The flight response induces the release of an insulin-like peptide from the intestine to inhibit cytoprotective mechanism in C. elegans

Abstract

The perpetuation of the flight response inhibits defensive cytoprotective mechanisms, leading to reduced resistance to environmental stressors and shorter lifespan. We recently shown that, in C. elegans, the flight response induces neuronal release of Tyramine (TA), which stimulates the intestinal adrenergic-like receptor TYRA-3. This leads to DAF-2/Insulin/IGF-1 pathway activation and inhibition of cytoprotective mechanisms in intestine and other tissues. However, the signals that bridge intestinal TYRA-3 stimulation with DAF-2 insulin receptor activation in other tissues remain unknown. C. elegans genome encodes 40 Insulin-like peptides (ILPs) that bind to DAF2, 28 of them expressed in the intestine. We test the resistance to environmental stressors (oxidative and thermal stress) silencing individual intestinal ILPs by RNAi. We found that silencing ins-3 improves stress resistance. In contrast to control, exogenous TA addition does not impair stress resistance in ins-3-silenced animals. Moreover, double-null mutants of ins-3 and TA are as resistant to environmental stress as single mutants. This suggests that tyramine and INS-3 act in the same pathway. Since ins-3 is also expressed in neurons, we performed tissue-specific rescues of ins-3 in neuron and intestine to assess the tissue where ins-3 is relevant for controlling stress resistance. Only intestinal ins-3 restores the resistance to wild-type levels. Moreover, stress resistance of ins-3 null-mutants is mediated, at least partially, by DAF-16/FOXO. We propose that intestinal activation of TYRA-3 by the escape neurohormone TA leads to INS-3 release which acts as endocrine, autocrine and/or paracrine signal to activate DAF-2 in the intestine and distal tissues. Given the high degree of conservation of fundamental mechanisms among species, this study can contribute to understanding molecular pathways and cellular communication involved in neural regulation of stress response in multicellular organisms