Research ArticleDRUG TOXICITY

Inflammation, necrosis, and the kinase RIP3 are key mediators of AAG-dependent alkylation-induced retinal degeneration

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Sci. Signal.  12 Feb 2019:
Vol. 12, Issue 568, eaau9216
DOI: 10.1126/scisignal.aau9216

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Preventing a side effect of chemotherapy

Chemotherapy kills cancer cells, but it is often also toxic to healthy tissues. Allocca et al. examined the mechanisms through which DNA-alkylating chemotherapies cause retinal degeneration (RD) and identified critical proteins (and potential therapeutic targets) that contribute to the death of photoreceptor cells in the retina. These include the alkylated DNA repair-initiating enzyme AAG, the necrosis and inflammation-associated kinase RIPK3, and various proinflammatory cytokines. For reasons that were unclear, female mice were less susceptible than males to RD in response to alkylating chemotherapy. These findings reveal previously unknown mechanisms of chemotherapy-induced RD and ways to potentially prevent it from developing in patients.

Abstract

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.

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