Gut Derived Cytokine Signaling Mediates Hypoxia Tolerance in Drosophila

Abstract

Our cells and organs need oxygen to function. However, in some disorders such as stroke, heart disease and cancer, our tissues are deprived of oxygen. This lack of oxygen, known as hypoxia, leads to the tissue damage and deregulation that characterizes these diseases. Understanding how tissues respond to low oxygen is therefore an important question in health research. While extensive studies have identified hypoxic responses in cell culture, they leave open the question of how tissues and organisms deal with hypoxia. This is important since tissue-to-tissue crosstalk often underlies hypoxic responses in animals. In their natural ecology, Drosophila have evolved to grow on rotting, fermenting food rich in microorganisms – an environment characterized by low ambient oxygen. Hence, they provide an excellent genetic model system to study how hypoxia influences physiology and development. Here I describe a mechanism for hypoxia tolerance in female Drosophila involving the cytokine Unpaired 3 (Upd3), a JAK/STAT pathway ligand and fly interleukin-6 homolog. I found that Upd3 whole-animal null mutant females, but not males, had reduced survival in hypoxia, indicating that the requirement for Upd3 signaling in hypoxia tolerance is sexually dimorphic. Using tissue-specific RNAi-mediated knockdown, I show that these survival effects require Upd3 production in the enterocyte cells of the fly intestine. I also identified transcription factors, Sima/HIF-1α and Yorkie/YAP, as regulators of Upd3 induction. I showed that intestinal Yorkie signaling was required for part of the Upd3 induction in hypoxia and that fat body Sima/HIF-1α, the classic hypoxia-induced factor required for low oxygen survival, acts non-autonomously to restrain excess intestinal Upd3 levels. I demonstrated that part of the lethality seen in whole-body Sima mutants could be rescued by lowering Upd3 levels. Furthermore, I identified that the gut derived Upd3 targets the fat body to modulate glycolysis which is a necessary adaptation in hypoxia to promote tolerance. These findings suggest Upd3 signaling must be tightly regulated in hypoxia: induction of Upd3 is required to mediate survival in low oxygen, but excessive Upd3 production can lead to a ‘cytokine-storm’-like response which can cause lethality. Previous studies have demonstrated a link between HIF-1α and immune system modulation, thereby already implicating a role of hypoxia in immunity. However, with my discovery that gut derived Upd3 is upregulated in hypoxia and is restrained by fat body Sima/HIF-1α, I have uncovered a role for tissue-to-tissue communication in mediating hypoxia tolerance.