ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration

Abstract

Upon apoptotic stimuli, epithelial cells compensate the gaps left by dead cells by activating proliferation. This has led to the proposal that dying cells signal to surrounding living cells to maintain homeostasis. Although the nature of these signals is not clear, reactive oxygen species (ROS) could act as a signaling mechanism as they can trigger pro-inflammatory responses to protect epithelia from environmental insults. Whether ROS emerge from dead cells and what is the genetic response triggered by ROS is pivotal to understand regeneration of Drosophila imaginal discs. We genetically induced cell death in wing imaginal discs, monitored the production of ROS and analyzed the signals required for repair. We found that cell death generates a burst of ROS that propagate to the nearby surviving cells. Propagated ROS activate p38 and induce tolerable levels of JNK. The activation of JNK and p38 results in the expression of the cytokines Unpaired (Upd), which triggers the JAK/STAT signaling pathway required for regeneration. Our findings demonstrate that this ROS/JNK/p38/Upd stress responsive module restores tissue homeostasis. This module is not only activated after cell death induction but also after physical damage and reveals one of the earliest responses for imaginal disc regeneration.

Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages

“…In this AiP model, ROS levels can be detected for up to 24 hours after apoptosis induction (Figure S2B,C). These data are consistent with a recent report about ROS production in a p35 -independent model in wing imaginal discs [27]. …”

“…In a recent study, ROS were found to be required for tissue repair of wing imaginal discs in a regenerative ( p35 -independent) model of AiP [27], consistent with our work. While a role of hemocytes was not investigated in this study [27], it should be noted that p35 -independent AiP models do not cause overgrowth, while undead ones like the ey>hid-p35 AiP model do.…”

“…While a role of hemocytes was not investigated in this study [27], it should be noted that p35 -independent AiP models do not cause overgrowth, while undead ones like the ey>hid-p35 AiP model do. It is therefore possible that ROS in p35 -independent AiP models are necessary for tissue repair independently of hemocytes, while ROS in conjunction with ROS-activated hemocytes in undead models mediate the overgrowth of the affected tissue.…”

Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model

“…We next analyzed how Actβ is induced in mitochondria-perturbed muscle. Perturbation of the mitochondrial complex I has been shown to robustly increase intracellular production of ROS (reactive oxygen species) signaling molecules and to activate various downstream kinase/transcriptional factor signaling pathways (16)(17)(18). We have also shown that complex I perturbation in the larval muscle triggers ROS production and activates transcription factors like FoxO, JNK, and NF-κB/Rel (8).…”

Cell reprogramming during regeneration in Drosophila : transgression of compartment boundaries

“…Although the mechanism of activation is not yet clear, recent work [27] points to the production of reactive oxygen species (ROS) by damaged tissue as a triggering factor.…”