediates BER, cell death, and inflammation, was increased in PR cells and associated with the release of proinflammatory chemokine HMGB1 from PR nuclei. Mice lacking the anti-inflammatory cytokine IL-10 exhibited more severe RD, whereas deficiency of RIP3 (also known as RIPK3) conferred partial protection. Female mice were partially protected from alkylation-induced RD, showing reduced necroptosis and inflammation compared to males. PRs in mice lacking the BER-initiating DNA glycosylase AAG did not exhibit alkylation-induced necroptosis or inflammation. Our findings show that AAG-initiated BER at alkylated DNA bases induces sex-dependent RD primarily by triggering necroptosis and activating an inflammatory response that amplifies the original damage and, furthermore, reveal new potential targets to prevent this side effect of chemotherapy.

中文翻译：

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炎症，坏死和激酶RIP3是AAG依赖性烷基化诱导的视网膜变性的关键介质。

DNA烷基化剂通常用于杀死癌细胞，但是它们触发的碱基切除修复（BER）途径也可以产生有毒的中间产物，引起组织损伤，例如视网膜变性（RD）。凋亡是程序性细胞死亡的过程，被认为是RD中这种烷基化诱导的感光细胞（PR）细胞死亡的主要机制。在这里，我们研究了烷基化诱导的RD中坏死病（另一个程序性细胞死亡过程）和炎症的参与。暴露于甲基化剂的雄性小鼠的视网膜PR细胞排数减少，活动性神经胶质增生，细胞因子诱导和巨噬细胞浸润。垂死的PR表现出坏死的形态，增加了8-羟基鸟苷的含量（一种氧化损伤标记），坏死病相关基因Rip1和Rip3的表达和过表达PR介导BER，细胞死亡和炎症的PARP1的活性在PR细胞中增加，并与PR核中促炎性趋化因子HMGB1的释放有关。缺乏抗炎细胞因子IL-10的小鼠表现出更严重的RD，而RIP3（也称为RIPK3）的缺乏赋予了部分保护。与雄性小鼠相比，雌性小鼠受到烷基化诱导的RD的部分保护，显示出减少的坏死性病变和炎症。缺乏BER启动DNA糖基化酶AAG的小鼠中的PRs没有表现出烷基化诱导的坏死性皮炎或炎症。